Number 11 November 2011

Atlas of Genetics and Cytogenetics

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Volume 15 - Number 11 November 2011

The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.

Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and educational items in the various related topics for students in Medicine and in Sciences.

Editorial correspondance

Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected]

Staff Mohammad Ahmad, Mélanie Arsaban, Marie-Christine Jacquemot-Perbal, Maureen Labarussias, Vanessa Le Berre, Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, Alain Zasadzinski. Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France).

The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008.

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http://AtlasGeneticsOncology.org

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Editor

Jean-Loup Huret (Poitiers, France) Editorial Board

Sreeparna Banerjee (Ankara, Turkey) Solid Tumours Section Alessandro Beghini (Milan, Italy) Genes Section Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukaemia Sections Judith Bovée (Leiden, The Netherlands) Solid Tumours Section Vasantha Brito-Babapulle (London, UK) Leukaemia Section Charles Buys (Groningen, The Netherlands) Deep Insights Section Anne Marie Capodano (Marseille, France) Solid Tumours Section Fei Chen (Morgantown, West Virginia) Genes / Deep Insights Sections Antonio Cuneo (Ferrara, Italy) Leukaemia Section Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumours Section Louis Dallaire (Montreal, Canada) Education Section Brigitte Debuire (Villejuif, France) Deep Insights Section François Desangles (Paris, France) Leukaemia / Solid Tumours Sections Enric Domingo-Villanueva (London, UK) Solid Tumours Section Ayse Erson (Ankara, Turkey) Solid Tumours Section Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections Ad Geurts van Kessel (Nijmegen, The Netherlands) Cancer-Prone Diseases Section Oskar Haas (Vienna, Austria) Genes / Leukaemia Sections Anne Hagemeijer (Leuven, Belgium) Deep Insights Section Nyla Heerema (Colombus, Ohio) Leukaemia Section Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections Sakari Knuutila (Helsinki, Finland) Deep Insights Section Lidia Larizza (Milano, Italy) Solid Tumours Section Lisa Lee-Jones (Newcastle, UK) Solid Tumours Section Edmond Ma (Hong Kong, China) Leukaemia Section Roderick McLeod (Braunschweig, Germany) Deep Insights / Education Sections Cristina Mecucci (Perugia, Italy) Genes / Leukaemia Sections Yasmin Mehraein (Homburg, Germany) Cancer-Prone Diseases Section Fredrik Mertens (Lund, Sweden) Solid Tumours Section Konstantin Miller (Hannover, Germany) Education Section Felix Mitelman (Lund, Sweden) Deep Insights Section Hossain Mossafa (Cergy Pontoise, France) Leukaemia Section Stefan Nagel (Braunschweig, Germany) Deep Insights / Education Sections Florence Pedeutour (Nice, France) Genes / Solid Tumours Sections Elizabeth Petty (Ann Harbor, Michigan) Deep Insights Section Susana Raimondi (Memphis, Tennesse) Genes / Leukaemia Section Mariano Rocchi (Bari, Italy) Genes Section Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section Albert Schinzel (Schwerzenbach, Switzerland) Education Section Clelia Storlazzi (Bari, Italy) Genes Section Sabine Strehl (Vienna, Austria) Genes / Leukaemia Sections Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections Dan Van Dyke (Rochester, Minnesota) Education Section Roberta Vanni (Montserrato, Italy) Solid Tumours Section Franck Viguié (Paris, France) Leukaemia Section José Luis Vizmanos (Pamplona, Spain) Leukaemia Section Thomas Wan (Hong Kong, China) Genes / Leukaemia Sections

Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11)

Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Volume 15, Number 11, November 2011

Table of contents

Gene Section

CTCF (CCCTC-binding factor (zinc finger protein)) 907 Jacques Piette EPS8 (epidermal growth factor receptor pathway substrate 8) 914 Anna A Bulysheva, W Andrew Yeudall FAM107A (family with sequence similarity 107, member A) 918 Kenji Kadomatsu, Ping Mu GAST (gastrin) 921 Celia Chao, Mark R Hellmich PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2) 928 Yuan-Hao Hsu TGFBRAP1 (transforming growth factor, beta receptor associated protein 1) 931 Jens U Wurthner AXIN1 (axin 1) 933 Nives Pecina-Slaus, Tamara Nikuseva Martic, Tomislav Kokotovic CCR2 (chemokine (C-C motif) receptor 2) 938 Jérôme Moreaux DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase)) 942 Dimitra Florou, Andreas Scorilas, Dido Vassilacopoulou, Emmanuel G Fragoulis DDR1 (discoidin domain receptor tyrosine kinase 1) 951 Barbara Roig, Elisabet Vilella ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)) 956 Luca Braccioli, Marilena V Iorio, Patrizia Casalini KIAA0101 (KIAA0101) 965 Shannon Joseph, Lingbo Hu, Fiona Simpson PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8) 968 Nikki Minnebo, Nele Van Dessel, Monique Beullens, Aleyde van Eynde, Mathieu Bollen SMYD2 (SET and MYND domain containing 2) 972 Hitoshi Tsuda, Shuhei Komatsu

Leukaemia Section t(1;9)(p34;q34) 974 Jean-Loup Huret

Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) Atlast(11;14)(q13;q32) of Genetics in multiple myeloma and Cytogenetics Huret JL, Laï JL in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Deep Insight Section

Understanding the structure and function of ASH2L 976 Paul F South, Scott D Briggs

Case Report Section

A new case of t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature 982 Sarah M Heaton, Frederick Koppitch, Anwar N Mohamed Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myelodysplastic syndrome. Case 0002M. 985 Kavita S Reddy Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myeloproliferative neoplasm. Case 0001M. 987 Kavita S Reddy

Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11)

Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

CTCF (CCCTC -binding factor (zinc finger protein)) Jacques Piette Institut de Genetique Moleculaire de Montpellier (CNRS-Université de Montpellier I-II UMR5535), 1919 Route de Mende, 34293, Montpellier-Cedex 5, France (JP)

Published in Atlas Database: April 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/CTCFID40187ch16q22.html DOI: 10.4267/2042/46051 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Description 76776 bp gene (Ensembl). HGNC (Hugo): CTCF Transcription Location: 16q22.1 Ubiquitously highly expressed gene (GeneCards), 12 Local order: AGRP, FAM65A, CTCF, RLTPR, ACD, exons, 11 introns with at least 5 differentially spliced PARD6A. transcripts (Ensembl). DNA/RNA Pseudogene Note No. See figure 1.

Figure 1. Schematic representation of CTCF location on chromosome 16, gene structure and transcripts. Chromosome 16 is represented with the characteristic banding pattern. The region surrounding the CTCF gene is enlarged. Genes are represented by arrows pointing in the direction of transcription. Transcripts are represented with exons as vertical bars and introns as lines. Distances are in kilo bases (NCBI Map Viewer).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 907 CTCF (CCCTC-binding factor (zinc finger protein)) Piette J

Figure 2. Schematic representation of the CTCF protein. Protein sequences encoded by exons are boxed. 11 ring fingers are indicated by green boxes as also putative AT-hooks by blue boxes (Ensembl). Phosphorylated residues are in black (PhosphoSitePlus), those sensitive to rapamycin are indicated by R (Chen et al., 2009) and those phosphorylated by CKII by CKII (El-Kady et al., 2005; Klenova et al., 2001), sumoylated residues are in red (Kitchen et al., 2010; MacPherson et al., 2009), acetylated residue is indicated by Ac (Choudhary et al., 2009). The domain containing poly(ADPribosyl)ation sites (PAR) is boxed in red (Farrar et al., 2010). Residues mutated in tumors are indicated (see further), BT = breast tumor, PT = prostate tumor and WT = Wilms tumor.

at the centrosomes and midbody during mitosis (Zhang Protein et al., 2004). It is associated with the nuclear matrix Description (Dunn et al., 2003; Yusufzai et al., 2004a) and the Lamina (Guelen et al., 2008; Ottaviani et al., 2009). CTCF was originally described as a c-myc activator Nucleolar translocation after growth arrest is (Klenova et al., 1993). It is a 727 aa protein with a MW accompanied by inhibition of nucleolar transcription of 82.8 kD, a charge of 8.5 and an iso electric point of (Torrano et al., 2006). Cytoplasmic expression was 6.95 (Ensembl). The central domain with 11 zinc described in sporadic breast tumors (Rakha et al., fingers of the C2H2 type is highly conserved. 2004). Expression Function CTCF is an abundant and ubiquitously expressed CTCF is an essential protein, since KO mice die before protein, yet absent in primary spermatocytes (Loukinov ED 9.5 (Heath et al., 2008) (reviewed in Filippova, et al., 2002). It is downregulated during differentiation 2008 and Phillips et al., 2009). It interacts with up to of human myeloid leukemia cells (Delgado et al., 1999; 39609 genomic sites (in ES cells) (Chen et al., 2008; Torrano et al., 2005). Post-traductional modifications Bao et al., 2007; Barski et al., 2007; Kim et al., 2007). include acetylation (Choudhary et al., 2009), The 11 Zn fingers would provide flexibility in DNA sumoylation (Kitchen et al., 2010; MacPherson et al., recognition (Filippova et al., 1996), the central 4 bind 2009), phosphorylation, in particular ser604-612 by to a consensus DNA sequence (Filippova et al., 1998; CKII (El-Kady et al., 2005; Klenova et al., 2001), and Renda et al., 2007). Multiple interacting proteins were poly(ADPribo)sylation (see figure 2). The latter described including RNA polymerase II (Chernukhin et modification is lost or decreased in proliferating cells al., 2007), cohesin (Parelho et al., 2008; Rubio et al., and in BT (Docquier et al., 2009) (for sites and role see 2008; Wendt et al., 2008), Suz12 (Li et al., 2008), Farrar et al., 2010 and Yu et al., 2004). CTCF is a CHD8 (Ishihara et al., 2006), YY1 (Donohoe et al., downstream target protein of growth factor-induced 2007), nucleophosmin (Yusufzai et al., 2004b), Kaiso pathways and is regulated by EGF and insulin through (Defossez et al., 2005) and Sin3A (Lutz et al., 2000). activation of ERK and AKT signaling cascades (Gao et Mediating DNA looping (Splinter et al., 2006) could be al., 2007). It was recently shown to be regulated by NF- at the basis of most functions of CTCF. Long range kB (Lu et al., 2010). interactions are cell type specific (Hou et al., 2010) and Localisation would depend on the chromosomal environment of the CTCF is localized in the nucleoplasm of proliferating CTCF-binding sites, in particular its interaction with cells with exclusion from the nucleolus. It was detected other factors (see concept of modular insulators in

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 908 CTCF (CCCTC-binding factor (zinc finger protein)) Piette J

Weth et al., 2010). One thoroughly studied factor is the 2008), however, there is no evidence that CTCF is the thyroid receptor (Awad et al., 1999; Lutz et al., 2003). TSG at 16q22.1 (Rakha et al., 2005), except possibly in Its chromosomal environment could also explain the lobular carcinoma in situ of the breast (Green et al., multiple (not necessarily exclusive) functions that were 2009). CTCF was also described to be overexpressed in described for CTCF, including chromatin barrier BT (Docquier et al., 2005). An indirect role of CTCF in (Cuddapah et al., 2008; Witcher et al., 2009), promoter tumor progression is mainly suggested by mutation or insulation from enhancer (Bell et al., 1999) or silencer aberrant methylation of its bindings sites (reviewed by (Hou et al., 2008), transcriptional activation (Gombert Recillas-Targa et al., 2006). Interestingly, a causal link et al., 2009) (for instance of the tumour suppressor between LOH of CTCF and hypermethylation was genes INK4A/ARF (Rodriguez et al., 2010) and p53 proposed by Mummert et al. in 2005, although no real (Soto-Reyes et al., 2010)), repression (for instance correlation was found by Yeh et al. in 2002. hTERT (Renaud et al., 2005)), nucleosome positioning Methylation of CTCF sites was first described in the (Fu et al., 2008b), protection from DNA methylation IGF2 imprinting control region in WT (Cui et al., (Mukhopadhyay et al., 2004; Schoenherr et al., 2003; 2001). Aberrant methylation of this region was also Guastafierro et al., 2008), preservation of triplet-repeat found in PT (Fu et al., 2008a; Paradowska et al., 2009), stability (Cho et al., 2005; Filippova et al., 2001; Libby HNSCC (De Castro Valente Esteves et al., 2006; et al., 2008), imprinting (Fedoriw et al., 2004; Esteves et al., 2005), colorectal cancer (Nakagawa et Fitzpatrick et al., 2007), X chromosome inactivation al., 2001), osteosarcoma (Ulaner et al., 2003), ovarian (Chao et al., 2002), chromosome "kissing" (Ling et al., carcinoma (Dammann et al., 2010) and laryngeal 2006), transvection (Liu et al., 2008), death signaling squamous cell carcinoma (Grbesa et al., 2008). (Docquier et al., 2005; Gomes et al., 2010; Li et al., Hypomethylation was described in bladder cancer 2007), replication timing (Bergstrom et al., 2007), (Takai et al., 2001). Microdeletions were described in mitotic bookmarking (Burke et al., 2005) or MHC class Beckwith-Wiedemann syndrome and WT (Prawitt et II gene expression (Majumder et al., 2008). al., 2005; Sparago et al., 2007). Other methylated Homology CTCF targets were found in the genes AWT1 or WT1- AS in WT (Hancock et al., 2007), Bcl6 in B cell 49 orthologues were described including D. lymphomas (Lai et al., 2010), p53, pRb (De La Rosa- melanogaster (Smith et al., 2009) and C. elegans Velazquez et al., 2007), ARF (Tam et al., 2003; proteins (Moon et al., 2005), 3 paralogues: CTCFL or Rodriguez et al., 2010), INK4B, BRCA1 (Butcher et BORIS, originating from a gene duplication in reptiles al., 2004; Butcher et al., 2007; Xu et al., 2010) and (Hore et al., 2008; Loukinov et al., 2002), and possibly Rasgrf1 (Yoon et al., 2005). ZFP64 (Mack et al., 1997) and the Histone H4 We describe below the rare cases of point mutations transcription factor HINF-P (van Wijnen et al., 1991). affecting the CTCF protein. Mutations Invasive ductal breast carcinoma, grade 2 Note Note SNP at AA 630 /K /E 90 /D /G 447 fR (NCBI). G2 grade tumor, no protein detected (Aulmann et al., Germinal 2003). Non-coding mutations only. Cytogenetics Somatic 14 bp insertion at AA D91, see figure 2. Mutations are rare and include point mutations of Zn- Invasive ductal breast carcinoma, grade fingers in breast (BT) (Aulmann et al., 2003), prostate 3 (PT) and Wilms tumor (WT) (Filippova et al., 2002) Note and insertion in BT (Aulmann et al., 2003) (see figure G3 grade tumor (Aulmann et al., 2003). 2). Cytogenetics Implicated in LOH and Q72H, figure 2. Breast cancer Various cancers Note Note Zinc finger mutation (Filippova et al., 2002). LOH of CTCF was described in many cancers together with potential tumor suppressor genes (TSG), including Cytogenetics E-Cad, since it is part of a larger deletion (Cancer LOH and K343E, figure 2. Chromosomes; Sanger institute). In addition to WT Prostate cancer (Yeh et al., 2002; Mummert et al., 2005), BT (Rakha et Note al., 2004), PT (Filippova et al., 1998), LOH was found in laryngeal squamous cell carcinoma (Grbesa et al., Zinc finger mutation (Filippova et al., 2002).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 909 CTCF (CCCTC-binding factor (zinc finger protein)) Piette J

Cytogenetics Filippova GN, Thienes CP, Penn BH, Cho DH, Hu YJ, Moore JM, Klesert TR, Lobanenkov VV, Tapscott SJ. CTCF-binding LOH and H344E, figure 2. sites flank CTG/CAG repeats and form a methylation-sensitive Wilms tumor insulator at the DM1 locus. Nat Genet. 2001 Aug;28(4):335-43 Note Klenova EM, Chernukhin IV, El-Kady A, Lee RE, Pugacheva EM, Loukinov DI, Goodwin GH, Delgado D, Filippova GN, Zinc finger mutation (Filippova et al., 2002). León J, Morse HC 3rd, Neiman PE, Lobanenkov VV. Cytogenetics Functional phosphorylation sites in the C-terminal region of the multivalent multifunctional transcriptional factor CTCF. Mol Cell LOH and R339W or R448Q, figure 2. Biol. 2001 Mar;21(6):2221-34 Nakagawa H, Chadwick RB, Peltomaki P, Plass C, Nakamura References Y, de La Chapelle A. Loss of imprinting of the insulin-like van Wijnen AJ, Ramsey-Ewing AL, Bortell R, Owen TA, Lian growth factor II gene occurs by biallelic methylation in a core JB, Stein JL, Stein GS. Transcriptional element H4-site II of region of H19-associated CTCF-binding sites in colorectal cell cycle regulated human H4 histone genes is a multipartite cancer. Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):591-6 protein/DNA interaction site for factors HiNF-D, HiNF-M, and Takai D, Gonzales FA, Tsai YC, Thayer MJ, Jones PA. Large HiNF-P: involvement of phosphorylation. J Cell Biochem. 1991 scale mapping of methylcytosines in CTCF-binding sites in the Jun;46(2):174-89 human H19 promoter and aberrant hypomethylation in human Klenova EM, Nicolas RH, Paterson HF, Carne AF, Heath CM, bladder cancer. Hum Mol Genet. 2001 Nov 1;10(23):2619-26 Goodwin GH, Neiman PE, Lobanenkov VV. CTCF, a Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT. CTCF, conserved nuclear factor required for optimal transcriptional a candidate trans-acting factor for X-inactivation choice. activity of the chicken c-myc gene, is an 11-Zn-finger protein Science. 2002 Jan 11;295(5553):345-7 differentially expressed in multiple forms. Mol Cell Biol. 1993 Dec;13(12):7612-24 Filippova GN, Qi CF, Ulmer JE, Moore JM, Ward MD, Hu YJ, Loukinov DI, Pugacheva EM, Klenova EM, Grundy PE, Filippova GN, Fagerlie S, Klenova EM, Myers C, Dehner Y, Feinberg AP, Cleton-Jansen AM, Moerland EW, Cornelisse Goodwin G, Neiman PE, Collins SJ, Lobanenkov VV. An CJ, Suzuki H, Komiya A, Lindblom A, Dorion-Bonnet F, exceptionally conserved transcriptional repressor, CTCF, Neiman PE, Morse HC 3rd, Collins SJ, Lobanenkov VV. employs different combinations of zinc fingers to bind diverged Tumor-associated zinc finger mutations in the CTCF promoter sequences of avian and mammalian c-myc transcription factor selectively alter tts DNA-binding specificity. oncogenes. Mol Cell Biol. 1996 Jun;16(6):2802-13 Cancer Res. 2002 Jan 1;62(1):48-52 Mack HG, Beck F, Bowtell DD. A search for a mammalian Loukinov DI, Pugacheva E, Vatolin S, Pack SD, Moon H, homologue of the Drosophila photoreceptor development gene Chernukhin I, Mannan P, Larsson E, Kanduri C, Vostrov AA, glass yields Zfp64, a zinc finger encoding gene which maps to Cui H, Niemitz EL, Rasko JE, Docquier FM, Kistler M, Breen the distal end of mouse chromosome 2. Gene. 1997 Jan JJ, Zhuang Z, Quitschke WW, Renkawitz R, Klenova EM, 31;185(1):11-7 Feinberg AP, Ohlsson R, Morse HC 3rd, Lobanenkov VV. Filippova GN, Lindblom A, Meincke LJ, Klenova EM, Neiman BORIS, a novel male germ-line-specific protein associated with PE, Collins SJ, Doggett NA, Lobanenkov VV. A widely epigenetic reprogramming events, shares the same 11-zinc- expressed transcription factor with multiple DNA sequence finger domain with CTCF, the insulator protein involved in specificity, CTCF, is localized at chromosome segment reading imprinting marks in the soma. Proc Natl Acad Sci U S 16q22.1 within one of the smallest regions of overlap for A. 2002 May 14;99(10):6806-11 common deletions in breast and prostate cancers. Genes Yeh A, Wei M, Golub SB, Yamashiro DJ, Murty VV, Tycko B. Chromosomes Cancer. 1998 May;22(1):26-36 Chromosome arm 16q in Wilms tumors: unbalanced Awad TA, Bigler J, Ulmer JE, Hu YJ, Moore JM, Lutz M, chromosomal translocations, loss of heterozygosity, and Neiman PE, Collins SJ, Renkawitz R, Lobanenkov VV, assessment of the CTCF gene. Genes Chromosomes Cancer. Filippova GN. Negative transcriptional regulation mediated by 2002 Oct;35(2):156-63 thyroid hormone response element 144 requires binding of the Aulmann S, Bläker H, Penzel R, Rieker RJ, Otto HF, Sinn HP. multivalent factor CTCF to a novel target DNA sequence. J Biol CTCF gene mutations in invasive ductal breast cancer. Breast Chem. 1999 Sep 17;274(38):27092-8 Cancer Res Treat. 2003 Aug;80(3):347-52 Bell AC, West AG, Felsenfeld G. The protein CTCF is required Dunn KL, Zhao H, Davie JR. The insulator binding protein for the enhancer blocking activity of vertebrate insulators. Cell. CTCF associates with the nuclear matrix. Exp Cell Res. 2003 1999 Aug 6;98(3):387-96 Aug 1;288(1):218-23 Delgado MD, Chernukhin IV, Bigas A, Klenova EM, León J. Lutz M, Burke LJ, LeFevre P, Myers FA, Thorne AW, Crane- Differential expression and phosphorylation of CTCF, a c-myc Robinson C, Bonifer C, Filippova GN, Lobanenkov V, transcriptional regulator, during differentiation of human Renkawitz R. Thyroid hormone-regulated enhancer blocking: myeloid cells. FEBS Lett. 1999 Feb 5;444(1):5-10 cooperation of CTCF and thyroid hormone receptor. EMBO J. Lutz M, Burke LJ, Barreto G, Goeman F, Greb H, Arnold R, 2003 Apr 1;22(7):1579-87 Schultheiss H, Brehm A, Kouzarides T, Lobanenkov V, Schoenherr CJ, Levorse JM, Tilghman SM. CTCF maintains Renkawitz R. Transcriptional repression by the insulator differential methylation at the Igf2/H19 locus. Nat Genet. 2003 protein CTCF involves histone deacetylases. Nucleic Acids Jan;33(1):66-9 Res. 2000 Apr 15;28(8):1707-13 Tam AS, Devereux TR, Patel AC, Foley JF, Maronpot RR, Cui H, Niemitz EL, Ravenel JD, Onyango P, Brandenburg SA, Massey TE. Perturbations of the Ink4a/Arf gene locus in Lobanenkov VV, Feinberg AP. Loss of imprinting of insulin-like aflatoxin B1-induced mouse lung tumors. Carcinogenesis. growth factor-II in Wilms' tumor commonly involves altered 2003 Jan;24(1):121-32 methylation but not mutations of CTCF or its binding site. Cancer Res. 2001 Jul 1;61(13):4947-50

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Ulaner GA, Vu TH, Li T, Hu JF, Yao XM, Yang Y, Gorlick R, El-Kady A, Klenova E. Regulation of the transcription factor, Meyers P, Healey J, Ladanyi M, Hoffman AR. Loss of CTCF, by phosphorylation with protein kinase CK2. FEBS Lett. imprinting of IGF2 and H19 in osteosarcoma is accompanied 2005 Feb 28;579(6):1424-34 by reciprocal methylation changes of a CTCF-binding site. Hum Mol Genet. 2003 Mar 1;12(5):535-49 Esteves LI, Javaroni AC, Nishimoto IN, Magrin J, Squire JA, Kowalski LP, Rainho CA, Rogatto SR. DNA methylation in the Butcher DT, Mancini-DiNardo DN, Archer TK, Rodenhiser DI. CTCF-binding site I and the expression pattern of the H19 DNA binding sites for putative methylation boundaries in the gene: does positive expression predict poor prognosis in early unmethylated region of the BRCA1 promoter. Int J Cancer. stage head and neck carcinomas? Mol Carcinog. 2005 2004 Sep 20;111(5):669-78 Oct;44(2):102-10 Fedoriw AM, Stein P, Svoboda P, Schultz RM, Bartolomei MS. Moon H, Filippova G, Loukinov D, Pugacheva E, Chen Q, Transgenic RNAi reveals essential function for CTCF in H19 Smith ST, Munhall A, Grewe B, Bartkuhn M, Arnold R, Burke gene imprinting. Science. 2004 Jan 9;303(5655):238-40 LJ, Renkawitz-Pohl R, Ohlsson R, Zhou J, Renkawitz R, Lobanenkov V. CTCF is conserved from Drosophila to humans Mukhopadhyay R, Yu W, Whitehead J, Xu J, Lezcano M, Pack and confers enhancer blocking of the Fab-8 insulator. EMBO S, Kanduri C, Kanduri M, Ginjala V, Vostrov A, Quitschke W, Rep. 2005 Feb;6(2):165-70 Chernukhin I, Klenova E, Lobanenkov V, Ohlsson R. The binding sites for the chromatin insulator protein CTCF map to Mummert SK, Lobanenkov VA, Feinberg AP. Association of DNA methylation-free domains genome-wide. Genome Res. chromosome arm 16q loss with loss of imprinting of insulin-like 2004 Aug;14(8):1594-602 growth factor-II in Wilms tumor. Genes Chromosomes Cancer. 2005 Jun;43(2):155-61 Rakha EA, Pinder SE, Paish CE, Ellis IO. Expression of the transcription factor CTCF in invasive breast cancer: a Prawitt D, Enklaar T, Gärtner-Rupprecht B, Spangenberg C, candidate gene located at 16q22.1. Br J Cancer. 2004 Oct Oswald M, Lausch E, Schmidtke P, Reutzel D, Fees S, Lucito 18;91(8):1591-6 R, Korzon M, Brozek I, Limon J, Housman DE, Pelletier J, Zabel B. Microdeletion of target sites for insulator protein Yu W, Ginjala V, Pant V, Chernukhin I, Whitehead J, Docquier CTCF in a chromosome 11p15 imprinting center in Beckwith- F, Farrar D, Tavoosidana G, Mukhopadhyay R, Kanduri C, Wiedemann syndrome and Wilms' tumor. Proc Natl Acad Sci U Oshimura M, Feinberg AP, Lobanenkov V, Klenova E, Ohlsson S A. 2005 Mar 15;102(11):4085-90 R. Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation. Nat Genet. 2004 Oct;36(10):1105-10 Rakha EA, Armour JA, Pinder SE, Paish CE, Ellis IO. High- resolution analysis of 16q22.1 in breast carcinoma using DNA Yusufzai TM, Felsenfeld G. The 5'-HS4 chicken beta-globin amplifiable probes (multiplex amplifiable probe hybridization insulator is a CTCF-dependent nuclear matrix-associated technique) and immunohistochemistry. Int J Cancer. 2005 May element. Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8620-4 1;114(5):720-9 Yusufzai TM, Tagami H, Nakatani Y, Felsenfeld G. CTCF Renaud S, Loukinov D, Bosman FT, Lobanenkov V, Benhattar tethers an insulator to subnuclear sites, suggesting shared J. CTCF binds the proximal exonic region of hTERT and insulator mechanisms across species. Mol Cell. 2004 Jan inhibits its transcription. Nucleic Acids Res. 2005;33(21):6850- 30;13(2):291-8 60 Zhang R, Burke LJ, Rasko JE, Lobanenkov V, Renkawitz R. Torrano V, Chernukhin I, Docquier F, D'Arcy V, León J, Dynamic association of the mammalian insulator protein CTCF Klenova E, Delgado MD. CTCF regulates growth and erythroid with centrosomes and the midbody. Exp Cell Res. 2004 Mar differentiation of human myeloid leukemia cells. 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CTCF (CCCTC-binding factor (zinc finger protein)). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):907-913.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 913 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

EPS8 (epidermal growth factor receptor pathway substrate 8) Anna A Bulysheva, W Andrew Yeudall VCU Philips Institute of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA (AAB, WAY)

Published in Atlas Database: April 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/EPS8ID40476ch12p12.html DOI: 10.4267/2042/46062 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Src homology (SH3) domain at amino acids 531-590; Identity intertwined dimer. HGNC (Hugo): EPS8 Expression Location: 12p12.3 Ubiquitous in adult; temporal expression in developing mouse embryo, in frontonasal neural crest cells, DNA/RNA branchial arches, liver primordium, central nervous Description system and submandibular glands. The EPS8 gene can be found on chromosome 12 at Localisation 12p12.3, starting at position 15664342 bp and ending at Plasma membrane; cytoplasm; perinuclear; possibly 15833601 bp from pter on the reverse strand. It nuclear. contains 21 exons. Function Transcription Scaffolding protein; participates in signal transduction The transcript consists of 4.1 kb and translates to a 822 downstream of receptor tyrosine kinases (incl. EGFR, residue protein. CSF1R, PDGFR); receptor endocytosis; cell motility; actin reorganization. Protein Homology Description 45 orthologues identified (Ensembl). 822 amino acids; contains pleckstrin homology (PH) 3 paralogues: EPS8L1; EPS8L2; EPS8L3. domain at amino acids 69-129 and 381-414; contains

Schematic representation of Homo sapiens EPS8.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 914 EPS8 (epidermal growth factor receptor pathway substrate 8) Bulysheva AA, Yeudall WA

Implicated in Pancreatic cancer Oncogenesis Cancer EPS8 was found to be overexpressed in multiple Note pancreatic tumors, with elevated levels primarily found Eps8 is reported to be expressed at elevated levels in a in pancreatic ductal cells, cell lines derived from range of human malignancies, including breast cancer, malignancies and ascites compared to lower levels in pancreatic cancer, colon cancer and head and neck primary tumors and normal pancreatic tissues. EPS8 squamous cell carcinoma. was reported to localize to the tips of F-actin filaments, Oncogenesis filopodia, and the leading edge of the cells, and was therefore correlated with the migratory potential of Overexpression of EPS8 has been reported to be tumor cells. sufficient to transform non-tumorigenic human cells to a tumorigenic phenotype. In a model system using Colon cancer murine fibroblasts, EPS8 overexpression led to Oncogenesis enhanced mitogenic signaling and growth factor- EPS8 was found to be overexpressed in the majority of dependent cellular transformation. Constitutive tyrosine colorectal tumors compared to their normal phosphorylation of EPS8 has been documented in counterparts. It was also found to modulate FAK human tumor cell lines, although the significance of expression and together, EPS8 and FAK were found to this for tumorigenesis remains to be established. play an important role in cell locomotion. Breast cancer Head and neck squamous cell Oncogenesis carcinoma EPS8 overexpression has been shown via integrated Oncogenesis cDNA array comparative genomic hybridization and Greater expression of EPS8 was found in malignant serial analyses of gene expression in a number of head and neck squamous cell carcinoma cell lines human breast cancer cell lines such as ductal carcinoma (HN12) compared to the primary tumor derived cells in situ cell lines, invasive ductal carcinomas and lymph (HN4) from the same patient. Ectopic overexpression node metastases, as novel candidate breast cancer of EPS8 in HN4 cells led to increased cell proliferation oncogenes. and migration in vitro and tumorgenicity in vivo.

Signaling processes involving EPS8. Dashed lines, direct protein interactions; blue circles, effector proteins.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 915 EPS8 (epidermal growth factor receptor pathway substrate 8) Bulysheva AA, Yeudall WA

Knockdown of EPS8 in HN12 cells led to reduced Maa MC, Lai JR, Lin RW, Leu TH. Enhancement of tyrosyl migration in vitro and reduced tumorgenicity in vivo. phosphorylation and protein expression of eps8 by v-Src. Biochim Biophys Acta. 1999 Jul 8;1450(3):341-51 EPS8 was found to mediate alphavbeta6 and alpha5beta1 integrin dependent activation of Rac1 and Scita G, Nordstrom J, Carbone R, Tenca P, Giardina G, Gutkind S, Bjarnegård M, Betsholtz C, Di Fiore PP. EPS8 and resulting cell migration. Suppression of either EPS8 or E3B1 transduce signals from Ras to Rac. Nature. 1999 Sep Rac1 resulted in reduced cell motility of the same 16;401(6750):290-3 tumor cells, however constitutive expression of Rac1 Lanzetti L, Rybin V, Malabarba MG, Christoforidis S, Scita G, rescued reduced cell migration in EPS8 knockdown Zerial M, Di Fiore PP. The Eps8 protein coordinates EGF cells. Therefore EPS8 and Rac1 likely modulate receptor signalling through Rac and trafficking through Rab5. integrin-dependent tumor cell motility. FOXM1, a cell Nature. 2000 Nov 16;408(6810):374-7 cycle related transcription factor, was found to be Burke P, Schooler K, Wiley HS. Regulation of epidermal upregulated in tumor cells with elevated EPS8. Further growth factor receptor signaling by endocytosis and studies showed cell proliferation and migration due to intracellular trafficking. Mol Biol Cell. 2001 Jun;12(6):1897-910 EPS8 occurs in part by FOXM1 deregulation and Kishan KV, Newcomer ME, Rhodes TH, Guilliot SD. Effect of induction of CXC-chemokine expression, which is pH and salt bridges on structural assembly: molecular mediated by PI3K and AKT-dependent mechanisms. structures of the monomer and intertwined dimer of the Eps8 SH3 domain. Protein Sci. 2001 May;10(5):1046-55 References Maa MC, Hsieh CY, Leu TH. Overexpression of p97Eps8 leads to cellular transformation: implication of pleckstrin homology Fazioli F, Minichiello L, Matoska V, Castagnino P, Miki T, domain in p97Eps8-mediated ERK activation. Oncogene. 2001 Wong WT, Di Fiore PP. Eps8, a substrate for the epidermal Jan 4;20(1):106-12 growth factor receptor kinase, enhances EGF-dependent mitogenic signals. EMBO J. 1993 Oct;12(10):3799-808 Scita G, Tenca P, Areces LB, Tocchetti A, Frittoli E, Giardina G, Ponzanelli I, Sini P, Innocenti M, Di Fiore PP. An effector Alvarez CV, Shon KJ, Miloso M, Beguinot L. Structural region in Eps8 is responsible for the activation of the Rac- requirements of the epidermal growth factor receptor for specific GEF activity of Sos-1 and for the proper localization of tyrosine phosphorylation of eps8 and eps15, substrates lacking the Rac-based actin-polymerizing machine. J Cell Biol. 2001 Src SH2 homology domains. J Biol Chem. 1995 Jul Sep 3;154(5):1031-44 7;270(27):16271-6 Innocenti M, Tenca P, Frittoli E, Faretta M, Tocchetti A, Di Avantaggiato V, Torino A, Wong WT, Di Fiore PP, Simeone A. Fiore PP, Scita G. Mechanisms through which Sos-1 Expression of the receptor tyrosine kinase substrate genes coordinates the activation of Ras and Rac. J Cell Biol. 2002 eps8 and eps15 during mouse development. Oncogene. 1995 Jan 7;156(1):125-36 Sep 21;11(6):1191-8 Calderwood DA, Fujioka Y, de Pereda JM, García-Alvarez B, Castagnino P, Biesova Z, Wong WT, Fazioli F, Gill GN, Di Nakamoto T, Margolis B, McGlade CJ, Liddington RC, Fiore PP. Direct binding of eps8 to the juxtamembrane domain Ginsberg MH. Integrin beta cytoplasmic domain interactions of EGFR is phosphotyrosine- and SH2-independent. with phosphotyrosine-binding domains: a structural prototype Oncogene. 1995 Feb 16;10(4):723-9 for diversity in integrin signaling. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2272-7 Matoskova B, Wong WT, Salcini AE, Pelicci PG, Di Fiore PP. Constitutive phosphorylation of eps8 in tumor cell lines: Innocenti M, Frittoli E, Ponzanelli I, Falck JR, Brachmann SM, relevance to malignant transformation. Mol Cell Biol. 1995 Di Fiore PP, Scita G. Phosphoinositide 3-kinase activates Rac Jul;15(7):3805-12 by entering in a complex with Eps8, Abi1, and Sos-1. J Cell Biol. 2003 Jan 6;160(1):17-23 Matòsková B, Wong WT, Nomura N, Robbins KC, Di Fiore PP. RN-tre specifically binds to the SH3 domain of eps8 with high Croce A, Cassata G, Disanza A, Gagliani MC, Tacchetti C, affinity and confers growth advantage to NIH3T3 upon Malabarba MG, Carlier MF, Scita G, Baumeister R, Di Fiore carboxy-terminal truncation. Oncogene. 1996 Jun PP. A novel actin barbed-end-capping activity in EPS-8 20;12(12):2679-88 regulates apical morphogenesis in intestinal cells of Caenorhabditis elegans. Nat Cell Biol. 2004 Dec;6(12):1173-9 Matòsková B, Wong WT, Seki N, Nagase T, Nomura N, Robbins KC, Di Fiore PP. RN-tre identifies a family of tre- Disanza A, Carlier MF, Stradal TE, Didry D, Frittoli E, related proteins displaying a novel potential protein binding Confalonieri S, Croce A, Wehland J, Di Fiore PP, Scita G. domain. Oncogene. 1996 Jun 20;12(12):2563-71 Eps8 controls actin-based motility by capping the barbed ends of actin filaments. Nat Cell Biol. 2004 Dec;6(12):1180-8 Biesova Z, Piccoli C, Wong WT. Isolation and characterization of e3B1, an eps8 binding protein that regulates cell growth. Funato Y, Terabayashi T, Suenaga N, Seiki M, Takenawa T, Oncogene. 1997 Jan 16;14(2):233-41 Miki H. IRSp53/Eps8 complex is important for positive regulation of Rac and cancer cell motility/invasiveness. Cancer Gallo R, Provenzano C, Carbone R, Di Fiore PP, Castellani L, Res. 2004 Aug 1;64(15):5237-44 Falcone G, Alemà S. Regulation of the tyrosine kinase substrate Eps8 expression by growth factors, v-Src and Leu TH, Yeh HH, Huang CC, Chuang YC, Su SL, Maa MC. terminal differentiation. Oncogene. 1997 Oct 16;15(16):1929- Participation of p97Eps8 in Src-mediated transformation. J Biol 36 Chem. 2004 Mar 12;279(11):9875-81 Kishan KV, Scita G, Wong WT, Di Fiore PP, Newcomer ME. Offenhäuser N, Borgonovo A, Disanza A, Romano P, The SH3 domain of Eps8 exists as a novel intertwined dimer. Ponzanelli I, Iannolo G, Di Fiore PP, Scita G. The eps8 family Nat Struct Biol. 1997 Sep;4(9):739-43 of proteins links growth factor stimulation to actin reorganization generating functional redundancy in the Inobe M, Katsube K, Miyagoe Y, Nabeshima Y, Takeda S. Ras/Rac pathway. Mol Biol Cell. 2004 Jan;15(1):91-8 Identification of EPS8 as a Dvl1-associated molecule. Biochem Biophys Res Commun. 1999 Dec 9;266(1):216-21

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 916 EPS8 (epidermal growth factor receptor pathway substrate 8) Bulysheva AA, Yeudall WA

Wunsch A, Strothmann K, Simoni M, Gromoll J, Nieschlag E, Xu M, Shorts-Cary L, Knox AJ, Kleinsmidt-DeMasters B, Luetjens CM. Epidermal growth factor receptor pathway Lillehei K, Wierman ME. Epidermal growth factor receptor substrate 8 (Eps8) expression in maturing testis. Asian J pathway substrate 8 is overexpressed in human pituitary Androl. 2004 Sep;6(3):195-203 tumors: role in proliferation and survival. Endocrinology. 2009 May;150(5):2064-71 Roffers-Agarwal J, Xanthos JB, Miller JR. Regulation of actin cytoskeleton architecture by Eps8 and Abi1. BMC Cell Biol. Yap LF, Jenei V, Robinson CM, Moutasim K, Benn TM, 2005 Oct 14;6:36 Threadgold SP, Lopes V, Wei W, Thomas GJ, Paterson IC. Upregulation of Eps8 in oral squamous cell carcinoma Disanza A, Mantoani S, Hertzog M, Gerboth S, Frittoli E, promotes cell migration and invasion through integrin- Steffen A, Berhoerster K, Kreienkamp HJ, Milanesi F, Di Fiore dependent Rac1 activation. Oncogene. 2009 Jul PP, Ciliberto A, Stradal TE, Scita G. Regulation of cell shape 9;28(27):2524-34 by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8-IRSp53 complex. Nat Cell Biol. 2006 Dec;8(12):1337- Zhang W, Wang L, Liu Y, Xu J, Zhu G, Cang H, Li X, Bartlam 47 M, Hensley K, Li G, Rao Z, Zhang XC. Structure of human lanthionine synthetase C-like protein 1 and its interaction with Khanday FA, Santhanam L, Kasuno K, Yamamori T, Naqvi A, Eps8 and glutathione. Genes Dev. 2009 Jun 15;23(12):1387- Dericco J, Bugayenko A, Mattagajasingh I, Disanza A, Scita G, 92 Irani K. Sos-mediated activation of rac1 by p66shc. J Cell Biol. 2006 Mar 13;172(6):817-22 Liu PS, Jong TH, Maa MC, Leu TH. The interplay between Eps8 and IRSp53 contributes to Src-mediated transformation. Yao J, Weremowicz S, Feng B, Gentleman RC, Marks JR, Oncogene. 2010 Jul 8;29(27):3977-89 Gelman R, Brennan C, Polyak K. Combined cDNA array comparative genomic hybridization and serial analysis of gene Wang H, Teh MT, Ji Y, Patel V, Firouzabadian S, Patel AA, expression analysis of breast tumor progression. Cancer Res. Gutkind JS, Yeudall WA. EPS8 upregulates FOXM1 2006 Apr 15;66(8):4065-78 expression, enhancing cell growth and motility. Carcinogenesis. 2010 Jun;31(6):1132-41 Maa MC, Lee JC, Chen YJ, Chen YJ, Lee YC, Wang ST, Huang CC, Chow NH, Leu TH. Eps8 facilitates cellular growth Welsch T, Younsi A, Disanza A, Rodriguez JA, Cuervo AM, and motility of colon cancer cells by increasing the expression Scita G, Schmidt J. Eps8 is recruited to lysosomes and and activity of focal adhesion kinase. J Biol Chem. 2007 Jul subjected to chaperone-mediated autophagy in cancer cells. 6;282(27):19399-409 Exp Cell Res. 2010 Jul 15;316(12):1914-24 Welsch T, Endlich K, Giese T, Büchler MW, Schmidt J. Eps8 is Yang TP, Chiou HL, Maa MC, Wang CJ. Mithramycin inhibits increased in pancreatic cancer and required for dynamic actin- human epithelial carcinoma cell proliferation and migration based cell protrusions and intercellular cytoskeletal involving downregulation of Eps8 expression. Chem Biol organization. Cancer Lett. 2007 Oct 8;255(2):205-18 Interact. 2010 Jan 5;183(1):181-6

Chen YJ, Shen MR, Chen YJ, Maa MC, Leu TH. Eps8 This article should be referenced as such: decreases chemosensitivity and affects survival of cervical cancer patients. Mol Cancer Ther. 2008 Jun;7(6):1376-85 Bulysheva AA, Yeudall WA. EPS8 (epidermal growth factor receptor pathway substrate 8). Atlas Genet Cytogenet Oncol Wang H, Patel V, Miyazaki H, Gutkind JS, Yeudall WA. Role Haematol. 2011; 15(11):914-917. for EPS8 in squamous carcinogenesis. Carcinogenesis. 2009 Jan;30(1):165-74

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 917 Atlas of Genetics and Cytogenetics

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Gene Section Mini Review

FAM107A (family with sequence similarity 107, member A) Kenji Kadomatsu, Ping Mu Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan (KK, PM)

Published in Atlas Database: April 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/FAM107AID42728ch3p14.html DOI: 10.4267/2042/46063 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Expression FAM107A protein is expressed in a wide variety of Other names: DRR1; FLJ30158; FLJ45473; TU3A normal tissues. High expression is found in the brain HGNC (Hugo): FAM107A and heart (Wang et al., 2000; Zhao et al., 2007). Location: 3p14.3 Localisation Note: The FAM107A protein is encoded by FAM107A Nucleus and cytoplasm (Wang et al., 2000; Zhao et al., gene. 2007; Le et al., 2010). DNA/RNA Function FAM107A is a candidate tumor suppressor gene. Description FAM107A protein is downregulated in several tumor FAM107A DNA contains 17742 bps (genomic size), cell lines and primary tumors. Overexpression of on negative strand. FAM107A can suppress tumor cell growth (Yamato et al., 1999; Wang et al., 2000; Kholodnyuk et al., 2006; Transcription van den Boom et al., 2006; Liu et al., 2009; Asano et FAM107A has two transcript variants. FAM107A al., 2010; Le et al., 2010). transcript variant 1 mRNA contains 3465 bps and 5 FAM107A protein is also involved in neuronal cell exons. FAM107A transcript variant 2 mRNA contains survival. Downregulation of FAM107A protein in 3367 bps and 4 exons. These two transcript variants primary cultured cortical neurons decrease cell number encode for the same protein. (Asano et al., 2010). FAM107A protein probably plays important roles in Protein embryo development (Zhao et al., 2007). FAM107A protein is a cytoskeletal crosslinker that regulates FA dynamics and cell movement. FAM107A protein is an important molecular in cell invasion (Le et al., 2010).

Homology Description No proteins with significant homology with FAM107A 144 amino acids, 17,5 kDa. protein were found (Wang et al., 2000). FAM107A protein includes a nuclear localization signal (NLS) and a coiled domain (Yamato et al., 1999;

Wang et al., 2000).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 918 FAM107A (family with sequence similarity 107, member A) Kadomatsu K, Mu P

Mutations Schizophrenia and bipolar disorder Note Note High expression level of FAM107A was found in the Up to now, no point mutations were identified. dorsolateral prefrontal cortex from schizophrenia and Implicated in bipolar disorder patient (Shao et al., 2007). Neuronal cell survival Renal cell carcimoma Note Disease FAM107A protein was mainly localized in the neurites Loss of FAM107A gene was found on 3p21.1 in renal of the primary culture of cerebral cortical neurons. cell carcinoma. Reduced expression was found in renal Downregulation of FAM107A expression with siRNA cell carcinoma cell lines and primary renal cell decreased neuron cell number. These data suggest that carcinomas. Overexpression of FAM107A in renal cell FAM107A plays a critical role in neuronal cell survival carcinoma cell line resulted in growth suppression of (Asano et al., 2010). these cells (Yamato et al., 1999; Wang et al., 2000). Also, FAM107A hypermethylation was detected in References renal cell carcimomas and significantly associated with Yamato T, Orikasa K, Fukushige S, Orikasa S, Horii A. advanced tumor stage (Awakura et al., 2008). Isolation and characterization of the novel gene, TU3A, in a commonly deleted region on 3p14.3-->p14.2 in renal cell Astrocytomas carcinoma. Cytogenet Cell Genet. 1999;87(3-4):291-5 Disease Wang L, Darling J, Zhang JS, Liu W, Qian J, Bostwick D, et al. FAM107A was expressed at significantly lower levels Loss of expression of the DRR 1 gene at chromosomal in secondary glioblastomas as compared to diffuse segment 3p21.1 in renal cell carcinoma. Genes Chromosomes astrocytomas (Van den Boom et al., 2006). Cancer. 2000 Jan;27(1):1-10 Lung cancer Kholodnyuk ID, Kozireva S, Kost-Alimova M, Kashuba V, Klein G, Imreh S. Down regulation of 3p genes, LTF, SLC38A3 and Disease DRR1, upon growth of human chromosome 3-mouse Loss of expression of FAM107A was found in non- fibrosarcoma hybrids in severe combined immunodeficiency mice. Int J Cancer. 2006 Jul 1;119(1):99-107 small cell lung cancer and primary lung cancers. Overexpression of FAM107A in non-small cell lung van den Boom J, Wolter M, Blaschke B, Knobbe CB, cancer cell line reduced cell proliferation activity and Reifenberger G. Identification of novel genes associated with astrocytoma progression using suppression subtractive induced apoptosis (Liu et al., 2009). hybridization and real-time reverse transcription-polymerase Neuroblastoma chain reaction. Int J Cancer. 2006 Nov 15;119(10):2330-8 Zhao XY, Liang SF, Yao SH, Ma FX, Hu ZG, Yan F, Yuan Z, Disease Ruan XZ, Yang HS, Zhou Q, Wei YQ. Identification and FAM107A protein was detected in the normal preliminary function study of Xenopus laevis DRR1 gene. ganglions and the ganglions exhibiting neuroblast Biochem Biophys Res Commun. 2007 Sep 14;361(1):74-8 hyperplasia from 2 weeks hemizygote MYCN Awakura Y, Nakamura E, Ito N, Kamoto T, Ogawa O. transgenic mice. However, the expression of Methylation-associated silencing of TU3A in human cancers. FAM107A completely disappeared in the tumors from Int J Oncol. 2008 Oct;33(4):893-9 8 weeks hemizygote MYCN transgenic mice (Asano et Shao L, Vawter MP. Shared gene expression alterations in al., 2010). schizophrenia and bipolar disorder. Biol Psychiatry. 2008 Jul 15;64(2):89-97 Brain tumor Zhao XY, Li HX, Liang SF, Yuan Z, Yan F, Ruan XZ, You J, Disease Xiong SQ, Tang MH, Wei YQ. Soluble expression of human FAM107A is not expressed in normal glial cells, it is DRR1 (down-regulated in renal cell carcinoma 1) in highly expressed in the invasive component of gliomas. Escherichia coli and preparation of its polyclonal antibodies. Biotechnol Appl Biochem. 2008 Jan;49(Pt 1):17-23 It was found that FAM107A associates with and organizes the actin and microtubular cytoskeletons. Liu Q, Zhao XY, Bai RZ, Liang SF, Nie CL, Yuan Z, Wang CT, FAM107A regulates focal adhesion disassembly and Wu Y, Chen LJ, Wei YQ. Induction of tumor inhibition and apoptosis by a candidate tumor suppressor gene DRR1 on cell invasion (Le et al., 2010). 3p21.1. Oncol Rep. 2009 Nov;22(5):1069-75 Embryo development Asano Y, Kishida S, Mu P, Sakamoto K, Murohara T, Kadomatsu K. DRR1 is expressed in the developing nervous Note system and downregulated during neuroblastoma The expression level of FAM107A gene increases carcinogenesis. Biochem Biophys Res Commun. 2010 Apr gradually with embryo development in the early stages 9;394(3):829-35 (Zhao et al., 2007).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 919 FAM107A (family with sequence similarity 107, member A) Kadomatsu K, Mu P

Frijters R, Fleuren W, Toonen EJ, Tuckermann JP, et al drives brain cancer invasion by regulating cytoskeletal-focal Prednisolone-induced differential gene expression in mouse adhesion dynamics. Oncogene. 2010 Aug 19;29(33):4636-47 liver carrying wild type or a dimerization-defective glucocorticoid receptor. BMC Genomics. 2010 Jun 5;11:359 This article should be referenced as such: Le PU, Angers-Loustau A, de Oliveira RM, Ajlan A, Brassard Kadomatsu K, Mu P. FAM107A (family with sequence similarity CL, Dudley A, Brent H, Siu V, Trinh G, Mölenkamp G, Wang J, 107, member A). Atlas Genet Cytogenet Oncol Haematol. Seyed Sadr M, Bedell B, Del Maestro RF, Petrecca K. DRR 2011; 15(11):918-920.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 920 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

GAST (gastrin) Celia Chao, Mark R Hellmich Department of Surgery, Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA (CC, MRH)

Published in Atlas Database: April 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/GASTID44214ch17q21.html DOI: 10.4267/2042/46064 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

the proteolytic cleavage of progastrin are gastrin-17 Identity (G17) and gastrin-34 (G34). Other names: GAS HGNC (Hugo): GAST Protein Location: 17q21.2 Note It should be noted that the numbering system of critical DNA/RNA amino acid residues involved in peptide cleavage and post-translational modifications of gastrin varies within Note the scientific literature. This is due to the fact that the The 4.3 kb gene for human gastrin contains two introns numbering system of some authors is based on the and 3 exons that encode preprogastrin, the gastrin sequence of preprogastrin, which includes the 21 amino precursor. It is located on chromosome 17(q21), and acids of the signal peptide sequence, whereas the consists of three exons that contain the code sequence numbering system of others is based on the sequence of for a prepropeptide of 101 amino acid residues with a progastrin. Our description of prohormone processing calculated molecular mass of 11.4 kDa (see diagram will be based on the 80 amino acid peptide sequence of below). The primary structure of human preprogastrin progastrin. protein consists of an N-terminal 21-amino acid signal After signal peptide cleavage, progastrin undergoes sequence followed by a spacer peptide, a bioactive additional post-translational modifications as it transits domain, and finally a hexapeptide C-terminal flanking from the ER through the Golgi to the trans-Golgi peptide (CTFP). Upon initiation of translation, the network before it is sorted into immature secretory signal sequence facilitates the translocation of the vesicles of the regulated exocytosis (secretory) elongating polypeptide into the endoplasmic reticulum pathway. The modifications include O-sulfation at (ER), where it is subsequently removed by a tyrosine residue 66 of the propeptide by tyrosylprotein membrane-bound signal peptidase that cleaves the sulfotransferases and/or phosphorylation at serine 75 by growing polypeptide chain between alanine residue 21 a calcium-dependent casein-like kinase. Although O- and serine 22 to generate the 80 amino acid peptide, sulfation is thought to occur primarily in the trans- progastrin. Progastrin is further processed (see protein Golgi network, a recent study provides evidence section below) into the two principal C-terminal alpha- suggesting that it may continue through later amidated forms of circulating gastrin generated from compartments of the regulated secretory pathway.

Chromosome 17 - NC_000017.10.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 921 GAST (gastrin) Chao C, Hellmich MR

Schematic representation of the preprogastrin gene, its mRNA, and the peptide precursor preprogastrin. The gene is transcribed as a 303 nucleotide RNA transcript and the mRNA is processed into a 101 amino acid (aa) preprohormone. The preprogastrin peptide consists of a 21-aa signal sequence, which is co-translationally cleaved, a N-terminal spacer, the active peptide and the C-terminal flanking peptide (CTFP). Progastrin is formed after removal of the signal peptide.

The extent of gastrin O-sulfation varies with species any amino acid, but usually not a Cysteine. PC1/3 and and cellular localization of peptide synthesis within the PC2 are involved in progastrin processing. GI tract as well as the developmental stage of the The two principal biologically active forms of tissues. For example, in adult humans, approximately circulating gastrin are gastrin-17 (G17) and gastrin-34 half of the gastrin peptide synthesized in G cells of the (G34). In rodent and human G cells of antrum and antrum and duodenum, and released into the circulation proximal duodenum, approximately 95% of the are sulfated, whereas all of the gastrin peptide produced progastrin is processed to partially sulfated G17 (85%) by the fetal pancreas appears to be sulfated. and G34 (10%). Although G17 is the predominant Functionally, sulfation of gastrin enhances product, G34 is the major circulating form of gastrin endoproteolytic processing of progastrin, and may due to its slower rate of clearance. In both humans, the promote protein-protein interactions and peptide half-life of circulating G34 is approximately five times sorting between secretory pathways. However, unlike longer than that of G17. sulfation of the related peptide, cholecystokinin (CCK), The proteolytic processing of progastrin involves sulfation of gastrin does not significantly affect its convertase-specific cleavage at three dibasic consensus affinity for its physiologic receptor. sites. PC1/3 is active early in the secretory pathway in Phosphorylation of serine 75 of progastrin may granules with a neutral pH (i.e., pH ≈ 7) and cleaves the promote proteolytic processing at the upstream arginine prohormone after the arginine 36-arginine 37 and residues at positions 73 and 74 (arginine 73-arginine arginine 73-arginine 74 sequences, releasing the C- 74) releasing the C-terminal flanking peptide, and may terminal flanking peptide, and generating G34. The affect the conversion of glycine-extended gastrin post-cleavage residual basic residues are then removed intermediates to mature C-terminal alpha-amidated by carboxypeptidase E, generating what are commonly peptides. However, since phosphorylation is not referred to as the glycine-extended gastrins (i.e., G34- essential for progastrin processing, its biological Glycine). In contrast to PC1/3, PC2 is mainly active in significance remains an enigma. mature granules at an acidic pH (i.e., pH ≈ 5). Cleavage Following sulfation and/or phosphorylation, progastrin of G34-glycine by PC2 after the dibasic amino acid exits the trans-Golgi network and enters immature sequence lysine 53-lysine 54 produces G17-glycine. granules of the regulated secretory pathway. The major These glycine-extended peptides are substrates for the proteolytic processing of progastrin to its biologically peptidyl-glycine alpha-amidating monooxygenase active peptides occurs in the maturing dense core (PAM) that utilizes the glycyl residue as an amide secretory granules of the regulated pathway. Progastrin donor to alpha-amidate the carboxyl group of the C- is cleaved by two types of proteases: endo- and terminus of the peptide. The ratio of amidated gastrins exopeptidases. Endopeptidases, also known as to processing intermediates varies considerably across prohormone convertases (PC), typically cleave tissues and cell types. Processing intermediates are polypeptides downstream of two adjacent basic amino quite scarce in the gastric antrum, making up only acid residues at the general motif (lysine/arginine)- about 1-5% of gastrin gene products, while in the (X)n-(lysine/arginine), where n=0, 2, 4, or 6 and X is duodenum the value has been reported to be as high

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 922 GAST (gastrin) Chao C, Hellmich MR

Processing of gastrin. The numbering system of critical amino acid residues involved in peptide cleavage and post-translational modifications of gastrin varies within the scientific literature. This is due to the fact that the numbering system of some authors is based on the sequence of preprogastrin, which includes the 21 amino acids of the signal peptide sequence, whereas the numbering system of others is based on the sequence of progastrin. The numbers at the top of the diagram represents the amino acid (aa) sequence for preprogastrin; the numbers at the bottom of the diagram represents the aa sequence for progastrin. The signal peptide is cleaved co- translationally in the rough ER by signal peptidase. In the Trans-Golgi-Network (TGN), progastrin is modified by sulfation at Tyr 66 and phosphorylation of Ser 75 by a casein-like kinase. Prohormone convertases (PC) and carboxypeptidase E (CPE) sequentially convert the prohormone to the glycine-extended forms (G71-Gly, G34-Gly, G17-Gly). Abbreviations: CTFP: C-terminal flanking peptide, TPST: tyrosyl-protein sulfotransferase, PAM: peptidyl-alpha-amidating-monooxygenase. as 20%. Carboxyl-terminus alpha-amidation is a tissue and plasma levels of PAI-2 are elevated. Gastrin prerequisite for high affinity binding of gastrin to its directly regulates PAI-2 expression in CCK 2 receptor- cognate receptor, CCK2 receptor. positive cells, and in neighboring receptor-negative cells, by way of paracrine mediators released from the Mutations CCK 2 receptor-expressing cells. Direct regulation involves cell automous activation of CRE and AP-1 Note transcription factors via a PKC, Ras, Raf, RhoA, and There are no known mutations in the gastrin gene the NFkappaB signaling pathways in CCK 2 receptor- causing a pathologic entity. Overexpression of gastrin, expressing cells by gastrin. The CRE and AP-1 or aberrant expression of gastrin, have both been transcription factors, in turn, regulate expression of the associated with gastric, colorectal, esophageal and genes for IL-8 and COX2. IL-8 acts through a pancreatic cancers. GACAGA site via the activating signal cointegrator 1 (ASC-1) complex, whereas prostaglandins, resulting Implicated in from the activation of COX2, target the Myc-associated Gastrinomas zinc finger protein (MAZ site via the small GTPase RhoA to stimulate PAI-2 expression in adjacent CCK 2 Note receptor-negative cells. Gastrinomas are neuroendocrine tumors that can arise Inflammation-associated carcinomas from the stomach, duodenum or pancreas. Patients with multiple endocrine neoplasia type 1 (MEN1) have a Note mutation in the menin gene and are at very high risk for In a rat intestinal epithelial cell model, MAPKs mediate developing gastrinomas. In patients with CCK 2 receptor regulation of cyclooxgenase 2 (COX-2). hypergastrinemia due to pernicious anemia or MEN1, COX-2 is an inducible enzyme catalyzing the rate-

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 923 GAST (gastrin) Chao C, Hellmich MR

limiting step in prostaglandin synthesis, converting Walsh JH, Debas HT, Grossman MI. Pure human big gastrin. arachidonic acid to prostaglandin H2. A large body of Immunochemical properties, disappearance half time, and acid-stimulating action in dogs. J Clin Invest. 1974 genetic and biochemical evidence support the important Aug;54(2):477-85 role of COX-2 and the subsequent synthesis of Dockray GJ, Taylor IL. Heptadecapeptide gastrin: prostaglandins in the regulation of inflammation and measurement in blood by specific radioimmunoassay. promotion of tumorigenesis. Gastrin has been shown to Gastroenterology. 1976 Dec;71(6):971-7 increase COX-2 expression in colorectal, gastric, and Larsson LI, Rehfeld JF, Sundler F, Håkanson R. Pancreatic esophageal cancers. gastrin in foetal and neonatal rats. Nature. 1976 Aug Gastric cancer 12;262(5569):609-10 Note Walsh JH, Isenberg JI, Ansfield J, Maxwell V. Clearance and acid-stimulating action of human big and little gastrins in Gastric carcinogenesis is a multistep process that arises duodenal ulcer subjects. J Clin Invest. 1976 May;57(5):1125- from superficial gastritis, chronic atrophic gastritis, 31 progressing to intestinal metaplasia, dysplasia, and Feldman M, Walsh JH, Wong HC, Richardson CT. Role of finally carcinoma. H. pylori is the most common gastrin heptadecapeptide in the acid secretory response to known cause of chronic gastritis in humans, secretes amino acids in man. J Clin Invest. 1978 Feb;61(2):308-13 urease, which converts urea to ammonia, and Thompson JC, Lowder WS, Peurifoy JT, Swierczek JS, neutralizes the acid in the stomach. H. pylori initiates a Rayford PL. Effect of selective proximal vagotomy and truncal host inflammatory response that is associated with the vagotomy on gastric acid and serum gastrin responses to a recruitment of mononuclear and polymorphonuclear meal in duodenal ulcer patients. Ann Surg. 1978 Oct;188(4):431-8 leukocytes, and bone marrow-derived cells. Specific inflammatory cytokines from immune cells are required Hirschowitz BI, Helman CA. Effects of fundic vagotomy and cholinergic replacement on pentagastrin dose responsive for the initiation and promotion of carcinogenesis. In gastric acid and pepsin secretion in man. Gut. 1982 addition to local inflammation, H. pylori induces the Aug;23(8):675-82 systemic elevation of serum gastrin (hypergastrinemia). Taylor IL, Byrne WJ, Christie DL, Ament ME, Walsh JH. Effect The combination of achlorhydria and hypergastrinemia, of individual l-amino acids on gastric acid secretion and serum induced by H. pylori infection, results in gastric gastrin and pancreatic polypeptide release in humans. bacterial overgrowth, lack of parietal cell Gastroenterology. 1982 Jul;83(1 Pt 2):273-8 differentiation, development of gastric metaplasia, and Boel E, Vuust J, Norris F, Norris K, Wind A, Rehfeld JF, eventual progression to gastric carcinoma. Marcker KA. Molecular cloning of human gastrin cDNA: evidence for evolution of gastrin by gene duplication. Proc Natl Colorectal cancer Acad Sci U S A. 1983 May;80(10):2866-9 Note Andersen BN. Measurement and occurrence of sulfated Gastrin and gastrin-like peptides are upregulated gastrins. Scand J Clin Lab Invest Suppl. 1984;168:5-24 locally in 78% of premalignant adenomatous polyps, Brand SJ, Andersen BN, Rehfeld JF. Complete tyrosine-O- before the appearance of invasive carcinoma, and sulphation of gastrin in neonatal rat pancreas. Nature. 1984 gastrin expression has been linked to key mutations in May 31-Jun 6;309(5967):456-8 the initiation of colorectal carcinogenesis. When the Brand SJ, Klarlund J, Schwartz TW, Rehfeld JF. Biosynthesis APC min-/+ mouse was crossed with a gastrin gene of tyrosine O-sulfated gastrins in rat antral mucosa. J Biol knockout mouse, the hybrid developed fewer intestinal Chem. 1984 Nov 10;259(21):13246-52 polyps. Gastrin transcription is linked to the Wnt/beta- Ito R, Sato K, Helmer T, Jay G, Agarwal K. Structural analysis catenin pathway by a binding site for the transcription of the gene encoding human gastrin: the large intron contains factor TCF4 in the gastrin promoter. Induction of the an Alu sequence. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4662-6 wild-type APC decreased gastrin mRNA expression, while transfection of constitutively active beta-catenin Saffouri B, DuVal JW, Makhlouf GM. Stimulation of gastrin increased gastrin promoter activity. secretion in vitro by intraluminal chemicals: regulation by intramural cholinergic and noncholinergic neurons. References Gastroenterology. 1984 Sep;87(3):557-61 Wiborg O, Berglund L, Boel E, Norris F, Norris K, Rehfeld JF, GREGORY RA, TRACY HJ. THE CONSTITUTION AND Marcker KA, Vuust J. Structure of a human gastrin gene. Proc PROPERTIES OF TWO GASTRINS EXTRACTED FROM Natl Acad Sci U S A. 1984 Feb;81(4):1067-9 HOG ANTRAL MUCOSA. Gut. 1964 Apr;5:103-14 Hollinshead JW, Debas HT, Yamada T, Elashoff J, Osadchey Korman MG, John DJ, Hansky J. Studies on serum gastrin B, Walsh JH. Hypergastrinemia develops within 24 hours of levels in pernicious anaemia. Gut. 1970 Nov;11(11):981 truncal vagotomy in dogs. Gastroenterology. 1985 Jan;88(1 Pt 1):35-40 Rehfeld JF, Stadil F. Gel filtration studies on immunoreactive gastrin in serum from Zollinger-Ellison patients. Gut. 1973 Nishi S, Seino Y, Takemura J, Ishida H, Seno M, Chiba T, May;14(5):369-73 Yanaihara C, Yanaihara N, Imura H. Vagal regulation of GRP, gastric somatostatin, and gastrin secretion in vitro. Am J Stadil F, Rehfeld JF. Release of gastrin by epinephrine in man. Physiol. 1985 Apr;248(4 Pt 1):E425-31 Gastroenterology. 1973 Aug;65(2):210-5

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Schubert ML, Saffouri B, Walsh JH, Makhlouf GM. Inhibition of Sandvik AK, Waldum HL. CCK-B (gastrin) receptor regulates neurally mediated gastrin secretion by bombesin antiserum. gastric histamine release and acid secretion. Am J Physiol. Am J Physiol. 1985 Apr;248(4 Pt 1):G456-62 1991 Jun;260(6 Pt 1):G925-8 Larsson H, Carlsson E, Mattsson H, Lundell L, Sundler F, Bachwich D, Merchant J, Brand SJ. Identification of a cis- Sundell G, Wallmark B, Watanabe T, Håkanson R. Plasma regulatory element mediating somatostatin inhibition of gastrin and gastric enterochromaffinlike cell activation and epidermal growth factor-stimulated gastrin gene transcription. proliferation. Studies with omeprazole and ranitidine in intact Mol Endocrinol. 1992 Aug;6(8):1175-84 and antrectomized rats. Gastroenterology. 1986 Feb;90(2):391-9 Chuang CN, Tanner M, Chen MC, Davidson S, Soll AH. Gastrin induction of histamine release from primary cultures of Lund T, Geurts van Kessel AH, Haun S, Dixon JE. The genes canine oxyntic mucosal cells. Am J Physiol. 1992 Oct;263(4 Pt for human gastrin and cholecystokinin are located on different 1):G460-5 chromosomes. Hum Genet. 1986 May;73(1):77-80 Schubert ML, Coy DH, Makhlouf GM. Peptone stimulates Dockray GJ, Varro A, Desmond H, Young J, Gregory H, gastrin secretion from the stomach by activating Gregory RA. Post-translational processing of the porcine bombesin/GRP and cholinergic neurons. Am J Physiol. 1992 gastrin precursor by phosphorylation of the COOH-terminal Apr;262(4 Pt 1):G685-9 fragment. J Biol Chem. 1987 Jun 25;262(18):8643-7 Dimaline R, Sandvik AK, Evans D, Forster ER, Dockray GJ. Holst JJ, Knuhtsen S, Orskov C, Skak-Nielsen T, Poulsen SS, Food stimulation of histidine decarboxylase messenger RNA Jensen SL, Nielsen OV. GRP nerves in pig antrum: role of abundance in rat gastric fundus. J Physiol. 1993 Jun;465:449- GRP in vagal control of gastrin secretion. Am J Physiol. 1987 58 Nov;253(5 Pt 1):G643-9 Chen D, Monstein HJ, Nylander AG, Zhao CM, Sundler F, Sandvik AK, Waldum HL, Kleveland PM, Schulze Søgnen B. Håkanson R. Acute responses of rat stomach Gastrin produces an immediate and dose-dependent histamine enterochromaffinlike cells to gastrin: secretory activation and release preceding acid secretion in the totally isolated, adaptation. Gastroenterology. 1994 Jul;107(1):18-27 vascularly perfused rat stomach. Scand J Gastroenterol. 1987 Sep;22(7):803-8 Prinz C, Scott DR, Hurwitz D, Helander HF, Sachs G. Gastrin effects on isolated rat enterochromaffin-like cells in primary Schubert ML, Makhlouf GM. Neural regulation of gastrin and culture. Am J Physiol. 1994 Oct;267(4 Pt 1):G663-75 somatostatin secretion in rat gastric antral mucosa. Am J Physiol. 1987 Dec;253(6 Pt 1):G721-5 Rehfeld JF, Johnsen AH. Identification of gastrin component I as gastrin-71. 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J Gastroenterol. 1997 Oct;32(5):579-86 Physiol Gastrointest Liver Physiol. 2001 Feb;280(2):G298-307 Todisco A, Takeuchi Y, Urumov A, Yamada J, Stepan VM, Bierkamp C, Kowalski-Chauvel A, Dehez S, Fourmy D, Yamada T. Molecular mechanisms for the growth factor action Pradayrol L, Seva C. Gastrin mediated cholecystokinin-2 of gastrin. Am J Physiol. 1997 Oct;273(4 Pt 1):G891-8 receptor activation induces loss of cell adhesion and scattering in epithelial MDCK cells. Oncogene. 2002 Oct 31;21(50):7656- Bishop L, Dimaline R, Blackmore C, Deavall D, Dockray GJ, 70 Varro A. Modulation of the cleavage of the gastrin precursor by prohormone phosphorylation. Gastroenterology. 1998 Guo YS, Cheng JZ, Jin GF, Gutkind JS, Hellmich MR, Nov;115(5):1154-62 Townsend CM Jr. Gastrin stimulates cyclooxygenase-2 expression in intestinal epithelial cells through multiple Friis-Hansen L, Sundler F, Li Y, Gillespie PJ, Saunders TL, signaling pathways. 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Gastroenterology. 2009 CCK-2 receptor-mediated cyclooxygenase-2 induction and Jul;137(1):231-41, 241.e1-10 prostaglandin E2 production. Br J Pharmacol. 2005 Feb;144(3):338-48 Baldwin GS, Patel O, Shulkes A. Evolution of gastrointestinal hormones: the cholecystokinin/gastrin family. Curr Opin Dufner MM, Kirchhoff P, Remy C, Hafner P, Müller MK, Cheng Endocrinol Diabetes Obes. 2010 Feb;17(1):77-88 SX, Tang LQ, Hebert SC, Geibel JP, Wagner CA. The calcium- sensing receptor acts as a modulator of gastric acid secretion Bundgaard JR, Rehfeld JF. Posttranslational processing of in freshly isolated human gastric glands. Am J Physiol progastrin. Results Probl Cell Differ. 2010;50:207-20 Gastrointest Liver Physiol. 2005 Dec;289(6):G1084-90 Ericsson P, Håkanson R, Norlén P. Gastrin response to Müerköster S, Isberner A, Arlt A, Witt M, Reimann B, candidate messengers in intact conscious rats monitored by Blaszczuk E, Werbing V, Fölsch UR, Schmitz F, Schäfer H. antrum microdialysis. Regul Pept. 2010 Aug 9;163(1-3):24-30 Gastrin suppresses growth of CCK2 receptor expressing colon cancer cells by inducing apoptosis in vitro and in vivo. Feng J, Petersen CD, Coy DH, Jiang JK, Thomas CJ, Pollak Gastroenterology. 2005 Sep;129(3):952-68 MR, Wank SA. Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and Alvarez A, Ibiza S, Hernández C, Alvarez-Barrientos A, gastrin secretion. Proc Natl Acad Sci U S A. 2010 Oct Esplugues JV, Calatayud S. Gastrin induces leukocyte- 12;107(41):17791-6 endothelial cell interactions in vivo and contributes to the inflammation caused by Helicobacter pylori. FASEB J. 2006 This article should be referenced as such: Nov;20(13):2396-8 Chao C, Hellmich MR. GAST (gastrin). Atlas Genet Cytogenet Jensen RT. Consequences of long-term proton pump Oncol Haematol. 2011; 15(11):921-927. blockade: insights from studies of patients with gastrinomas. Basic Clin Pharmacol Toxicol. 2006 Jan;98(1):4-19

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 927 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Mini Review

PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2) Yuan-Hao Hsu Department of Chemistry and Biochemistry and Pharmacology, School of Medicine, San Diego, La Jolla, California 92093-0601, USA (YHH)

Published in Atlas Database: April 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/PAK2ID41634ch3q29.html DOI: 10.4267/2042/46065 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

followed by autophosphorylation. In the inactive state, Identity the AID interacts with the catalytic domain to inhibit its Other names: PAK65; PAKgamma kinase activity. GTP-bound Cdc42 can disrupt HGNC (Hugo): PAK2 autoinhibition, which, in turn, leads to autophosphorylation and activation of PAK. Pak2's Location: 3q29 basal autophosphorylation activity is observed and Pak2 is autophosphorylated at 5 sites, serines 19, 20, DNA/RNA 55, 192 and 197. Additional three phosphorylation sites Description (serines 141 and 165 and threonine 402) are autophosphorylated in the presence of Cdc42(GTP) and Pak2 gene at 193763319 to 193859670 bp from pter ATP. Autophosphorylation of Thr402 in the activation contains 96352 bases and 34 exons. Pak2 gene at the loop is required for the kinase activity of Pak2. alternative location starts at 196466728 and ends at Pak2 can be activated in response to a lot of stresses. 196559518 bp from pter. The PAK2 gene in this Moderate stresses, like hyperosmolarity, ionizing location contains 20 exons. radiation, DNA-damaging agents and serum- deprivation, induce Pak2 activation in cells and lead to Protein cell cycle arrest at G2/M. Activated Pak2 inhibits translation by phosphorylation of various substrates. Description Pak2 has specific protein substrates, e.g. histone 4, Pak2 has an N-terminal regulatory domain and a C- myosin light chain (MLC), prolactin, c-Abl, eukaryote terminal catalytic domain. In the regulatory domain, translation initiation factor 3 (eIF3), eIF4B, eIF4G, and Pak2 have several conserved regions, including an Mnk1. Pak2 recognizes the consensus sequence autoinhibitory domain (AID), a p21-binding domain (K/RRXS). (PBD), dimerization domain, proline-rich regions, and Pak2 is the only member of the PAK family that is an acidic region. The schematic structure of Pak2 is directly activated by caspase 3. When Pak2 is cleaved shown in figure above. The catalytic domain of Pak is a and activated by caspase 3, Pak2 promotes the conserved bilobal structure in most of the protein morphological and biochemical changes of apoptosis. kinases. The pro-apoptosis protease, caspase 3 cleaves Pak2 Expression after Asp 212, and thus produces a p27 fragment containing primarily the regulatory domain, and a p34 Pak2 is 58.8 kDa (524 residues) and expressed fragment containing a small piece of the regulatory ubiquitously in mammalian cells. domain and the entire catalytic domain. Function Autophosphorylation results in a constitutively active PAK activation is through disruption of autoinhibition, p34 kinase domain.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 928 PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2) Hsu YH

The Linear schematic of Pak2. Functional domains, including proline rich regions (P), acidic region (A), p21-binding domain (PBD), Cdc42 and Rac interaction and binding sequence (CRIB) and autoinhibitory domain (AID) are designated. Autophosphorylation sites (*) and caspase 3 cleavage site (v) are marked. The regulatory domain is blue; the protein kinase domain is green; the overlapping region between PBD and AID is pink.

The nuclear import signal (245-251) is required for Rudel T, Bokoch GM. Membrane and morphological changes nuclear localization. Disruption of the region (197- in apoptotic cells regulated by caspase-mediated activation of PAK2. Science. 1997 Jun 6;276(5318):1571-4 246), containing nuclear export signal results in the nuclear localization of the Pak2 p34 fragment. Tuazon PT, Spanos WC, Gump EL, Monnig CA, Traugh JA. Determinants for substrate phosphorylation by p21-activated Homology protein kinase (gamma-PAK). Biochemistry. 1997 Dec 23;36(51):16059-64 Pak1, Pak2 and Pak3 are highly homologous. The primary sequence of human Pak2 is 72 % identical to Frost JA, Khokhlatchev A, Stippec S, White MA, Cobb MH. Differential effects of PAK1-activating mutations reveal activity- Pak1 and 71 % identical to Pak3. dependent and -independent effects on cytoskeletal regulation. J Biol Chem. 1998 Oct 23;273(43):28191-8 Mutations Walter BN, Huang Z, Jakobi R, Tuazon PT, Alnemri ES, Note Litwack G, Traugh JA. Cleavage and activation of p21- activated protein kinase gamma-PAK by CPP32 (caspase 3). None is reported. Effects of autophosphorylation on activity. J Biol Chem. 1998 Oct 30;273(44):28733-9 Implicated in Zhao ZS, Manser E, Chen XQ, Chong C, Leung T, Lim L. A conserved negative regulatory region in alphaPAK: inhibition of Tumors PAK kinases reveals their morphological roles downstream of Prognosis Cdc42 and Rac1. Mol Cell Biol. 1998 Apr;18(4):2153-63 Huang (2004) showed Pak2 is a negative regulator of Gatti A, Huang Z, Tuazon PT, Traugh JA. Multisite Myc and suggested Pak2 may be the product of a tumor autophosphorylation of p21-activated protein kinase gamma- PAK as a function of activation. J Biol Chem. 1999 Mar suppressor gene. Coniglio (2008) reported Pak2 19;274(12):8022-8 mediates tumor invasion in breast carcinoma cells. Tu H, Wigler M. Genetic evidence for Pak1 autoinhibition and Inhibition of RhoA in Pak2-depleted cells decreases its release by Cdc42. Mol Cell Biol. 1999 Jan;19(1):602-11 MLC phosphorylation and restores cell invasion. Also, the NF2 tumor suppressor Merlin is a substrate of Pak2. Roig J, Traugh JA. Cytostatic p21 G protein-activated protein kinase gamma-PAK. Vitam Horm. 2001;62:167-98 Wilkes (2009) showed that Erbin regulates the function of Merlin through Pak2 binding to Merlin. Kissil JL, Johnson KC, Eckman MS, Jacks T. Merlin phosphorylation by p21-activated kinase 2 and effects of Immunodeficiency phosphorylation on merlin localization. J Biol Chem. 2002 Mar 22;277(12):10394-9 Note Human immunodeficiency virus type 1 HIV-1. Jakobi R, McCarthy CC, Koeppel MA, Stringer DK. Caspase- activated PAK-2 is regulated by subcellular targeting and Prognosis proteasomal degradation. J Biol Chem. 2003 Oct Human immunodeficiency virus type 1 Nef associates 3;278(40):38675-85 with a active Pak2 independently of binding to Nck or Huang Z, Traugh JA, Bishop JM. Negative control of the Myc PIX. Nef recruits the GEF Vav1 to plasma membrane protein by the stress-responsive kinase Pak2. Mol Cell Biol. to associate with Pak2. 2004 Feb;24(4):1582-94 Orton KC, Ling J, Waskiewicz AJ, Cooper JA, Merrick WC, References Korneeva NL, Rhoads RE, Sonenberg N, Traugh JA. Phosphorylation of Mnk1 by caspase-activated Pak2/gamma- Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L. A brain PAK inhibits phosphorylation and interaction of eIF4G with serine/threonine protein kinase activated by Cdc42 and Rac1. Mnk. J Biol Chem. 2004 Sep 10;279(37):38649-57 Nature. 1994 Jan 6;367(6458):40-6 Ling J, Morley SJ, Traugh JA. Inhibition of cap-dependent Lee N, MacDonald H, Reinhard C, Halenbeck R, Roulston A, translation via phosphorylation of eIF4G by protein kinase Shi T, Williams LT. Activation of hPAK65 by caspase cleavage Pak2. EMBO J. 2005 Dec 7;24(23):4094-105 induces some of the morphological and biochemical changes Coniglio SJ, Zavarella S, Symons MH. Pak1 and Pak2 mediate of apoptosis. Proc Natl Acad Sci U S A. 1997 Dec tumor cell invasion through distinct signaling mechanisms. Mol 9;94(25):13642-7 Cell Biol. 2008 Jun;28(12):4162-72

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 929 PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2) Hsu YH

Hsu YH, Johnson DA, Traugh JA. Analysis of conformational Hsu YH, Traugh JA. Reciprocally coupled residues crucial for changes during activation of protein kinase Pak2 by amide protein kinase Pak2 activity calculated by statistical coupling hydrogen/deuterium exchange. J Biol Chem. 2008 Dec analysis. PLoS One. 2010 Mar 1;5(3):e9455 26;283(52):36397-405 This article should be referenced as such: Wilkes MC, Repellin CE, Hong M, Bracamonte M, Penheiter SG, Borg JP, Leof EB. Erbin and the NF2 tumor suppressor Hsu YH. PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2). Merlin cooperatively regulate cell-type-specific activation of Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):928-930. PAK2 by TGF-beta. Dev Cell. 2009 Mar;16(3):433-44

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Gene Section Mini Review

TGFBRAP1 (transforming growth factor, beta receptor associated protein 1) Jens U Wurthner Translational Pharmacology and Discovery Medicine, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, USA (JUW)

Published in Atlas Database: April 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/TGFBRAP1ID42542ch2q12.html DOI: 10.4267/2042/46066 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Protein Other names: TRAP-1; TRAP1 Description HGNC (Hugo): TGFBRAP1 A fragment of TGFBRAP1 was initially identified in a Location: 2q12.1 Yeast-2-Hybrid screen as a TGF-beta type I receptor interacting protein (Charng et al., 2002). Further work DNA/RNA by Wurthner et al. demonstrated binding of the full- length molecule exclusively to either TGF-beta Description receptor I and TGF-beta receptor II, or to Smad4, Encoded on the minus strand. 12 exons, exon number 1 suggesting TGFBRAP1 to be a Smad4 chaperone is not depicted in the diagram and appears to undergo (Wurthner et al., 2001). Furthermore, receptor activated differential splicing, according to recent NCBI- Smads were shown to compete for binding of TRAP1 AceView (accessed 17 Apr 2011). with Smad4, suggesting only a transient association between TRAP1 and Smad4. In addition, an interaction Transcription of TRAP1 with 5-lipoxgenase in a yeast two-hybrid Work by the Wurthner lab in 2003-2005 identified an system was described by a different group (Provost et 860 aa protein that could be matched with genomic al., 1999). Gene inactivation of TGFBRAP1 through sequences. Recently predicted proteins from mRNA conventional targeting leads to early developmental variants describe translation products of 896, 952, 161 arrest of murine embryos around day E 6.5 (Messler et and 30 aminino acids (NCBI AceView, accessed 17 al., 2010). April 2011).

Generated by BlastAnalyser in 2005 (unpublished). Contig: NT_022171.13 (gi: 29789878).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 931 TGFBRAP1 (transforming growth factor, beta receptor associated protein 1) Wurthner JU

CNH: Citron Homology Domain; CLH: Clathrin Homology Domain; VPS39: Vesicle Protein Sorting Protein 39 Domain.

Expression Provost P, Samuelsson B, Rådmark O. Interaction of 5- lipoxygenase with cellular proteins. Proc Natl Acad Sci U S A. Ubiquitous. 1999 Mar 2;96(5):1881-5 Localisation Wurthner JU, Frank DB, Felici A, Green HM, Cao Z, Schneider MD, McNally JG, Lechleider RJ, Roberts AB. Transforming Punctate pattern suggestive of endosomal localisation. growth factor-beta receptor-associated protein 1 is a Smad4 Function chaperone. J Biol Chem. 2001 Jun 1;276(22):19495-502 Chaperone for Smad4 in the TGF-beta signal Felici A, Wurthner JU, Parks WT, Giam LR, Reiss M, Karpova TS, McNally JG, Roberts AB. TLP, a novel modulator of TGF- transduction cascade (Wurthner et al., 2001). beta signaling, has opposite effects on Smad2- and Smad3- Endosomal trafficking (circumstantial evidence: dependent signaling. EMBO J. 2003 Sep 1;22(17):4465-77 domain structure and early embryonic lethality; Messler S, Kropp S, Episkopou V, Felici A, Würthner J, Lemke Messler et al., 2010). R, Jerabek-Willemsen M, Willecke R, Scheu S, Pfeffer K, Wurthner JU. The TGF-β signaling modulators Homology TRAP1/TGFBRAP1 and VPS39/Vam6/TLP are essential for hVPS39 (hVam6, hTrap-like-Protein). early embryonic development. Immunobiology. 2011 Mar;216(3):343-50

References This article should be referenced as such: Charng MJ, Zhang D, Kinnunen P, Schneider MD. A novel Wurthner JU. TGFBRAP1 (transforming growth factor, beta protein distinguishes between quiescent and activated forms of receptor associated protein 1). Atlas Genet Cytogenet Oncol the type I transforming growth factor beta receptor. J Biol Haematol. 2011; 15(11):931-932. Chem. 1998 Apr 17;273(16):9365-8

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Gene Section Review

AXIN1 (axin 1) Nives Pecina-Slaus, Tamara Nikuseva Martic, Tomislav Kokotovic Department of Biology, Laboratory for Neurooncology, Croatian Institute for Brain Research, Medical School University of Zagreb, Salata 12, Zagreb, Croatia (NPS, TN, TK)

Published in Atlas Database: May 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/AXIN1ID379ch16p13.html DOI: 10.4267/2042/46067 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

compared to variant 1 (NM 181050.2). According to Identity Ensembl there are six transcripts of AXIN1 of which Other names: AXIN; MGC52315 first two are well known isoforms a and b and the HGNC (Hugo): AXIN1 remaining 4 are still in research. Location: 16p13.3 Protein Note According to Entrez gene and Ensembl the isoform a Note starts at 337440 and ends at 402464 bp with the total Protein name: Axin 1, Axin, Axis inhibitor, Axis lenght of 65025 bp. The isoform b starts at 338122 and inhibitor protein 1. ends at 397025 with the total lenght of 58904 bp. Zeng Description et al. (1997) renamed the gene that was originally At least two isoforms of protein axin are expressed. termed Fu to Axin in order to avoid confusion with the Longer isoform has all eleven exons translated and unrelated Drosophila gene fused. consists of 862 aminoacids while shorter has 826 aminoacids translated from ten exons. Axin 1 protein DNA/RNA can be recognized primarily by two domains, the N- Description terminal RGS domain (regulators of G-protein signaling) and the C-terminal DIX domain (dishevelled Axin 1 consists of 11 exons (isoform a). Full gene and axin) (Luo et al., 2005; Shibata et al., 2007). RGS transcript product length is 3675 bp. Isoform b lacks an domain is needed for APC binding while DIX domain in-frame exon in the 3' coding region and is shorter for homodimerization and heterodimerization with sequence length of 3567 bp (Salahshor and (Ehebauer and Arias, 2009; Noutsou et al., 2011). Woodgett, 2005) (Figure 1). There is also a central region of the protein that binds Transcription GSK3beta and beta-catenin. Axin protein has nuclear There are two transcript variants. Variant 1 (encoding localization (NLS) and nuclear export (NES) sequences for isoform a) represents the longer transcript (NM as well. It is well known that axin is a scaffold protein 003502.3). Variant 2 (encoding for isoform b) is shorter that can shuttle between the cytoplasm and the nucleus.

Figure 1. Genomic structure of Axin 1. Axin 1 is composed of 10 exons and they encode isoform a, while in isoform b exon 8 is spliced out.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 933 AXIN1 (axin 1) Pecina-Slaus N, et al.

Nucleo-cytoplasmatic shuttling under normal Distribution of axin was reported previously by circumstances suggests existence of possible "salvage Anderson et al. (2002) in neoplastic colon. Altered pathway" that would be activated by axin translocation nuclear expression of axin seen in colon polyps and to the nucleus in order to reduce beta-catenin oncogenic carcinomas may be a consequence of the loss of full- activity by exporting nuclear beta-catenin and length APC and the advent of nuclear beta-catenin. degrading it in the cytoplasm (Wiechens et al., 2004). Axin can also undergo posttranslational modifications. Phosphorilation by casein kinase 1 (CK1) enhances binding of GSK3beta and AXIN1. For activation of JNK pathway axin needs to be SUMOylated (Kim et al., 2008) (Figure 2).

Figure 2. Two crystallized domains of the Axin 1 protein are shown: (A) RGS and (B) DIX. Expression Figure 3. Glioblastoma samples immunohistochemically Axin is expressed ubiquitously. stained for protein expression of axin. (A) Cytoplasmic localization of axin and (B) nuclear localization of axin. Localisation Function Axin is predominantlly expressed in the cytoplasm, but Tumor suppressor protein Axin 1 is an inhibitor of the periplasmic and nuclear localization are also observed Wnt signaling pathway (Polakis, 2000; Salahshor and depending on the stimulation of the cells (Cong and Woodgett, 2005). As a scaffold protein, its main role is Varmus, 2004; Luo and Lin, 2004). In nonstimulated binding multiple members of Wnt signaling and cells, axin colocalizes with Smad3. The subcellular formation of the beta-catenin destruction complex. It location of axin is not well defined in the literature. It down-regulates beta-catenin, wnt pathway's main has been reported that physiological concentrations of effector signaling molecule, by facilitating its axin is low in Xenopus egg cells. It has also been phosphorylation by GSK3-beta (Hart et al., 1998). It shown that it is located in cytoplasmic puncta in living binds directly to APC (adenomatous polyposis coli), mammalian cells. Wang et al. (2009) report that axin 1 beta-catenin, GSK3-beta and dishevelled forming a so is highly co-localized with beta-catenin in the called "beta-catenin destruction complex" in which cytoplasm of human cumulus cells and that this phosphorylated beta-catenin is targeted for quick localization denotes intact wnt signaling. Pecina-Slaus ubiquitinilation and degradation in the 26S proteosome et al. (2011) showed the subcellular location of axin in (Yamamoto et al., 1999; Logan and Nusse, 2004). In normal brain white matter and glioblastoma tissue. The response to wnt signaling, or under the circumstances majority of glioblastomas (69.04%) had axin localized of mutated axin or APC, beta-catenin is stabilized, in the cytoplasm. Nevertheless, 9.5% of glioblastomas accumulates in the cytoplasm and enters the nucleus, samples had axin localized in the nucleus (Figure 3).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 934 AXIN1 (axin 1) Pecina-Slaus N, et al.

where it finds a partner, a member of the DNA binding deletion, and a 12 bp insertion. Loss of heterozygosity protein family LEF/TCF. Together they stimulate the at the AXIN1 locus was present in four of five expression of target genes including c-myc, c-jun, fra-1 informative HCCs with AXIN1 mutations, suggesting a and cyclin D1. In developement Axin controls tumor suppressor function of this gene. Park et al. dorsoventral polarity axis formation (Zeng et al., 1997; (2005) showed that mutations of AXIN 1 are late Wodarz and Nusse, 1998) by two independent events in hepatocellular carcinogenesis. mechanisms: downregulation of beta-catenin, but also Medulloblastoma by activation of Wnt-independent JNK signaling activation. Axin has a role in determining cell's fate Note upon damage, haematopoetic stem cells differentiation To find out if Axin is also involved in the pathogenesis (Reya et al., 2003) and transforming growth factor beta of sporadic medulloblastomas, Dahmen et al. (2001) signaling (Furuhashi et al., 2001). Reports indicate that analyzed 86 cases and 11 medulloblastoma cell lines beta-catenin and axin regulate critical developmental for mutations in the AXIN1 gene. Using single-strand processes of normal CNS development (Pecina-Slaus, conformation polymorphism analysis, screening for 2010). large deletions by reverse transcription-PCR, and Axin interacts with a number of proteins including: sequencing analysis, a single somatic point mutation in APC, Axam, Axin, beta-catenin, Ccd1, CKI, DAXX, exon 1 (Pro255Ser) and seven large deletions (12%) of DCAP, Diversin, Dvl, gamma-tubulin, GSK3beta, AXIN1 were detected. Baeza et al. (2003) screened 39 HIPK2, I-mfa, LRP5/LRP6, MDFIC, MEKK1, sporadic cerebellar medulloblastomas for alterations in MEKK4, P53, PIAS, Pirh2, PP2A, Rnf11, Zbed3, the AXIN1 gene. The authors found missense AXIN1 Tip60, Smad3, Smad6, and Smad7 (Cliffe et al., 2003; mutations in two tumours, CCC-->TCC at codon 255 Chen et al., 2009; Fumoto et al., 2009; Li et al., 2009; (exon 1, Pro-->Ser) and TCT-->TGT at codon 263 Choi et al., 2010; Kim and Jho, 2010). (exon 1, Ser-->Cys). Furthermore, the A allele at the G/A polymorphism at nucleotide 16 in intron 4 was Homology significantly over-represented in medulloblastomas (39 Homologs are found in: Pan troglodytes, Canis lupus cases; G 0.76 vs-A 0.24) compared to healthy familiaris, Bos taurus, Mus musculus, Rattus individuals (86 cases; G 0.91 vs A 0.09; P=0.0027). norvegicus, Gallus gallus, Danio rerio. Yokota et al. (2002) showed another AXIN1 mutation in exon 3, corresponding to GSK-3beta binding site. Mutations Colorectal carcinoma Note Note According to HGMD there are 3 missense mutations Hart et al. (1998) report on overexpression of Axin1 in reported for AXIN 1 in colorectal carcinoma. Nikuseva connection to the downregulation of wild-type beta- Martic et al. (2010) identified gross deletions (Loss of catenin in colon cancer cells. In addition, Axin1 Heterozygosity) of AXIN 1 in 6.3% of glioblastomas, dramatically facilitated the phosphorylation of APC in one neuroepithelial dysembrioplastic tumor and in and beta-catenin by GSK3 beta in vitro. Another group one medulloblastoma. In a primary hepatocellular (Jin et al., 2003) analyzed 54 colorectal cancer tissues carcinoma 13 somatic events were reported by OMIM, for mutations in AXIN1 gene. They found 3 silent a 33-bp deletion in exon 3 of the AXIN1 gene, and 12 mutations, 6 missense point mutations in different missense mutations. OMIM also reports on functionally important regions. The missense mutation hypermethylation of AXIN 1 promotor region in caudal rate was hence 11%, suggesting that Axin 1 deficiency duplication anomaly. may contribute to the onset of colorectal tumorigenesis. Segditsas and Tomlinson (2006) report on mutations in Implicated in AXIN1 in microsatellite-unstable colon cancers. Three AXIN1 missense variants P312T, R398H, and L445M Hepatocellular carcinoma were detected in 1 of 124 patients with multiple Note colorectal adenomas. Three other missense mutations, In a primary hepatocellular carcinoma (HCC), Satoh et D545E, G700S, and R891Q, were found. The overall al. (2000) found a 33-bp deletion in exon 3 of the frequency of the rare variants was significantly higher AXIN1 gene, involving 2 glycogen synthase kinase-3- in the patients as compared with the controls beta phosphorylation sites. In addition to this deletion (Fearnhead et al., 2004). they found 12 missense mutations, of which 9 occurred Brain tumors in codons encoding serine or threonine residues. They confirmed that all 13 mutations found in primary HCCs Note occurred as somatic events. Taniguchi et al. (2002) A sample of 72 neuroepithelial brain tumors was found investigated for AXIN-1 gene changes by Nikuseva AXIN1 mutations in seven (9.6%) HCCs. The AXIN1 Martic et al. (2010). Polymorphic marker for AXIN-1, mutations included seven missense mutations, a 1 bp showed loss of heterozygosity in 11.1% of tumors.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 935 AXIN1 (axin 1) Pecina-Slaus N, et al.

Down regulation of axin expression and up regulation with the caudal duplication anomalies. Oates et al. of beta-catenin were detected. Axin was observed in (2006) examined methylation at the promoter region of the cytoplasm in 68.8% of samples, in 28.1% in both the AXIN1 gene in monozygotic twins. The promoter the cytoplasm and nucleus and 3.1% had no expression. region of the AXIN1 gene was significantly more Comparison of mean values of relative increase of axin methylated in the twin with the caudal duplication than and beta-catenin showed that they were significantly in the unaffected twin. reversely proportional (P=0.014) in a set of neuroepithelial brain tumors. Pecina-Slaus et al. (2011) References also explored axin's existence at the subcellular level in Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL 3rd, glioblastomas and showed that the highest relative Lee JJ, Tilghman SM, Gumbiner BM, Costantini F. The mouse quantity of axin was measured when the protein was in Fused locus encodes Axin, an inhibitor of the Wnt signaling the nucleus and the lowest relative quantity of axin pathway that regulates embryonic axis formation. Cell. 1997 when the protein was localized in the cytoplasm. Jul 11;90(1):181-92 Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P. Ovarian endometroid adenocarcinomas Downregulation of beta-catenin by human Axin and its Note association with the APC tumor suppressor, beta-catenin and Wu et al. (2001) report on a nonsense mutation in one GSK3 beta. Curr Biol. 1998 May 7;8(10):573-81 ovarian endometroid adenocarcinoma (OEA). They Wodarz A, Nusse R. Mechanisms of Wnt signaling in also found another missense AXIN1 sequence development. Annu Rev Cell Dev Biol. 1998;14:59-88 alteration in OEA-derived cell lines. Yamamoto H, Kishida S, Kishida M, Ikeda S, Takada S, Kikuchi A. Phosphorylation of axin, a Wnt signal negative Lung cancer regulator, by glycogen synthase kinase-3beta regulates its Note stability. J Biol Chem. 1999 Apr 16;274(16):10681-4 In 105 lung SCC and adenocarcinoma tissue samples, Polakis P. Wnt signaling and cancer. Genes Dev. 2000 Aug the cytoplasmic expression of Axin was significantly 1;14(15):1837-51 lower than in normal lung tissues. Western blot Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, et al. AXIN1 analysis also demonstrated that the relative expression mutations in hepatocellular carcinomas, and growth quantity of Axin was significantly reduced in lung suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 2000 Mar;24(3):245-50 cancer tissues compared with normal lung tissues. Nuclear expression of Axin was observed in 21 cases Dahmen RP, Koch A, Denkhaus D, Tonn JC, Sörensen N, (20%) of lung cancers (Xu et al., 2011). Berthold F, Behrens J, Birchmeier W, Wiestler OD, Pietsch T. Deletions of AXIN1, a component of the WNT/wingless Oesophageal squamous cell carcinoma pathway, in sporadic medulloblastomas. Cancer Res. 2001 Oct 1;61(19):7039-43 Note Furuhashi M, Yagi K, Yamamoto H, Furukawa Y, Shimada S, Nakajima et al. (2003) found reduced expression of Nakamura Y, Kikuchi A, Miyazono K, Kato M. Axin facilitates Axin1 in oesophageal squamous cell carcinoma. Smad3 activation in the transforming growth factor beta Several mutations have also been reported in signaling pathway. Mol Cell Biol. 2001 Aug;21(15):5132-41 oesophageal squamous cell carcinoma. Wu R, Zhai Y, Fearon ER, Cho KR. Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid Cervical cancer adenocarcinomas. Cancer Res. 2001 Nov 15;61(22):8247-55 Note Anderson CB, Neufeld KL, White RL. Subcellular distribution of Su et al. (2003) examined AXIN1 in cervical cancer. Wnt pathway proteins in normal and neoplastic colon. Proc Among the 30 tested cervical cancers mutation analysis Natl Acad Sci U S A. 2002 Jun 25;99(13):8683-8 of AXIN1 revealed that one specimen had a Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy heterozygous mutation at codon 740. Six LM, Nagorney DM, Burgart LJ, Roche PC, Smith DI, Ross JA, polymorphisms were also found. Liu W. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 Immunohistochemistry showed no relationship between in hepatocellular carcinomas and hepatoblastomas. Oncogene. 2002 Jul 18;21(31):4863-71 the protein expression patterns and mutation of AXIN1. Yokota N, Nishizawa S, Ohta S, Date H, Sugimura H, Namba Prostate cancer H, Maekawa M. Role of Wnt pathway in medulloblastoma Note oncogenesis. Int J Cancer. 2002 Sep 10;101(2):198-201 Yardy et al. (2009) reported on AXIN1 mutations in Baeza N, Masuoka J, Kleihues P, Ohgaki H. AXIN1 mutations advanced prostate cancer. They found 7 mutations in but not deletions in cerebellar medulloblastomas. Oncogene. 2003 Jan 30;22(4):632-6 prostate cancer cases and 4 polymorphisms in prostate cancer cell lines. Cliffe A, Hamada F, Bienz M. A role of Dishevelled in relocating Axin to the plasma membrane during wingless Caudal duplication anomaly signaling. Curr Biol. 2003 May 27;13(11):960-6 Note Jin LH, Shao QJ, Luo W, Ye ZY, Li Q, Lin SC. Detection of Hypermethylation of the AXIN1 promoter is associated point mutations of the Axin1 gene in colorectal cancers. Int J Cancer. 2003 Dec 10;107(5):696-9

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 936 AXIN1 (axin 1) Pecina-Slaus N, et al.

Nakajima M, Fukuchi M, Miyazaki T, Masuda N, Kato H, Kim MJ, Chia IV, Costantini F. SUMOylation target sites at the Kuwano H. Reduced expression of Axin correlates with tumour C terminus protect Axin from ubiquitination and confer protein progression of oesophageal squamous cell carcinoma. Br J stability. FASEB J. 2008 Nov;22(11):3785-94 Cancer. 2003 Jun 2;88(11):1734-9 Chen T, Li M, Ding Y, Zhang LS, Xi Y, Pan WJ, Tao DL, Wang Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, JY, Li L. Identification of zinc-finger BED domain-containing 3 Hintz L, Nusse R, Weissman IL. A role for Wnt signalling in (Zbed3) as a novel Axin-interacting protein that activates self-renewal of haematopoietic stem cells. Nature. 2003 May Wnt/beta-catenin signaling. J Biol Chem. 2009 Mar 22;423(6938):409-14 13;284(11):6683-9 Su TH, Chang JG, Yeh KT, Lin TH, Lee TP, Chen JC, Lin CC. Ehebauer MT, Arias AM. The structural and functional Mutation analysis of CTNNB1 (beta-catenin) and AXIN1, the determinants of the Axin and Dishevelled DIX domains. BMC components of Wnt pathway, in cervical carcinomas. Oncol Struct Biol. 2009 Nov 12;9:70 Rep. 2003 Sep-Oct;10(5):1195-200 Fumoto K, Kadono M, Izumi N, Kikuchi A. Axin localizes to the Cong F, Varmus H. Nuclear-cytoplasmic shuttling of Axin centrosome and is involved in microtubule nucleation. EMBO regulates subcellular localization of beta-catenin. Proc Natl Rep. 2009 Jun;10(6):606-13 Acad Sci U S A. 2004 Mar 2;101(9):2882-7 Li Q, Lin S, Wang X, Lian G, Lu Z, Guo H, Ruan K, Wang Y, Fearnhead NS, Wilding JL, Winney B, Tonks S, Bartlett S, Ye Z, Han J, Lin SC. Axin determines cell fate by controlling Bicknell DC, Tomlinson IP, Mortensen NJ, Bodmer WF. the p53 activation threshold after DNA damage. Nat Cell Biol. Multiple rare variants in different genes account for 2009 Sep;11(9):1128-34 multifactorial inherited susceptibility to colorectal adenomas. Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15992-7 Wang HX, Tekpetey FR, Kidder GM. Identification of WNT/beta-CATENIN signaling pathway components in human Logan CY, Nusse R. The Wnt signaling pathway in cumulus cells. Mol Hum Reprod. 2009 Jan;15(1):11-7 development and disease. Annu Rev Cell Dev Biol. 2004;20:781-810 Yardy GW, Bicknell DC, Wilding JL, Bartlett S, Liu Y, Winney B, Turner GD, Brewster SF, Bodmer WF. Mutations in the Luo W, Lin SC. Axin: a master scaffold for multiple signaling AXIN1 gene in advanced prostate cancer. Eur Urol. 2009 pathways. Neurosignals. 2004 May-Jun;13(3):99-113 Sep;56(3):486-94 Wiechens N, Heinle K, Englmeier L, Schohl A, Fagotto F. Choi SH, Choi KM, Ahn HJ. Coexpression and protein-protein Nucleo-cytoplasmic shuttling of Axin, a negative regulator of complexing of DIX domains of human Dvl1 and Axin1 protein. the Wnt-beta-catenin Pathway. J Biol Chem. 2004 Feb BMB Rep. 2010 Sep;43(9):609-13 13;279(7):5263-7 Kim S, Jho EH. The protein stability of Axin, a negative Luo W, Zou H, Jin L, Lin S, Li Q, Ye Z, Rui H, Lin SC. Axin regulator of Wnt signaling, is regulated by Smad ubiquitination contains three separable domains that confer intramolecular, regulatory factor 2 (Smurf2). J Biol Chem. 2010 Nov homodimeric, and heterodimeric interactions involved in 19;285(47):36420-6 distinct functions. J Biol Chem. 2005 Feb 11;280(6):5054-60 Nikuseva Marti ć T, Pe ćina-Slaus N, Kusec V, Kokotovi ć T, Park JY, Park WS, Nam SW, Kim SY, Lee SH, Yoo NJ, Lee Musinovi ć H, Tomas D, Zeljko M. Changes of AXIN-1 and JY, Park CK. Mutations of beta-catenin and AXIN I genes are a beta-catenin in neuroepithelial brain tumors. Pathol Oncol Res. late event in human hepatocellular carcinogenesis. Liver Int. 2010 Mar;16(1):75-9 2005 Feb;25(1):70-6 Pe ćina-Slaus N. Wnt signal transduction pathway and Salahshor S, Woodgett JR. The links between axin and apoptosis: a review. Cancer Cell Int. 2010 Jun 30;10:22 carcinogenesis. J Clin Pathol. 2005 Mar;58(3):225-36 Noutsou M, Duarte AM, Anvarian Z, Didenko T, Minde DP, Oates NA, van Vliet J, Duffy DL, Kroes HY, Martin NG, Kuper I, de Ridder I, Oikonomou C, Friedler A, Boelens R, Boomsma DI, Campbell M, Coulthard MG, Whitelaw E, Chong Rüdiger SG, Maurice MM. Critical scaffolding regions of the S. Increased DNA methylation at the AXIN1 gene in a tumor suppressor Axin1 are natively unfolded. J Mol Biol. 2011 monozygotic twin from a pair discordant for a caudal Jan 21;405(3):773-86 duplication anomaly. Am J Hum Genet. 2006 Jul;79(1):155-62 Pe ćina-Slaus N, Marti ć TN, Kokotovi ć T, Kusec V, Tomas D, Segditsas S, Tomlinson I. Colorectal cancer and genetic Hras ćan R. AXIN-1 protein expression and localization in alterations in the Wnt pathway. Oncogene. 2006 Dec glioblastoma. Coll Antropol. 2011 Jan;35 Suppl 1:101-6 4;25(57):7531-7 Xu HT, Yang LH, Li QC, Liu SL, Liu D, Xie XM, Wang EH. Shibata N, Tomimoto Y, Hanamura T, Yamamoto R, Ueda M, Disabled-2 and Axin are concurrently colocalized and Ueda Y, Mizuno N, Ogata H, Komori H, Shomura Y, Kataoka underexpressed in lung cancers. Hum Pathol. 2011 Apr 13; M, Shimizu S, Kondo J, Yamamoto H, Kikuchi A, Higuchi Y. Crystallization and preliminary X-ray crystallographic studies of This article should be referenced as such: the axin DIX domain. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2007 Jun 1;63(Pt 6):529-31 Pecina-Slaus N, Nikuseva Martic T, Kokotovic T. AXIN1 (axin 1). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):933- 937.

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Gene Section Mini Review

CCR2 (chemokine (C -C motif) receptor 2) Jérôme Moreaux Institut de Recherche en Biotherapie, INSERM U847, Hopital Saint-Eloi, CHU de Montpellier, 80 av Augustin Fliche, 34295 Montpellier Cedex 5, France (JM)

Published in Atlas Database: May 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/CCR2ID964ch3p21.html DOI: 10.4267/2042/46068 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

- C-C chemokine receptor type 2 isoform A. Identity CCDS43078.1 Other names: CC-CKR-2; CCR2A; CCR2B; CD192; - C-C chemokine receptor type 2 isoform B. CKR2; CKR2A; CKR2B; CMKBR2; FLJ78302; MCP- CCDS46813.1 1-R; MGC103828; MGC111760; MGC168006 Transcription HGNC (Hugo): CCR2 Homo sapiens chemokine (C-C motif) receptor 2 Location: 3p21.31 (CCR2), transcript variant A, mRNA: 2689 bp. Homo sapiens chemokine (C-C motif) receptor 2 DNA/RNA (CCR2), transcript variant B, mRNA: 2335 bp. Note Pseudogene CCR2 is a member of the beta chemokine receptor No pseudogenes have been reported for CCR2. family. CCR2 is a seven transmembrane protein similar to G protein-coupled receptors. This gene encodes two Protein isoforms of a receptor for monocyte chemoattractant protein-1, a chemokine which specifically mediates Note monocyte chemotaxis. Monocyte chemoattractant Chemokine receptors are cytokine receptors found on protein-1 is involved in monocyte infiltration in the surface of cells, which interact with a type of inflammatory diseases such as rheumatoid arthritis as cytokine called a chemokine. They have a 7 well as in the inflammatory response against tumors. transmembrane structure and couple to G-protein for The receptors encoded by this gene mediate agonist- signal transduction within a cell, making them dependent calcium mobilization and inhibition of members of a large protein family of G protein-coupled adenylyl cyclase. This gene is located in the chemokine receptors. Following interaction with their specific receptor gene cluster region including CCR1, CCRL2, chemokine ligands, chemokine receptors trigger a flux 2+ CCR3, CCR5 and CCXCR1 on chromosome 3p. in intracellular calcium (Ca ) ions (calcium signaling). This causes cell responses, including the onset of a Description process known as chemotaxis that traffics the cell to a Size: 7195 bases. desired location within the organism. 2 isoforms:

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 938 CCR2 (chemokine (C-C motif) receptor 2) Moreaux J

Structure of CCR2. The typical serpentine structure is depicted with three extracellular (top) and three intracellular (bottom) loops and seven transmembrane domains.

Chemokine receptors share many common structural Localisation features; they are composed of about 350 amino acids Cell membrane; multi-pass membrane protein. that are divided into a short and acidic N-terminal end, seven helical transmembrane domains with three Function intracellular and three extracellular hydrophilic loops, Receptor for the MCP-1/CCL2, MCP-3/CCL7 and and an intracellular C-terminus containing serine and MCP-4/CCL13 chemokines. Transduces a signal by threonine residues that act as phosphorylation sites increasing the intracellular calcium ions level. during receptor regulation. The first two extracellular Alternative coreceptor with CD4 for HIV-1 infection. loops of chemokine receptors are linked together by disulfide bonding between two conserved cysteine Homology residues. The N-terminal end of a chemokine receptor CCR2 proteins contains amino acid sequence binds to chemokine(s) and is important for ligand homology to other C-C chemokines. CCR1 (56%), specificity. G-proteins couple to the C-terminal end, CCR5 (71%), CCR3 (78%), CCR4 (75%). which is important for receptor signaling following ligand binding. Implicated in Description Multiple myeloma 374 amino acids; 41915 Da. Prognosis Expression In a cohort of 80 patients with Multiple Myeloma Peripheral blood monocytes, activated T cells, B cells (MM), patients with active disease showed significant and immature dendritic cells. lower expression of CCR1, CCR2 and CXCR4 than patients with non-active disease.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 939 CCR2 (chemokine (C-C motif) receptor 2) Moreaux J

Oncogenesis marrow endothelial cells induces PC-3 cell line CCR1 and CCR2 are overexpressed in myeloma cells transendothelial cell migration via activation of the compared to normal B cells. Osteoclasts express genes small GTPase Rac. In a cell co-culture system, prostate coding for CCR2 chemokines specifically (CCL2, cancer cell-conditioned medium induces CCL2 CCL7, CCL8, and CCL13) and high CCR2 gene overexpression in endothelial cells and osteoblasts. In expression in myeloma cells is associated with osteoblasts, this secretion is mediated in part by increased bone lesions in MM patients. CCR2 is parathyroid hormone-related protein. significantly overexpressed in MM cells compared to normal bone marrow plasma cells. Osteoclasts can In mouse model, neutralizing antibody against CCL2 directly recruit MMC by CCR2 chemokines inhibits prostate cancer PC-3 and VCaP growth in production, promote MMC survival, growth, and drug bone. Same results were obtained with CCL2 resistance by producing various growth factors. MMC knockdown. CCL2 induces surviving expression in will promote osteoclast progenitor recruitment and prostate cancer cells and protect them from autophagic differentiation producing CCL3, MIP-1beta, and death. CXCL12 chemokines, IGF-1, and increasing RANKL Breast cancer production by stromal cells. Osteoclasts are the main cells in the BM environment that produce various Prognosis CCR2 chemokines enabling malignant plasma cells Overexpression of the chemokine CCL2 is frequently attraction. associated with advanced tumor stage and metastatic relapse in breast cancer. Neuroblastoma Oncogenesis Oncogenesis Overexpression of CCL2 promotes breast cancer 98 untreated primary neuroblastomas from patients metastasis to both lung and bone in mice. Blocking with metastatic disease were analyzed for tumor- CCL2 with a neutralizing antibody reduced lung and infiltrating iNKTs (Valpha24-Jalpha18-invariant bone metastases. The enhancement of lung metastases natural killer T cells) using RT-PCR and by CCL2 was associated with increased macrophage immunofluorescent microscopy. 53% of tumors infiltration. In bone, it was associated with osteoclast contained iNKTs. CCR2 is more frequently expressed differentiation. CCL2 produced by breast tumor cells by iNKT compared to T cells and natural killer cells activates CCR2 positive stromal cells of monocytic from blood. iNKTs migrate toward neuroblastoma cells origin (including macrophages and preosteoclasts) in a CCL2-dependent manner, preferentially infiltrating leading to metastases in lung and bone. MYCN nonamplified proto-oncogene tumors that express CCL2. Esophageal carcinoma Melanoma Oncogenesis CCL2 is expressed by tumor cells of esophageal Oncogenesis squamous cell carcinoma. CCL2 produced by tumor MCP-1 may play a role in tumor angiogenesis and cell and CCR2 expressed on vascular endothelial cells early tumor growth of human malignant melanoma by may participate in esophageal carcinoma tumor inducing VEGF and inflammatory cytokines angiogenesis. production (IL-1alpha and TNFalpha by the tumor- associated macrophages (TAM) and Gastric cancer autocrine/paracrine effects on melanoma cells in a Oncogenesis mouse model. CCL2 produced by human gastric carcinoma cells is Prostate cancer involved in angiogenesis via macrophage recruitment and activation via CCR2. CCL2 produced by gastric Prognosis carcinoma cells induces tumor growth in ectopic The pleiotropic roles of CCL2 in the development of xenografts and increased tumorigenicity and induced prostate cancer are mediated through its receptor, lymph node metastases and ascites in orthotopic CCR2. An association between prostate cancer xenografts. progression and CCR2 expression was demonstrated on tissue microarray specimens of patients. CCR2 mRNA References and protein were significantly overexpressed within prostate cancer metastatic tissues compared to localized De Vos J, Couderc G, Tarte K, Jourdan M, Requirand G, Delteil MC, Rossi JF, Mechti N, Klein B. Identifying intercellular prostate cancer and benign prostate tissue. CCR2 signaling genes expressed in malignant plasma cells by using overexpression was also associated with higher complementary DNA arrays. Blood. 2001 Aug 1;98(3):771-80 Gleason score and higher clinical pathologic stages. Ohta M, Kitadai Y, Tanaka S, Yoshihara M, Yasui W, Mukaida Oncogenesis N, Haruma K, Chayama K. Monocyte chemoattractant protein- CCL2 support prostate cancer cell survival via 1 expression correlates with macrophage infiltration and tumor vascularity in human gastric carcinomas. Int J Oncol. 2003 PI3K/AKT in vitro. CCL2 derived from human bone Apr;22(4):773-8

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 940 CCR2 (chemokine (C-C motif) receptor 2) Moreaux J

Koide N, Nishio A, Sato T, Sugiyama A, Miyagawa S. and growth of malignant melanoma in mice. Biochem Biophys Significance of macrophage chemoattractant protein-1 Res Commun. 2008 Jan 11;365(2):279-84 expression and macrophage infiltration in squamous cell carcinoma of the esophagus. Am J Gastroenterol. 2004 Soria G, Ben-Baruch A. The inflammatory chemokines CCL2 Sep;99(9):1667-74 and CCL5 in breast cancer. Cancer Lett. 2008 Aug 28;267(2):271-85 Metelitsa LS, Wu HW, Wang H, Yang Y, Warsi Z, Asgharzadeh S, Groshen S, Wilson SB, Seeger RC. Natural killer T cells Lu X, Kang Y. Chemokine (C-C motif) ligand 2 engages infiltrate neuroblastomas expressing the chemokine CCL2. J CCR2+ stromal cells of monocytic origin to promote breast Exp Med. 2004 May 3;199(9):1213-21 cancer metastasis to lung and bone. J Biol Chem. 2009 Oct 16;284(42):29087-96 Kuroda T, Kitadai Y, Tanaka S, Yang X, Mukaida N, Yoshihara M, Chayama K. Monocyte chemoattractant protein-1 Zhang J, Lu Y, Pienta KJ. Multiple roles of chemokine (C-C transfection induces angiogenesis and tumorigenesis of gastric motif) ligand 2 in promoting prostate cancer growth. J Natl carcinoma in nude mice via macrophage recruitment. Clin Cancer Inst. 2010 Apr 21;102(8):522-8 Cancer Res. 2005 Nov 1;11(21):7629-36 Zhang J, Patel L, Pienta KJ. CC chemokine ligand 2 (CCL2) Vande Broek I, Leleu X, Schots R, Facon T, Vanderkerken K, promotes prostate cancer tumorigenesis and metastasis. Van Camp B, Van Riet I. Clinical significance of chemokine Cytokine Growth Factor Rev. 2010 Feb;21(1):41-8 receptor (CCR1, CCR2 and CXCR4) expression in human Moreaux J, Hose D, Kassambara A, Reme T, Moine P, myeloma cells: the association with disease activity and Requirand G, Goldschmidt H, Klein B. Osteoclast-gene survival. Haematologica. 2006 Feb;91(2):200-6 expression profiling reveals osteoclast-derived CCR2 Chavey C, Bibeau F, Gourgou-Bourgade S, Burlinchon S, chemokines promoting myeloma cell migration. Blood. 2011 Boissière F, Laune D, Roques S, Lazennec G. Oestrogen Jan 27;117(4):1280-90 receptor negative breast cancers exhibit high cytokine content. Breast Cancer Res. 2007;9(1):R15 This article should be referenced as such: Koga M, Kai H, Egami K, Murohara T, Ikeda A, Yasuoka S, Moreaux J. CCR2 (chemokine (C-C motif) receptor 2). Atlas Egashira K, Matsuishi T, Kai M, Kataoka Y, Kuwano M, Genet Cytogenet Oncol Haematol. 2011; 15(11):938-941. Imaizumi T. Mutant MCP-1 therapy inhibits tumor angiogenesis

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 941 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase)) Dimitra Florou, Andreas Scorilas, Dido Vassilacopoulou, Emmanuel G Fragoulis Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens 15701, Panepistimiopolis, Athens, Greece (DF, AS, DV, EGF)

Published in Atlas Database: May 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/DDCID50590ch7p12.html DOI: 10.4267/2042/46069 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

epidermal growth factor (EGF) gene (Craig et al., Identity 1992). Other names: AADC Transcription HGNC (Hugo): DDC Alternative splicing events are responsible for the Location: 7p12.1 production of two distinct DDC mRNAs, termed neural Local order: Centromere to telomere. and non-neural, which differ in their 5' untranslated region (UTR). The neural-type transcript includes exon DNA/RNA N1 (83 bps) that is located 17.8 kbs upstream of exon two. The non-neural type DDC mRNA bears exon L 1 Note (200 bps), which is located 4.2 kbs upstream to the The complete nucleotide structure of the human DDC location of exon N 1. The second exon contains the gene has been determined from tissues of neural and translation start site and is located 22 kbs downstream non-neural origin (Sumi-Ichinose et al., 1992; Ichinose from the non-neural (L 1) exon (Ichinose et al., 1992). et al., 1992). The full DDC cDNA sequence has been The transcription of the gene starts at position -111 cloned from human cells, such as pheochromocytoma (Sumi-Ichinose et al., 1992). (Ichinose et al., 1989), liver (Ichinose et al., 1992), It has been reported that the two alternative DDC hepatoma cells (Scherer et al., 1992), placenta (Siaterli transcripts share identical coding regions and that their et al., 2003), peripheral leukocytes (Kokkinou et al., production is a result of alternative splicing and 2009b), as well as from several human cell lines, such alternative promoter usage (Ichinose et al., 1992; Sumi- as, U937 macrophage cells (Kokkinou et al., 2009a), Ichinose et al., 1995). Neural and non-neural promoters SH-SY5Y, HTB-14 and HeLa cells (Chalatsa et al., have been identified 5' to the flanking region of the 2011). respective exon 1 (Le Van Thai et al., 1993; Sumi- Description Ichinose et al., 1995; Chatelin et al., 2001; Dugast- Darzacq et al., 2004). The generation of the two The human DDC gene exists as a single-copy in the alternative DDC mRNAs is not a mutually exclusive haploid genome. It is composed of 15 exons and 14 and tissue-specific event as previously thought (Siaterli introns, spanning for more than 85 kbs (Sumi-Ichinose et al., 2003; Vassilacopoulou et al., 2004; Kokkinou et et al., 1992). The size of the exons was found to range al., 2009a; Kokkinou et al., 2009b; Chalatsa et al., from 20 to 406 bps (Sumi-Ichinose et al., 1992), 2011).An alternative splicing event has been described whereas the size of the introns ranged from 927 to within the coding region of DDC mRNA, leading to the 24077 bps (Sumi-Ichinose et al., 1992; Yu et al., 2006). formation of a shorter transcript lacking exon 3 The DDC gene is located in close proximity to the (O'Malley et al., 1995; Chang et al., 1996).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 942 DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase)) Florou D, et al.

Table 1. Expression of DDC mRNA transcripts in human tissues, cells and cancer cell lines.

It must be noted that the above authors did not specify Description the nature, neural or non-neural, of this shorter transcript. Recent evidence have revealed the neural The DDC enzyme (EC 4.1.1.28) was initially purified nature of this alternative transcript in humans and characterized from pig kidney (Christenson et al., (Kokkinou et al., 2009a; Kokkinou et al., 2009b; 1970) as well as from the insects Calliphora vicina Chalatsa et al., 2011). (Fragoulis and Sekeris, 1975) and Ceratitis capitata A novel DDC mRNA coding region splice-variant, (Mappouras and Fragoulis, 1988; Bossinakou and resulting in the formation of a truncated DDC mRNA Fragoulis, 1996). DDC is a homodimer of 100-110 has been also identified. This human DDC mRNA (1.8 kDa, with a subunit molecular mass of 50-55 kDa kbs), termed as Alt-DDC, lacks exons 10-15 of the full- (Voltattorni et al., 1979; Mappouras et al., 1990; length transcript, but includes an alternative exon 10 Bossinakou and Fragoulis, 1996). The full-length (Vassilacopoulou et al., 2004). The Alt-DDC exon 10 protein molecule consists of 480 amino acids (Ichinose (358 bps) was found within intron 9 of the DDC gene. et al., 1989). DDC is a pyridoxal-5-phosphate (PLP)- Although Alt-DDC mRNA was detected in human dependent enzyme possessing a single binding-site for placenta, high expression levels of this alternative PLP per subunit (Voltattorni et al., 1982; Ichinose et transcript were found in human kidney al., 1989; Burkhard et al., 2001). (Vassilacopoulou et al., 2004). Expression of the DDC gene, in humans, results in the The notion that transcription of the human DDC gene production of additional protein isoforms (O'Malley et leads to the production of multiple mRNA isoforms, al., 1995; Chang et al., 1996; Vassilacopoulou et al., which are expressed in a non-mutually exclusive and 2004). O'Malley et al. (1995) identified of a new DDC tissue-specific manner, underlines the complexity of protein isoform (O'Malley et al., 1995). The truncated the expression patterns of this gene (table 1). DDC protein isoform (Mr; 50 kDa) consists of 442 amino acid residues (DDC 442 ). This isoform was found Pseudogene to be inactive towards the decarboxylation of both L- None has been identified yet. Dopa to Dopamine and 5-Hydroxytryptophan (5-HTP) to serotonin (O'Malley et al., 1995). As mentioned Protein above, the translation of Alt-DDC mRNA resulted in the synthesis of a truncated 338 amino acid long Note polypeptide, termed as Alt-DDC (Mr; 37 kDa). This Although, it was initially suggested that the DDC gene isoform was identical to the full-length DDC protein up encoded for a single protein product (Sumi-Ichinose et to amino acid residue 315. The remaining 23 amino al., 1992), evidence that demonstrated the expression of acids of the C-terminal sequence are encoded by the additional DDC protein isoforms in humans, argue alternative DDC exon 10 and are not incorporated in against it (O'Malley et al., 1995; Chang et al., 1996; Vassilacopoulou et al., 2004).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 943 DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase)) Florou D, et al.

Table 2. Human DDC identity. the full-length DDC protein sequence (Vassilacopoulou Nevertheless, additional experimental findings have et al., 2004). demonstrated that a population of enzymatically active Although previous data had suggested that DDC was a DDC molecules is associated with the cellular rather unregulated molecule, several findings have membrane fraction in the mammalian CNS (Poulikakos indicated that DDC activity can be modulated by many et al., 2001). Membrane-associated, enzymatically factors, such as D1, DA receptor antagonists (Rossetti active DDC subpopulations were detected in the highly et al., 1990), a 2-adrenergic receptor antagonists hydrophobic fractions of normal human leukocytes and (Rossetti et al., 1989), D1, D2 receptor antagonists U937 cancer cells (Kokkinou et al., 2009a; Kokkinou et (Zhu et al., 1992; Hadjiconstantinou et al., 1993), DA al., 2009b). receptor agonists (Zhu et al., 1993), PK-A and PK-C Function mediated pathways (Young et al., 1993; Young et al., 1994) and by endogenous inhibitors isolated from In terms of substrate specificity, the DDC molecule human serum (Vassiliou et al., 2005) and placenta purified from insects demonstrated a remarkably high (Vassiliou et al., 2009). affinity towards the decarboxylation of L-Dopa to dopamine (Fragoulis and Sekeris, 1975; Mappouras Expression and Fragoulis, 1988; Bossinakou and Fragoulis, 1996). DDC has been detected throughout the length of the However, work by Mappouras et al. (1990) in the gastrointestinal tract (Eisenhofer et al., 1997) and in normal human kidney has suggested that the enzyme is blood plasma (Boomsma et al., 1986). DDC is capable of also decarboxylating L-5- expressed in normal human kidney and placenta Hydroxytryptophan to serotonin, although the (Mappouras et al., 1990; Siaterli et al., 2003). DDC decarboxylation activity towards L-5- expression was observed in normal peripheral Hydroxytryptophan was found to be considerably lower leukocytes and T-lymphocytes (Kokkinou et al., than the one observed for L-Dopa (Mappouras et al., 2009b). Furthermore, DDC is expressed in the human 1990). Since DDC expression results in the production cancer cell lines U937 (Kokkinou et al., 2009a), SH- of multiple protein isoforms, it is conceivable that these SY5Y, HeLa and HTB-14 (Chalatsa et al., 2011). different protein molecules could be responsible for the Interestingly, the expression of the alternative DDC decarboxylation of other aromatic L-amino acids. isoform (Alt-DDC) was also demonstrated in peripheral Homology leukocytes (Kokkinou et al., 2009b), U937 (Kokkinou et al., 2009a), SH-SY5Y and HeLa cell lines (Chalatsa Comparison of the amino acid sequence of DDC from et al., 2011). different species, suggested that the enzyme is an In the central nervous system, increased DDC evolutionarily conserved molecule. The amino acid enzymatic activity is detected in the hypothalamus, sequence around the coenzyme binding lysine is also epiphysis, striatum, locus ceruleus, olfactory bulb and evolutionarily conserved (Bossa et al., 1977; Ichinose retina (Park et al., 1986). Elevated enzymatic DDC et al., 1989). The conserved amino acids are residues activity is also detected in peripheral organs such as 267-317, which surround the PLP-binding site liver, pancreas, kidney, lungs, spleen, stomach, salivary (Ichinose et al., 1989), as well as, the extended regions glands, as well as in the endothelial cells of blood of amino acids 64-155 and 182-204, which according vessels (Lovenberg et al., 1962; Rahman et al., 1981; to Maras et al. (1991) are important for the enzyme's Lindström and Sehlin, 1983). catalytic function (Maras et al., 1991). Table 2 shows the percentage of human DDC amino acid identity to Localisation other species (Maras et al., 1991; Mantzouridis et al., DDC was considered to be a cytosolic molecule 1997). (Lovenberg et al., 1962; Sims et al., 1973).

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serve as a potential novel biomarker in prostate cancer Mutations (Avgeris et al., 2008). Wafa et al. (2007) have indicated by immunohistochemistry that DDC was found to be a putative neuroendocrine marker for prostate cancer. In certain NE tumor cells of the prostate gland, DDC was found to be co-expressed with AR. DDC expression was increased after hormone-ablation therapy, as well as, in metastatic tumors that have progressed to the androgen-independent phenotypes (Wafa et al., 2007). Disease Increased DDC mRNA and/or elevated protein expression levels were detected in the LnCaP cell line following synthetic androgen treatment. DDC protein was found to be enzymatically active in the androgen- treated LnCaP cells as compared to the untreated controls. In treated LnCaP cells, DDC was up-regulated during AR-activation, while DDC expression was down-regulated following AR-inhibition. These findings support a coactivator role for DDC in AR activation (Shao et al., 2007). DDC over-expression affects the gene expression profile of the androgen- dependent prostate cancer cell line, LnCaP, as revealed by microarray analysis (Margiotti et al., 2007). Prognosis Statistically significant elevated DDC mRNA levels were observed in prostate cancer tissue specimens when compared to benign hyperplasia human samples. Multivariate survival analysis indicated that the Table 3. The mutations of the DDC gene in the AADC disorder. expression of the DDC gene could be used as an Germinal independent marker for the differential diagnosis between prostate cancer and benign hyperplasia Such mutations have not been identified so far. patients, using tissue biopsies. DDC mRNA expression Somatic was also shown to be associated with advanced tumor Aromatic L-amino acid decarboxylase (AADC) stage and higher Gleason score. This finding suggested deficiency, a rare autosomaly-recessive inherited an unfavorable prognostic value for DDC expression in defect, is associated with mutations of the DDC gene. patients with tumors in their prostate glands (Avgeris et This disorder leads to profound modifications in the al., 2008). homeostasis of central and peripheral nervous system Colorectal carcinoma (Hyland et al., 1992). In their majority, such mutations Note are missense and are listed above (table 3). Other High L-Dopa decarboxylase activity has been detected mutations of the human DDC gene that are related to in almost half of the original colorectal carcinomas AADC-deficiency are also included (Fiumara et al., examined, as well as, in the majority of cultured cell 2002; Chang et al., 2004; Pons et al., 2004; Tay et al., lines, established from human primary and metastatic 2007; Lee et al., 2009). tumors (Park et al., 1987). Other data have shown that most solid colorectal tumors exhibited DDC activity at Implicated in lower levels when compared to the enzymatic DDC Prostate cancer activity displayed by the NE tumors (Gazdar et al., 1988). DDC mRNA expression was found to be Note elevated in well-differentiated (grade I) intestinal Neuroendocrine differentiation features have been adenocarcinomas as compared to more aggressive identified in prostatic adenocarcinoma. Aggressiveness tumors (Kontos et al., 2010). of the disease is increased as the cells reach the androgen-independent phase (Speights et al., 1997; Prognosis Nelson et al., 2002). L-Dopa decarboxylase has been Increased DDC mRNA levels were observed in grade I identified as a novel androgen receptor (AR) colorectal adenocarcinomas. Survival analysis revealed coactivator protein (Wafa et al., 2003). Recent evidence a significantly lower risk of disease recurrence and have shown that the expression of DDC mRNA could longer overall survival for patients with DDC-positive

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 945 DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase)) Florou D, et al.

colorectal neoplasms. These results indicate that DDC It is noted that conventional light microscopy cannot mRNA expression might represent a possible future clearly differentiate between neuroblastoma and other biomarker for the prognosis of colorectal cancer small round-cell tumors of the childhood. Co- patients (Kontos et al., 2010). expression of DDC and Tyrosine Hydroxylase (TH) Gastric cancer has been used for the differential diagnosis of these types of tumors (Gilbert et al., 1999). Note Prognosis Advanced gastric cancer is characterized by peritoneal Elevated levels of plasma L-Dopa, in neuroblastoma dissemination, the most common disease relapse, which patients, could provide an indication for residual tumor. is caused by the dispersal of free gastric cancer cells These findings could be associated with dismal into the peritoneal cavity (Baba et al., 1989; Abe et al., prognosis for neuroblastoma patients. Furthermore, a 1995). sharp increase in plasma DDC enzymatic activity could Disease be related to disease reccurence (Boomsma et al., It has been proposed that increased DDC mRNA 1989). DDC mRNA was detected in all bone marrow expression could be an accurate tool for the detection and peripheral blood samples obtained from of gastric cancer micrometastases in the peritoneal neuroblastoma patients at relapse. Given these results, cavity. According to Sakakura et al. (2004), DDC Bozzi et al. (2004) have suggested that DDC mRNA expression levels were equivalent to the degree of expression could represent a specific molecular marker dissemination potential of gastric cancer cells. for monitoring bone marrow and peripheral blood Pheochromocytomas neuroblastoma metastases (Bozzi et al., 2004). Furthermore, DDC mRNA levels could be used as a Note sensitive indicator to predict minimal residual disease Pheochromocytomas are characterized by over- as well as the outcome for patients (Träger et al., 2008). production of catecholamines (Eisenhofer et al., 2001). Lung carcinomas Disease These non-innervated tumors originate, in most cases, Note from adrenal medullary cells which are capable for Elevated DDC enzymatic activity was observed in catecholamine biosynthesis (Yanase et al., 1986). small-cell lung carcinoma (SCLC) as compared to Catecholamine release by these cells is not initiated by normal lung epithelia (Nagatsu et al., 1985). The nerve impulses. Elevated DDC mRNA levels have been majority of non-SCLC (NSCLC) exhibited low levels detected in pheochromocytoma tissues as compared to or no DDC enzyme activity (Gazdar et al., 1981; normal adrenal medullary cells. Isobe et al. (1998) Bepler et al., 1988). It is noted that in some NSCLC suggested that high DDC expression could lead to the cases, high DDC activity values have been reported development or growth of pheochromocytomas (Isobe (Baylin et al., 1980), although in these lung lesions the et al., 1998). detection of DDC activity was restricted to large-cell carcinomas and adenocarcinomas, while squamous cell Neuroblastomas carcinomas did not exhibit any enzymatic activity Note (Gazdar et al., 1988). In the neuroblastoma cell line, the SH-SY5Y cells, both Disease neural full-length DDC mRNA and the neural mRNA DDC activity appears to be a valuable neuroendocrine isoform lacking exon 3, were detected (Chalatsa et al., marker for identifying SCLC tumor cells in culture 2011). (Baylin et al., 1980). DDC enzymatic activity is highest Disease during the exponential cellular growth phase and/or Neuroblastomas, the most common extracranial solid when the cells are during the transition from G 2 to the neoplasms in children, originate from sympathetic M phase of the cell cycle (Francis et al., 1983). DDC neural crest cells and their characteristic is the activity has been also used as a useful biomarker for the production of catecholamines and their metabolites distinction of SCLC from NSCLC. Furthermore, DDC (Boomsma et al., 1989). Neuroblastomas are activity has been used for the differentiation between categorized as small round-cell tumors of the childhood the classical SCLC cell lines (SCLC-C), which express (Gilbert et al., 1999). In the active untreated state, high DDC activity levels, from the variant subtype of plasma L-Dopa values and/or DDC enzymatic activity the SCLC (SCLC-V), which does not express the levels have been found to be elevated. Interestingly, enzyme (Carney et al., 1985; Gazdar et al., 1985). following chemotherapy treatment, DDC enzymatic Prognosis activity levels fall within the physiological range. The elevated DDC enzymatic activity, which is Elevated levels of plasma L-Dopa and especially DDC observed in patients harboring SCLC tumors, seems to enzyme activity are observed during disease relapse be associated with disease differentiation grade. High (Boomsma et al., 1989). DDC activity has been associated with better prognosis and patient's outcome (Bepler et al., 1987).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 946 DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase)) Florou D, et al.

Medullary thyroid carcinoma Pearse AG. The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and Note the embryologic, physiologic and pathologic implications of the The expression of L-Dopa decarboxylase has been concept. J Histochem Cytochem. 1969 May;17(5):303-13 detected in medullary carcinoma of the thyroid gland Christenson JG, Dairman W, Udenfriend S. Preparation and (Pearse, 1969; Atkins et al., 1973). properties of a homogeneous aromatic L-amino acid decarboxylase from hog kidney. Arch Biochem Biophys. 1970 Disease Nov;141(1):356-67 Medullary thyroid carcinoma (MTC) originates from Atkins FL, Beaven MA, Keiser HR. Dopa decarboxylase in the calcitonin (CT)-secreting thyroid C cells and is a medullary carcinoma of the thyroid. N Engl J Med. 1973 Sep unique malignancy of endocrine origin (Tashjian and 13;289(11):545-8 Melvin, 1968). Malignancy progression could be Sims KL, Davis GA, Bloom FE. Activities of 3,4-dihydroxy-L- monitored, in patients with the virulent phenotype of phenylalanine and 5-hydroxy-L-tryptophan decarboxylases in the disease, using the simultaneous increased levels of rat brain: assay characteristics and distribution. J Neurochem. DDC and histaminase (Trump et al., 1979; Lippman et 1973 Feb;20(2):449-64 al., 1982). It has been proposed that increased DDC Fragoulis EG, Sekeris CE. Purification and characteristics of enzymatic activity might represent an early DOPA-decarboxylase from the integument of Calliphora vicina differentiation marker in the virulent form of this larve. Arch Biochem Biophys. 1975 May;168(1):15-25 neoplasm (Berger et al., 1984). Bossa F, Martini F, Barra D, Voltattorni CB, Minelli A, Turano C. The chymotryptic phosphopyridoxyl peptide of DOPA Neuroendocrine tumors (NETs): decarboxylase from pig kidney. Biochem Biophys Res bronchial, liver and ileal carcinoids, Commun. 1977 Sep 9;78(1):177-84 gastric / pancreatic / pulmonary tumors Trump DL, Mendelsohn G, Baylin SB. Discordance between plasma calcitonin and tumor-cell mass in medullary thyroid Note carcinoma. N Engl J Med. 1979 Aug 2;301(5):253-5 DDC enzymatic activity constitutes an excellent Voltattorni CB, Minelli A, Vecchini P, Fiori A, Turano C. cellular marker for identifying tumors of the Purification and characterization of 3,4-dihydroxyphenylalanine neuroendocrine (NE) origin. The majority of NE decarboxyase from pig kidney. Eur J Biochem. 1979 Jan tumors tested were found to express relatively high 2;93(1):181-8 DDC enzymatic activity (Gazdar et al., 1988). DDC Baylin SB, Abeloff MD, Goodwin G, Carney DN, Gazdar AF. expression and/or activity have been reported in NETs, Activities of L-dopa decarboxylase and diamine oxidase particularly in SCLC. For these reasons, DDC has been (histaminase) in human lung cancers and decarboxylase as a marker for small (oat) cell cancer in cell culture. Cancer Res. considered as a general endocrine marker (Gazdar et 1980 Jun;40(6):1990-4 al., 1988; Jensen et al., 1990). Gazdar AF, Zweig MH, Carney DN, Van Steirteghen AC, Disease Baylin SB, Minna JD. Levels of creatine kinase and its BB Strikingly higher DDC mRNA expression levels were isoenzyme in lung cancer specimens and cultures. Cancer revealed in all bronchial carcinoids and pulmonary Res. 1981 Jul;41(7):2773-7 NETs when compared to their normal corresponding Rahman MK, Nagatsu T, Kato T. Aromatic L-amino acid types of tissues. Immunohistochemical data have decarboxylase activity in central and peripheral tissues and confirmed DDC protein expression in all of these serum of rats with L-DOPA and L-5-hydroxytryptophan as substrates. Biochem Pharmacol. 1981 Mar 15;30(6):645-9 tumors. In the gastroenteropancreatic NETs examined, the detected DDC mRNA levels were comparable to Lippman SM, Mendelsohn G, Trump DL, Wells SA Jr, Baylin SB. The prognostic and biological significance of cellular those of normal gastric, ileal and pancreatic tissues. heterogeneity in medullary thyroid carcinoma: a study of Almost half of the pancreatic and stomach NETs and calcitonin, L-dopa decarboxylase, and histaminase. J Clin all ileal carcinoids were found to be DDC Endocrinol Metab. 1982 Feb;54(2):233-40 immunoreactive (Uccella et al., 2006). Interestingly, Voltattorni CB, Minelli A, Cirotto C, Barra D, Turano C. Subunit hepatic carcinoid tumors demonstrated a 20-fold structure of 3, 4-dihydroxyphenylalanine decarboxylase from increase in DDC activity as compared with normal pig kidney. Arch Biochem Biophys. 1982 Aug;217(1):58-64 surrounding liver tissues (Gilbert et al., 1995). Francis J, Thompson R, Bernal SD, Luk GD, Baylin SB. Effects Hybrid/Mutated gene of dibutyryl cyclic adenosine 3':5'-monophosphate on the growth of cultured human small-cell lung carcinoma and the Not yet discovered. specific cellular activity of L-dopa decarboxylase. Cancer Res. 1983 Feb;43(2):639-45 References Lindström P, Sehlin J. Mechanisms underlying the effects of 5- LOVENBERG W, WEISSBACH H, UDENFRIEND S. Aromatic hydroxytryptamine and 5-hydroxytryptophan in pancreatic L-amino acid decarboxylase. J Biol Chem. 1962 Jan;237:89-93 islets. A proposed role for L-aromatic amino acid decarboxylase. Endocrinology. 1983 Apr;112(4):1524-9 Tashjian AH Jr, Melvin EW. Medullary carcinoma of the thyroid gland. Studies of thyrocalcitonin in plasma and tumor extracts. Berger CL, de Bustros A, Roos BA, Leong SS, Mendelsohn G, N Engl J Med. 1968 Aug 8;279(6):279-83 Gesell MS, Baylin SB. Human medullary thyroid carcinoma in culture provides a model relating growth dynamics, endocrine cell differentiation, and tumor progression. 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Carney DN, Gazdar AF, Bepler G, Guccion JG, Marangos PJ, Rossetti Z, Krajnc D, Neff NH, Hadjiconstantinou M.. Moody TW, Zweig MH, Minna JD. Establishment and Modulation of retinal aromatic L-amino acid decarboxylase via identification of small cell lung cancer cell lines having classic alpha 2 adrenoceptors. J Neurochem. 1989 Feb;52(2):647-52. and variant features. Cancer Res. 1985 Jun;45(6):2913-23 Jensen SM, Gazdar AF, Cuttitta F, Russell EK, Linnoila RI.. A Gazdar AF, Carney DN, Nau MM, Minna JD. Characterization comparison of synaptophysin, chromogranin, and L-dopa of variant subclasses of cell lines derived from small cell lung decarboxylase as markers for neuroendocrine differentiation in cancer having distinctive biochemical, morphological, and lung cancer cell lines. Cancer Res. 1990 Sep 15;50(18):6068- growth properties. Cancer Res. 1985 Jun;45(6):2924-30 74. Nagatsu T, Ichinose H, Kojima K, Kameya T, Shimase J, Mappouras DG, Stiakakis J, Fragoulis EG.. Purification and Kodama T, Shimosato Y. Aromatic L-amino acid characterization of L-dopa decarboxylase from human kidney. decarboxylase activities in human lung tissues: comparison Mol Cell Biochem. 1990 May 10;94(2):147-56. between normal lung and lung carcinomas. Biochem Med. 1985 Aug;34(1):52-9 Rossetti ZL, Silvia CP, Krajnc D, Neff NH, Hadjiconstantinou M.. Aromatic L-amino acid decarboxylase is modulated by D1 Boomsma F, van der Hoorn FA, Schalekamp MA. dopamine receptors in rat retina. J Neurochem. 1990 Determination of aromatic-L-amino acid decarboxylase in Mar;54(3):787-91. human plasma. Clin Chim Acta. 1986 Sep 15;159(2):173-83 Maras B, Dominici P, Barra D, Bossa F, Voltattorni CB.. Pig Park DH, Teitelman G, Evinger MJ, Woo JI, Ruggiero DA, kidney 3,4-dihydroxyphenylalanine (dopa) decarboxylase. Albert VR, Baetge EE, Pickel VM, Reis DJ, Joh TH. Primary structure and relationships to other amino acid Phenylethanolamine N-methyltransferase-containing neurons decarboxylases. Eur J Biochem. 1991 Oct 15;201(2):385-91. in rat retina: immunohistochemistry, immunochemistry, and molecular biology. J Neurosci. 1986 Apr;6(4):1108-13 Craig SP, Thai AL, Weber M, Craig IW.. Localisation of the gene for human aromatic L-amino acid decarboxylase (DDC) Yanase T, Nawata H, Kato K, Ibayashi H. Catecholamines and to chromosome 7p13-->p11 by in situ hybridisation. Cytogenet opioid peptides in human phaeochromocytomas. Acta Cell Genet. 1992;61(2):114-6. Endocrinol (Copenh). 1986 Nov;113(3):378-84 Hyland K, Surtees RA, Rodeck C, Clayton PT.. Aromatic L- Bepler G, Jaques G, Koehler A, Gropp C, Havemann K. amino acid decarboxylase deficiency: clinical features, Markers and characteristics of human SCLC cell lines. diagnosis, and treatment of a new inborn error of Neuroendocrine markers, classical tumor markers, and neurotransmitter amine synthesis. Neurology. 1992 chromosomal characteristics of permanent human small cell Oct;42(10):1980-8. lung cancer cell lines. J Cancer Res Clin Oncol. 1987;113(3):253-9 Ichinose H, Sumi-Ichinose C, Ohye T, Hagino Y, Fujita K, Nagatsu T.. Tissue-specific alternative splicing of the first exon Park JG, Oie HK, Sugarbaker PH, Henslee JG, Chen TR, generates two types of mRNAs in human aromatic L-amino Johnson BE, Gazdar A. Characteristics of cell lines established acid decarboxylase. Biochemistry. 1992 Nov 24;31(46):11546- from human colorectal carcinoma. Cancer Res. 1987 Dec 50. 15;47(24 Pt 1):6710-8 Scherer LJ, McPherson JD, Wasmuth JJ, Marsh JL.. Human Bepler G, Koehler A, Kiefer P, Havemann K, Beisenherz K, dopa decarboxylase: localization to human chromosome 7p11 Jaques G, Gropp C, Haeder M. Characterization of the state of and characterization of hepatic cDNAs. Genomics. 1992 differentiation of six newly established human non-small-cell Jun;13(2):469-71. lung cancer cell lines. Differentiation. 1988;37(2):158-71 Sumi-Ichinose C, Ichinose H, Takahashi E, Hori T, Nagatsu T.. Gazdar AF, Helman LJ, Israel MA, Russell EK, Linnoila RI, Molecular cloning of genomic DNA and chromosomal Mulshine JL, Schuller HM, Park JG. Expression of assignment of the gene for human aromatic L-amino acid neuroendocrine cell markers L-dopa decarboxylase, decarboxylase, the enzyme for catecholamine and serotonin chromogranin A, and dense core granules in human tumors of biosynthesis. Biochemistry. 1992 Mar 3;31(8):2229-38. endocrine and nonendocrine origin. Cancer Res. 1988 Jul 15;48(14):4078-82 Zhu MY, Juorio AV, Paterson IA, Boulton AA.. Regulation of aromatic L-amino acid decarboxylase by dopamine receptors Mappouras DG, Fragoulis EG.. Purification and in the rat brain. J Neurochem. 1992 Feb;58(2):636-41. characterization of L-DOPA decarboxylase from the white puparia of Ceratitis capitata. Insect Biochem. 1988 Hadjiconstantinou M, Wemlinger TA, Sylvia CP, Hubble JP, Jan;18(4):369-376. Neff NH.. Aromatic L-amino acid decarboxylase activity of mouse striatum is modulated via dopamine receptors. J Baba H, Korenaga D, Okamura T, Saito A, Sugimachi K.. Neurochem. 1993 Jun;60(6):2175-80. Prognostic factors in gastric cancer with serosal invasion. Univariate and multivariate analyses. Arch Surg. 1989 Le Van Thai A, Coste E, Allen JM, Palmiter RD, Weber MJ.. Sep;124(9):1061-4. Identification of a neuron-specific promoter of human aromatic L-amino acid decarboxylase gene. Brain Res Mol Brain Res. Boomsma F, Ausema L, Hakvoort-Cammel FG, Oosterom R, 1993 Mar;17(3-4):227-38. Man in't Veld AJ, Krenning EP, Hahlen K, Schalekamp MA.. Combined measurements of plasma aromatic L-amino acid Young EA, Neff NH, Hadjiconstantinou M.. Evidence for cyclic decarboxylase and DOPA as tumour markers in diagnosis and AMP-mediated increase of aromatic L-amino acid follow-up of neuroblastoma. Eur J Cancer Clin Oncol. 1989 decarboxylase activity in the striatum and midbrain. J Jul;25(7):1045-52. Neurochem. 1993 Jun;60(6):2331-3. Ichinose H, Kurosawa Y, Titani K, Fujita K, Nagatsu T.. Zhu MY, Juorio AV, Paterson IA, Boulton AA.. Regulation of Isolation and characterization of a cDNA clone encoding striatal aromatic L-amino acid decarboxylase: effects of human aromatic L-amino acid decarboxylase. Biochem blockade or activation of dopamine receptors. Eur J Biophys Res Commun. 1989 Nov 15;164(3):1024-30. Pharmacol. 1993 Jul 20;238(2-3):157-64.

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Young EA, Neff NH, Hadjiconstantinou M.. Phorbol ester Poulikakos P, Vassilacopoulou D, Fragoulis EG.. L-DOPA administration transiently increases aromatic L-amino acid decarboxylase association with membranes in mouse brain. decarboxylase activity of the mouse striatum and midbrain. J Neurochem Res. 2001 May;26(5):479-85. Neurochem. 1994 Aug;63(2):694-7. Fiumara A, Brautigam C, Hyland K, Sharma R, Lagae L, Abe S, Yoshimura H, Tabara H, Tachibana M, Monden N, Stoltenborg B, Hoffmann GF, Jaeken J, Wevers RA.. Aromatic Nakamura T, Nagaoka S.. Curative resection of gastric cancer: L-amino acid decarboxylase deficiency with hyperdopaminuria. limitation of peritoneal lavage cytology in predicting the Clinical and laboratory findings in response to different outcome. J Surg Oncol. 1995 Aug;59(4):226-9. therapies. Neuropediatrics. 2002 Aug;33(4):203-8. Gilbert JA, Bates LA, Ames MM.. Elevated aromatic-L-amino Nelson PS, Clegg N, Arnold H, Ferguson C, Bonham M, White acid decarboxylase in human carcinoid tumors. Biochem J, Hood L, Lin B.. The program of androgen-responsive genes Pharmacol. 1995 Sep 7;50(6):845-50. in neoplastic prostate epithelium. Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11890-5. Epub 2002 Aug 16. O'Malley KL, Harmon S, Moffat M, Uhland-Smith A, Wong S.. The human aromatic L-amino acid decarboxylase gene can be Siaterli MZ, Vassilacopoulou D, Fragoulis EG.. Cloning and alternatively spliced to generate unique protein isoforms. J expression of human placental L-Dopa decarboxylase. Neurochem. 1995 Dec;65(6):2409-16. Neurochem Res. 2003 Jun;28(6):797-803. Sumi-Ichinose C, Hasegawa S, Ichinose H, Sawada H, Wafa LA, Cheng H, Rao MA, Nelson CC, Cox M, Hirst M, Kobayashi K, Sakai M, Fujii T, Nomura H, Nomura T, Nagatsu Sadowski I, Rennie PS.. Isolation and identification of L-dopa I, et al.. Analysis of the alternative promoters that regulate decarboxylase as a protein that binds to and enhances tissue-specific expression of human aromatic L-amino acid transcriptional activity of the androgen receptor using the decarboxylase. J Neurochem. 1995 Feb;64(2):514-24. repressed transactivator yeast two-hybrid system. Biochem J. 2003 Oct 15;375(Pt 2):373-83. Bossinakou KS, Fragoulis EG.. Purification and characterisation of L-DOPA decarboxylase from pharate pupae Bozzi F, Luksch R, Collini P, Gambirasio F, Barzano E, Polastri of Ceratitis capitata. A comparison with the enzyme purified D, Podda M, Brando B, Fossati-Bellani F.. Molecular detection from the white prepupae. Comp Biochem Physiol B Biochem of dopamine decarboxylase expression by means of reverse Mol Biol. 1996 Feb;113(2):213-20. transcriptase and polymerase chain reaction in bone marrow and peripheral blood: utility as a tumor marker for Chang YT, Mues G, Hyland K.. Alternative splicing in the neuroblastoma. Diagn Mol Pathol. 2004 Sep;13(3):135-43. coding region of human aromatic L-amino acid decarboxylase mRNA. Neurosci Lett. 1996 Jan 5;202(3):157-60. Chang YT, Sharma R, Marsh JL, McPherson JD, Bedell JA, Knust A, Brautigam C, Hoffmann GF, Hyland K.. Levodopa- Eisenhofer G, Aneman A, Friberg P, Hooper D, Fandriks L, responsive aromatic L-amino acid decarboxylase deficiency. Lonroth H, Hunyady B, Mezey E.. Substantial production of Ann Neurol. 2004 Mar;55(3):435-8. dopamine in the human gastrointestinal tract. J Clin Endocrinol Metab. 1997 Nov;82(11):3864-71. Dugast-Darzacq C, Egloff S, Weber MJ.. Cooperative dimerization of the POU domain protein Brn-2 on a new motif Mantzouridis TD, Sideris DC, Fragoulis EG.. cDNA cloning of activates the neuronal promoter of the human aromatic L- L-dopa decarboxylase from the eclosion stage of the insect amino acid decarboxylase gene. Brain Res Mol Brain Res. Ceratitis capitata. Evolutionary relationship to other species 2004 Jan 5;120(2):151-63. decarboxylases. Gene. 1997 Dec 19;204(1-2):85-9. Pons R, Ford B, Chiriboga CA, Clayton PT, Hinton V, Hyland Speights VO Jr, Cohen MK, Riggs MW, Coffield KS, Keegan K, Sharma R, De Vivo DC.. Aromatic L-amino acid G, Arber DA.. Neuroendocrine stains and proliferative indices decarboxylase deficiency: clinical features, treatment, and of prostatic adenocarcinomas in transurethral resection prognosis. Neurology. 2004 Apr 13;62(7):1058-65. (REVIEW) samples. Br J Urol. 1997 Aug;80(2):281-6. Sakakura C, Takemura M, Hagiwara A, Shimomura K, Isobe K, Nakai T, Yukimasa N, Nanmoku T, Takekoshi K, Miyagawa K, Nakashima S, Yoshikawa T, Takagi T, Kin S, Nomura F.. Expression of mRNA coding for four Nakase Y, Fujiyama J, Hayasizaki Y, Okazaki Y, Yamagishi H.. catecholamine-synthesizing enzymes in human adrenal Overexpression of dopa decarboxylase in peritoneal pheochromocytomas. Eur J Endocrinol. 1998 Apr;138(4):383- dissemination of gastric cancer and its potential as a novel 7. marker for the detection of peritoneal micrometastases with Gilbert J, Haber M, Bordow SB, Marshall GM, Norris MD.. Use real-time RT-PCR. Br J Cancer. 2004 Feb 9;90(3):665-71. of tumor-specific gene expression for the differential diagnosis Vassilacopoulou D, Sideris DC, Vassiliou AG, Fragoulis EG.. of neuroblastoma from other pediatric small round-cell Identification and characterization of a novel form of the human malignancies. Am J Pathol. 1999 Jul;155(1):17-21. L-dopa decarboxylase mRNA. Neurochem Res. 2004 Burkhard P, Dominici P, Borri-Voltattorni C, Jansonius JN, Oct;29(10):1817-23. Malashkevich VN.. Structural insight into Parkinson's disease Vassiliou AG, Vassilacopoulou D, Fragoulis EG.. Purification of treatment from drug-inhibited DOPA decarboxylase. Nat Struct an endogenous inhibitor of L-Dopa decarboxylase activity from Biol. 2001 Nov;8(11):963-7. human serum. 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in the dopa decarboxylase (DDC) gene are associated with disease when measured at diagnosis. Int J Cancer. 2008 Dec smoking behavior in European-Americans and African- 15;123(12):2849-55. Americans. Hum Mol Genet. 2006 Jul 15;15(14):2192-9. Epub 2006 Jun 1. Kokkinou I, Fragoulis EG, Vassilacopoulou D.. The U937 macrophage cell line expresses enzymatically active L-Dopa Margiotti K, Wafa LA, Cheng H, Novelli G, Nelson CC, Rennie decarboxylase. J Neuroimmunol. 2009a Nov 30;216(1-2):51-8. PS.. Androgen-regulated genes differentially modulated by the Epub 2009 Oct 1. androgen receptor coactivator L-dopa decarboxylase in human prostate cancer cells. Mol Cancer. 2007 Jun 6;6:38. Kokkinou I, Nikolouzou E, Hatzimanolis A, Fragoulis EG, Vassilacopoulou D.. Expression of enzymatically active L- Tay SK, Poh KS, Hyland K, Pang YW, Ong HT, Low PS, Goh DOPA decarboxylase in human peripheral leukocytes. Blood DL.. Unusually mild phenotype of AADC deficiency in 2 Cells Mol Dis. 2009b Jan-Feb;42(1):92-8. Epub 2008 Nov 28. siblings. Mol Genet Metab. 2007 Aug;91(4):374-8. Epub 2007 May 29. Lee HF, Tsai CR, Chi CS, Chang TM, Lee HJ.. Aromatic L- amino acid decarboxylase deficiency in Taiwan. Eur J Paediatr Shao C, Wang Y, Yue HH, Zhang YT, Shi CH, Liu F, Bao TY, Neurol. 2009 Mar;13(2):135-40. Epub 2008 Jun 24. Yang ZY, Yuan JL, Shao GX.. Biphasic effect of androgens on prostate cancer cells and its correlation with androgen receptor Vassiliou AG, Fragoulis EG, Vassilacopoulou D.. Detection, coactivator dopa decarboxylase. J Androl. 2007 Nov- purification and identification of an endogenous inhibitor of L- Dec;28(6):804-12. Epub 2007 Jun 20. Dopa decarboxylase activity from human placenta. Neurochem Res. 2009 Jun;34(6):1089-100. Epub 2008 Nov 13. Wafa LA, Palmer J, Fazli L, Hurtado-Coll A, Bell RH, Nelson CC, Gleave ME, Cox ME, Rennie PS.. Comprehensive Kontos CK, Papadopoulos IN, Fragoulis EG, Scorilas A.. expression analysis of L-dopa decarboxylase and established Quantitative expression analysis and prognostic significance of neuroendocrine markers in neoadjuvant hormone-treated L-DOPA decarboxylase in colorectal adenocarcinoma. Br J versus varying Gleason grade prostate tumors. Hum Pathol. Cancer. 2010 Apr 27;102(9):1384-90. 2007 Jan;38(1):161-70. Epub 2006 Sep 25. Chalatsa I, Nikolouzou E, Fragoulis EG, Vassilacopoulou D.. L- Avgeris M, Koutalellis G, Fragoulis EG, Scorilas A.. Expression Dopa decarboxylase expression profile in human cancer cells. analysis and clinical utility of L-Dopa decarboxylase (DDC) in Mol Biol Rep. 2011 Feb;38(2):1005-11. Epub 2010 Jun 11. prostate cancer. Clin Biochem. 2008 Oct;41(14-15):1140-9. Epub 2008 Jun 10. This article should be referenced as such: Trager C, Vernby A, Kullman A, Ora I, Kogner P, Kagedal B.. Florou D, Scorilas A, Vassilacopoulou D, Fragoulis EG. DDC mRNAs of tyrosine hydroxylase and dopa decarboxylase but (dopa decarboxylase (aromatic L-amino acid decarboxylase)). not of GD2 synthase are specific for neuroblastoma minimal Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):942-950. disease and predicts outcome for children with high-risk

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Gene Section Review

DDR1 (discoidin domain receptor tyrosine kinase 1) Barbara Roig, Elisabet Vilella Hospital Psiquiatic Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, C/Sant Llorenc 21, 43201 REUS, Spain (BR, EV)

Published in Atlas Database: May 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/DDR1ID40280ch6p21.html DOI: 10.4267/2042/46052 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

kb of the genomic sequence on chromosome 6 (from Identity position 30851861 bp to 30867933 bp in the positive Other names: CAK; CD167; DDR; EDDR1; HGK2; strand orientation). MCK10; NEP; NTRK4; PTK3; PTK3A; RTK6; TRKE Transcription HGNC (Hugo): DDR1 The 3840-bp mRNA is transcribed in a centromeric to Location: 6p21.33 telomeric orientation. Alternative splicing can occur, and 5 named isoforms (DDR1a-e) are recognised. DNA/RNA Pseudogene Description No pseudogene has been described. The DDR1 gene comprises 17 exons and spans 12

Genomic organisation of the DDR1 gene on chromosome 6. Exons that are implicated in the alternative splicing process of the DDR1 gene are represented by open boxes. The alternative splicing process of exon 10 to exon 14 generates 5 DDR1 isoforms, which are affixed a-e.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 951 DDR1 (discoidin domain receptor tyrosine kinase 1) Roig B, Vilella E

Protein Expression DDR1 is ubiquitously expressed in a variety of epithelial tissues (Alves et al., 1995; Curat and Vogel, 2002; Ferri et al., 2004; Hou et al., 2001; Mohan et al., 2001; Sakamoto et al., 2001; Tanaka et al., 1998). DDR1 is also expressed in endothelial blood capillary cells and oligodendrocytes in the human brain (Franco- Pons et al., 2009; Roig et al., 2010). DDR1 is significantly overexpressed in several human cancers (Barker et al., 1995; Colas et al., 2011; Ford et al., 2007; Hajdu et al., 2010; Heinzelmann-Schwarz et al., 2004; Laval et al., 1994; Nemoto et al., 1997; Park et al., 2007; Tun et al., 2011; Weiner et al., 1996; Weiner et al., 2000; Yamanaka et al., 2006; Yoshida et al., 2007) and carcinoma cell lines (Alves et al., 1995; Gu et al., 2011; Park et al., 2007; Sakuma et al., 1996). Localisation Transmembrane. Function Receptor tyrosine kinases are key components of several signal transduction pathways. These kinases control multiple cellular processes, including motility, proliferation, differentiation, metabolism and survival. DDR1 is actively involved in tumorigenesis and promotes the proliferation of neoplasic cells. The interaction of DDR1 and Notch1 displays a prosurvival effect (Kim et al., 2011). DDR1 participates in the collective migration of cancer cells by coordinating the Schematic diagram of the DDR1 protein and localization of cell polarity regulators Par3 and Par6 (Hidalgo-Carcedo the DDR1 Tyrosine phosphorylated sites at intracellular et al., 2011). domain. Description Homology DDR1 belongs to the DDRs subfamily of tyrosine - P. troglodytes, discoidin domain receptor tyrosine kinase receptors. This subfamily is composed of only kinase 1, DDR1 two members, DDR1 and DDR2, and it is distinguished - C. lupus, discoidin domain receptor tyrosine kinase 1, by an extracellular domain that is homologous to the DDR1 carbohydrate-binding lectin discoidin-I in - M. musculus, discoidin domain receptor family Dictyostelium discoideum. The Discoidin domain is member 1, Ddr1 essential for the ability of DDRs to bind ligands. To- - R. norvegicus, discoidin domain receptor tyrosine date, collagen is the only unique DDR1 ligand that has kinase 1 been identified. Five isoforms of DDR1 that are - D. rerio, discoidin domain receptor family member 1 generated by alternative splicing have been described. The longest DDR1 transcript codes for the full-length Mutations receptor (DDR1c isoform) and is composed of 919 Note amino acids. DDR1a and DDR1b isoforms lack 37 Few somatic mutations have been described. Four amino acids in the juxtamembrane domain or 6 amino mutations (G1486T, A496S, CC2469/2470TT, acids in the kinase domain. DDR1d and DDR1e R824W) have been identified in a cohort of 26 primary isoforms are C-terminally truncated receptors. DDR1d lung neoplasms (Davies et al., 2005). One somatic lacks exons 11 and 12 causing a frame-shift mutation mutation (A803V) was found in 4 acute myeloid that generates a stop codon and premature termination leukaemia patients (Tomasson et al., 2008). of transcription. Finally, DDR1e lacks exons 11 and 12 as well as the first half of exon 10 (Alves et al., 1995).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 952 DDR1 (discoidin domain receptor tyrosine kinase 1) Roig B, Vilella E

Implicated in Brain tumours Note Breast cancer DDR1 was originally isolated in malignant childhood Note brain tumours, which overexpressed DDR1 (Weiner et DDR1 overexpression was observed in human primary al., 1996). Replicable findings were found in metastatic breast tumours samples compared to that in normal brain neoplasms and glioma cells (Yamanaka et al., breast tissues (Barker et al., 1995). In addition, invasive 2006; Weiner et al., 2000). In glioma cells, DDR1 was ductal and lobular carcinomas showed differential involved in cell proliferation and invasion via cell expression of DDR1. DDR1 was downregulated in interactions with the extracellular matrix (Ram et al., lobular carcinomas (Turashvili et al., 2007a; Turashvili 2005; Yamanaka et al., 2006). Moreover, a study on et al., 2007b). DDR1a and DDR1b isoforms overexpression in glioma cells has identified distinct roles for each DDR1 Osteosarcoma isoforms in the cell attachment process, which is Note mediated by collagen I (Ram et al., 2005). The analysis The DDR1 promoter presents a potential p53 binding- of the expression profile in mice that had PDGF- site. A previous study has shown that p53 expression induced glioma showed overexpression of DDR1 upregulated the mRNA expression levels of DDR1 in (Johansson et al., 2005). human osteosarcoma cells (Sakuma et al., 1996). Primary central nervous system Oesophageal cancer lymphoma (PCNSL) Note Note The overexpression of DDR1 was reported in 12 A PCNSL pathway analysis revealed upregulation of carcinomatous oesophageal tissues compared to that in DDR1 expression in the extracellular matrix and the normal tissues. Furthermore, a positive correlation was adhesion-related pathways (Tun et al., 2011). identified between DDR1 mRNA expression and the proliferative activity of the tumoural cells (Nemoto et Pituitary adenoma al., 1997). Note Ovarian cancer In different subtypes of pituitary adenoma, DDR1 expression was related to the hormonal background. Note DDR1 was more highly expressed in macroadenomas, DDR1 was highly expressed in 158 histological compared to microadenomas, and in PRL- and GH- subtypes of primary epithelial ovarian cancers (EOC) producing adenomas (Yoshida et al., 2007). compared to that in normal ovarian surface epithelium samples (Heinzelmann-Schwarz et al., 2004). Lung cancer Endometrial cancer Note DDR1 was upregulated in tumour lung tissue compared Note to that in normal tissue and was an independent DDR1 has been implicated as a potential molecular favourable predictor for prognosis (Ford et al., 2007). marker of endometrial cancer (Colas et al., 2011; Similarly, DDR1 was highly phosphorylated in non- Domenyuk et al., 2007). A gene expression screening small cell lung cancer (NSCLC) (Rikova et al., 2007). of 52 carcinomas samples showed differential One study described the presence of DDR1 somatic expression of several genes, including the DDR1 gene. mutations in lung cancer (Davies et al., 2005). These data were also demonstrated in 50 tumoural and However, no mutations were detected in another lung non-tumoural uterine aspirates (Colas et al., 2011). cancer study (Ford et al., 2007).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 953 DDR1 (discoidin domain receptor tyrosine kinase 1) Roig B, Vilella E

Liver cancer Curat CA, Vogel WF. Discoidin domain receptor 1 controls growth and adhesion of mesangial cells. J Am Soc Nephrol. Note 2002 Nov;13(11):2648-56 DDR1a and DDR1b isoforms were overexpressed in Ferri N, Carragher NO, Raines EW. Role of discoidin domain hepatocellular carcinoma cell lines HLE and Huh-7. receptors 1 and 2 in human smooth muscle cell-mediated DDR1 isoform overexpression enhanced the migration collagen remodeling: potential implications in atherosclerosis and invasion of the hepatocellular carcinoma cell lines and lymphangioleiomyomatosis. Am J Pathol. 2004 May;164(5):1575-85 in association with the matrix metalloproteinases MMP2 and MMP9 (Park et al., 2007). Heinzelmann-Schwarz VA, Gardiner-Garden M, Henshall SM, Scurry J, Scolyer RA, Davies MJ, Heinzelmann M, Kalish LH, The downregulation of miR-199a-5p, which is a direct Bali A, Kench JG, Edwards LS, Vanden Bergh PM, Hacker NF, target of DDR1, deregulated DDR1 functionality and Sutherland RL, O'Brien PM. Overexpression of the cell increased cell invasion in human hepatocellular adhesion molecules DDR1, Claudin 3, and Ep-CAM in carcinoma (HCC) (Shen et al., 2010). metaplastic ovarian epithelium and ovarian cancer. Clin Finally, a profiling study on receptor tyrosine kinase Cancer Res. 2004 Jul 1;10(13):4427-36 phosphorylation in cholangiocarcinoma patients Davies H, Hunter C, Smith R, Stephens P, Greenman C, showed high levels of phosphorylation of DDR1 and Bignell G, Teague J, Butler A, Edkins S, Stevens C, Parker A, O'Meara S, Avis T, Barthorpe S, Brackenbury L, Buck G, other tyrosine kinases in tumour tissues in comparison Clements J, Cole J, Dicks E, Edwards K, Forbes S, Gorton M, to para-tumour tissues (Gu et al., 2011). Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Mesenchymal neoplasm Raine K, Shepherd R, Small A, Solomon H, Stephens Y, Tofts Note C, Varian J, Webb A, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Green A, Knowles M, Leung SY, Solitary fibrous tumour (SFT) expression profiling of Looijenga LH, Malkowicz B, Pierotti MA, Teh BT, Yuen ST, 23 samples showed an over-expression of several Lakhani SR, Easton DF, Weber BL, Goldstraw P, Nicholson receptor tyrosine kinase genes, including DDR1. AG, Wooster R, Stratton MR, Futreal PA. Somatic mutations of However, no mutations were identified using cDNA the protein kinase gene family in human lung cancer. Cancer Res. 2005 Sep 1;65(17):7591-5 sequencing (Hajdu et al., 2010). Johansson FK, Göransson H, Westermark B. Expression analysis of genes involved in brain tumor progression driven by References retroviral insertional mutagenesis in mice. Oncogene. 2005 Jun Alves F, Vogel W, Mossie K, Millauer B, Höfler H, Ullrich A. 2;24(24):3896-905 Distinct structural characteristics of discoidin I subfamily Ram R, Lorente G, Nikolich K, Urfer R, Foehr E, Nagavarapu receptor tyrosine kinases and complementary expression in U. Discoidin domain receptor-1a (DDR1a) promotes glioma cell human cancer. Oncogene. 1995 Feb 2;10(3):609-18 invasion and adhesion in association with matrix Barker KT, Martindale JE, Mitchell PJ, Kamalati T, Page MJ, metalloproteinase-2. J Neurooncol. 2006 Feb;76(3):239-48 Phippard DJ, Dale TC, Gusterson BA, Crompton MR. Yamanaka R, Arao T, Yajima N, Tsuchiya N, Homma J, Expression patterns of the novel receptor-like tyrosine kinase, Tanaka R, Sano M, Oide A, Sekijima M, Nishio K. Identification DDR, in human breast tumours. Oncogene. 1995 Feb of expressed genes characterizing long-term survival in 2;10(3):569-75 malignant glioma patients. Oncogene. 2006 Sep Perez JL, Jing SQ, Wong TW. Identification of two isoforms of 28;25(44):5994-6002 the Cak receptor kinase that are coexpressed in breast tumor Domenyuk VP, Litovkin KV, Verbitskaya TG, Dubinina VG, cell lines. Oncogene. 1996 Apr 4;12(7):1469-77 Bubnov VV. Identification of new DNA markers of endometrial Sakuma S, Saya H, Tada M, Nakao M, Fujiwara T, Roth JA, cancer in patients from the Ukrainian population. Exp Oncol. Sawamura Y, Shinohe Y, Abe H. Receptor protein tyrosine 2007 Jun;29(2):152-5 kinase DDR is up-regulated by p53 protein. FEBS Lett. 1996 Ford CE, Lau SK, Zhu CQ, Andersson T, Tsao MS, Vogel WF. Dec 2;398(2-3):165-9 Expression and mutation analysis of the discoidin domain Weiner HL, Rothman M, Miller DC, Ziff EB. Pediatric brain receptors 1 and 2 in non-small cell lung carcinoma. Br J tumors express multiple receptor tyrosine kinases including Cancer. 2007 Mar 12;96(5):808-14 novel cell adhesion kinases. Pediatr Neurosurg. 1996 Park HS, Kim KR, Lee HJ, Choi HN, Kim DK, Kim BT, Moon Aug;25(2):64-71; discussion 71-2 WS. Overexpression of discoidin domain receptor 1 increases Nemoto T, Ohashi K, Akashi T, Johnson JD, Hirokawa K. the migration and invasion of hepatocellular carcinoma cells in Overexpression of protein tyrosine kinases in human association with matrix metalloproteinase. Oncol Rep. 2007 esophageal cancer. Pathobiology. 1997;65(4):195-203 Dec;18(6):1435-41 Weiner HL, Huang H, Zagzag D, Boyce H, Lichtenbaum R, Ziff Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, EB. Consistent and selective expression of the discoidin Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, domain receptor-1 tyrosine kinase in human brain tumors. Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Neurosurgery. 2000 Dec;47(6):1400-9 Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb MJ. Global Alves F, Saupe S, Ledwon M, Schaub F, Hiddemann W, Vogel survey of phosphotyrosine signaling identifies oncogenic WF. Identification of two novel, kinase-deficient variants of kinases in lung cancer. Cell. 2007 Dec 14;131(6):1190-203 discoidin domain receptor 1: differential expression in human colon cancer cell lines. FASEB J. 2001 May;15(7):1321-3 Turashvili G, Bouchal J, Baumforth K, Wei W, Dziechciarkova M, Ehrmann J, Klein J, Fridman E, Skarda J, Srovnal J,

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Hajduch M, Murray P, Kolar Z. Novel markers for differentiation Shen Q, Cicinnati VR, Zhang X, Iacob S, Weber F, of lobular and ductal invasive breast carcinomas by laser Sotiropoulos GC, Radtke A, Lu M, Paul A, Gerken G, microdissection and microarray analysis. BMC Cancer. 2007a Beckebaum S. Role of microRNA-199a-5p and discoidin Mar 27;7:55 domain receptor 1 in human hepatocellular carcinoma invasion. Mol Cancer. 2010 Aug 27;9:227 Turashvili G, Bouchal J, Ehrmann J, Fridman E, Skarda J, Kolar Z. Novel immunohistochemical markers for the Colas E, Perez C, Cabrera S, Pedrola N, Monge M, Castellvi J, differentiation of lobular and ductal invasive breast carcinomas. Eyzaguirre F, Gregorio J, Ruiz A, Llaurado M, Rigau M, Garcia Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. M, Ertekin T, Montes M, Lopez-Lopez R, Carreras R, 2007b Jun;151(1):59-64 Xercavins J, Ortega A, Maes T, Rosell E, Doll A, Abal M, Reventos J, Gil-Moreno A. Molecular markers of endometrial Yoshida D, Teramoto A. Enhancement of pituitary adenoma carcinoma detected in uterine aspirates. Int J Cancer. 2011 cell invasion and adhesion is mediated by discoidin domain Jan 4; receptor-1. J Neurooncol. 2007 Mar;82(1):29-40 Gu TL, Deng X, Huang F, Tucker M, Crosby K, Rimkunas V, Tomasson MH, Xiang Z, Walgren R, Zhao Y, Kasai Y, Miner T, Wang Y, Deng G, Zhu L, Tan Z, Hu Y, Wu C, Nardone J, Ries RE, Lubman O, Fremont DH, McLellan MD, Payton JE, MacNeill J, Ren J, Reeves C, Innocenti G, Norris B, Yuan J, Westervelt P, DiPersio JF, Link DC, Walter MJ, Graubert TA, Yu J, Haack H, Shen B, Peng C, Li H, Zhou X, Liu X, Rush J, Watson M, Baty J, Heath S, Shannon WD, Nagarajan R, Comb MJ. Survey of tyrosine kinase signaling reveals ROS Bloomfield CD, Mardis ER, Wilson RK, Ley TJ. Somatic kinase fusions in human cholangiocarcinoma. PLoS One. 2011 mutations and germline sequence variants in the expressed Jan 6;6(1):e15640 tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood. 2008 May 1;111(9):4797-808 Hidalgo-Carcedo C, Hooper S, Chaudhry SI, Williamson P, Harrington K, Leitinger B, Sahai E. Collective cell migration Tun HW, Personett D, Baskerville KA, Menke DM, Jaeckle KA, requires suppression of actomyosin at cell-cell contacts Kreinest P, Edenfield B, Zubair AC, O'Neill BP, Lai WR, Park mediated by DDR1 and the cell polarity regulators Par3 and PJ, McKinney M. Pathway analysis of primary central nervous Par6. Nat Cell Biol. 2011 Jan;13(1):49-58 system lymphoma. Blood. 2008 Mar 15;111(6):3200-10 Kim HG, Hwang SY, Aaronson SA, Mandinova A, Lee SW. Franco-Pons N, Tomàs J, Roig B, Auladell C, Martorell L, DDR1 receptor tyrosine kinase promotes prosurvival pathway Vilella E. Discoidin domain receptor 1, a tyrosine kinase through Notch1 activation. J Biol Chem. 2011 May receptor, is upregulated in an experimental model of 20;286(20):17672-81 remyelination and during oligodendrocyte differentiation in vitro. J Mol Neurosci. 2009 May;38(1):2-11 This article should be referenced as such: Hajdu M, Singer S, Maki RG, Schwartz GK, Keohan ML, Roig B, Vilella E. DDR1 (discoidin domain receptor tyrosine Antonescu CR. IGF2 over-expression in solitary fibrous kinase 1). Atlas Genet Cytogenet Oncol Haematol. 2011; tumours is independent of anatomical location and is related to 15(11):951-955. loss of imprinting. J Pathol. 2010 Jul;221(3):300-7

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 955 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)) Luca Braccioli, Marilena V Iorio, Patrizia Casalini Molecular Targeting Unit, Experimenatal Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, 20133 Milano, Italy (LB, MVI, PC)

Published in Atlas Database: May 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/ERBB2ID162ch17q11.html DOI: 10.4267/2042/46053 This article is an update of :Casalini P, Iorio MV. ERBB2 (erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) ). Atlas Genet Cytogenet Oncol Haematol 2005;9(1):6-12.

Polymorphisms: allelic variations at amino acid Identity positions 654 and 655 of isoform (a) (positions 624 and Other names: CD340; HER2; HER-2; HER-2/neu; 625 of isoform (b)) have been reported, with the most MLN 19; NEU; NGL; TKR1 common allele B1 (Ile-654/Ile-655); allele B2 (Ile- Location: 17q12 654/Val-655); allele B3 (Val-654/Val-655). This nucleotide polymorphism could be associated with development of gastric carcinoma and with breast cancer risk, particularly among younger women. Transcription Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. - mRNA transcript variant: this variant (1) represents the shorter transcript but encodes the longer isoform (a) Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular (protein: erbB-2 isoform (a)). Cytogenetics. - mRNA transcript variant: this variant (2) (protein: Note erbB-2 isoform (b)) contains additional exons at its 5' Tyrosine-kinase receptor (RTK). The HER family of end and lacks an alternate 5' noncoding exon, compared RTKs consists of four receptors: epidermal growth to variant (1). These differences result in translation factor receptor (EGFR, also called HER-1 or erbB-1), initiation at an in-frame, downstream AUG and an HER-2 (also called erbB-2 or Neu), HER-3 and HER-4 isoform (b) with a shorter N-terminus compared to (also called erbB-3 and erbB-4, respectively). isoform (a). - mRNA transcript variant: herstatin HER2-ECD DNA/RNA 1300 bp alternative erbB-2 transcript that retains intron 8. This alternative transcript specifies 340 residues Description identical to subdomains I and II from the extracellular Sequence length: 40522; CDS: 3678. 30 exons, 26 domain of p185erbB-2 followed by a unique C- coding exons; total exon length: 4816, max exon terminal sequence of 79 aa encoded by intron 8. The length: 969, min exon length: 48. Number of SNPs: 17. herstatin mRNA is expressed in normal human fetal kidney and liver, but is at reduced levels relative to

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 956 ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma Braccioli L, et al. derived oncogene homolog (avian))

p185erbB-2 mRNA in carcinoma cells that contain an domain of these receptors acts as an inhibitor until they amplified erbB-2 gene. are bound by ligand. This isoform can cause resistance - mRNA transcript variant: an alternative transcript to trastuzumab, an antibody that works by binding to a form of the human homologous gene erbB-2, domain in the external domain of HER2. HER2p95 containing an in-frame deletion encompassing exon 19, fragments arise through at least 2 different has been detected in human breast carcinomas. mechanisms: proteolytic shedding of the extracellular - mRNA transcript variant: an alternative transcript domain of the full-length receptor and translation of the form of the human homologous gene erbB-2, called mRNA encoding HER2 from internal initiation codons. HER2 ∆16, has been detected in human breast Shedding of the ectodomain of HER2 generates a 95- carcinomas. This splicing variant, contains an in-frame to 100-kDa HER2 p95 membrane-anchored fragment. deletion and encodes a receptor lacking exon 16, which Translation of the mRNA encoding HER2 can be immediately precedes the transmembrane domain initiated from the AUG codon that gives rise to the full- containing two cysteines. The loss of these cysteine length protein of 1255 amino acids or, alternatively, residues might induce a change in the conformation of from 2 internal initiation codons at positions 611 and HER2 receptor extracellular domain that promotes 678, located upstream and downstream of the intermolecular disulfide bonding and, in turn, transmembrane domain, respectively. homodimers capable of transforming cells. Ectopic Expression expression of HER2 ∆16 promotes receptor dimerization, cell invasion, and trastuzumab resistant HER2 protein is expressed in several human organs and tumor cell lines. The potential metastatic and oncogenic tissues: normal epithelium, endometrium and ovarian properties of HER2 ∆16 were mediated through direct epithelium and at neuromuscular level; prostate, coupling of HER2 ∆16 to Src kinase. pancreas, lung, kidney, liver, heart, hematopoietic cells. HER2 expression is low in mononuclear cells from Protein bone marrow, peripheral blood (PB) and mobilized PB. The higher expression has been found in cord blood- Description derived cells. Quiescent CD34+ progenitor cells from erbB2 encodes a 185-kDa, 1255 amino acids, orphan all blood sources and resting lymphocytes are HER2 receptor tyrosine kinase, and displays potent oncogenic negative, but the expression of this receptor is up- activity when overexpressed. The proto-oncogene regulated during cell-cycle recruitment of progenitor consists of three domains: a single transmembrane cells. Similarly, it increases in mature, hematopoietic domain that separates an intracellular kinase domain proliferating cells, underlying the correlation between from an extracellular ligand-binding domain. An HER2 and the proliferating status of hematopoietic aberrant form of HER2, missing the extracellular cells. domain, so-called Localisation HER2p95, has been found in some breast cancers. Plasma membrane. HER2p95 is constitutively active because the external

HER2 protein: schematic representation. Receptor tyrosin-kinases (RTKs) are cell surface allosteric enzymes consisting of: an extracellular ligand-binding domain (blue); a single transmembrane (TM) domain has an extensive homology to the epidermal grow factor receptor (brown); a cytoplasmic domain with catalityc activity (green).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 957 ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma Braccioli L, et al. derived oncogene homolog (avian))

Function Mutations Activation and interactions For the other member of the HER family, ligand Somatic binding induces receptor homo- or heterodimerization, The Cancer Genome Project and Collaborative Group which is essential for TKs activation and subsequent sequenced the erbB-2 gene from 120 primary lung recruitment of target proteins, in turn initiating a tumors and identified 4% that had mutations within the complex signaling cascade that leads into distinct kinase domain; in the adenocarcinoma subtype of lung transcriptional programs. There are several HER- cancer, 10% of cases had mutations. specific ligands. HER2, which apparently has no direct In non small cell lung cancer (adenocarcinoma) the or specific ligand, plays a major coordinating role in following erbB-2 mutations were found: the HER network because of its ability to enhance and insertion/duplication of GCATACGTGATG at stabilize the dimerization: each receptor with a specific nucleotide 2322 of the erbB-2 gene, resulting in a 4- ligand appears in fact to prefer HER-2 as its amino acid insertion (AYVM) at codon 774. Insertion heterodimeric partner. HER-2-containing heterodimers of CTGTGGGCT at nucleotide 2335 of the erbB-2 are characterized by extremely high signaling potency gene, resulting in a 3-amino acid insertion (VGS) because HER-2 dramatically reduces the rate of ligand starting at codon 779; a 2-bp substitution in the erbB-2 dissociation, allowing strong and prolonged activation gene, TT-CC at nucleotides 2263 and 2264, resulting in of downstream signaling pathways. a leu755-to-pro (L755P) substitution. Signaling and cellular In lung cancer a C44645G transition in the erbB-2 gene The most important intracellular pathways activated by that caused a pro1170-to-ala substitution (P1170A). HER2 are those involving mitogen activated protein In a glioblastoma a 2740G-A transition in the erbB-2 kinase (MAPK) and phosphatidylinositol-3 kinase gene that caused a glu914-to-lys substitution (E914K). (PI3K). HER2 expression in cancer, besides its role in In a gastric tumor a 2326G-A transition in the erbB-2 proliferation, enhances and prolongs survivals signals, gene that caused a gly776-to-ser (G776S) substitution. associating up-regulation of this receptor to the In an ovarian tumor, a 2570A-G transition in the erbB- malignant phenotype. At the same time, and depending 2 gene that caused an asn857-to-ser (N857S) on cellular status, the role of this receptor in controlling substitution. cell fate can also lead to differentiation and apoptosis. Physiological Implicated in Role in development and differentiation: - HER2 has several non-oncogenic roles in regulating Hematological malignancies growth, differentiation, apoptosis and/or remodeling in Disease normal mammary glands. Dominant-negative forms of HER2 expression can be detected in blast cells from HER2 have significant defects in mammary patients with hematological malignancies including development and lactation. acute lymphoblastic leukemia (ALL). It could be used - HER2 has an important role in development and as a potential target for the application of HER2- function of heart. Cre-Lox technology to mutate erbB-2 directed treatment strategies in ALL including specifically in ventricular cardiomyocytes leads to a vaccination approaches. severe cardiomyopathy. This is inferred also by the adverse cardiac side effects observed in breast cancer Bladder cancer patients treated with the monoclonal anti-HER2 Ab Prognosis Trastuzumab. HER2 is overexpressed in 25% to 40% of several - HER2 has a role in control of Schwann cell human tumors and associated with the malignancy of myelination and it has been demonstrated that HER2 the disease, high mitotic index and a shorter survival signaling is also critical for oligodendrocyte time for the patient. Overexpression of ErbB-2 is also differentiation in vivo. associated with transitional cell carcinoma of the - HER2 has a dual role in both muscle spindle bladder. HER2 overexpression occurs in muscle- maintenance and survival of myoblasts. Muscle- invasive urothelial carcinomas of the bladder and is specific HER2 KO results in fact in viable mice with a associated with worse survival; amplifications of erbB- progressive defect in proprioception due to loss of 2 gene are also frequently linked to alterations of the muscles spindles. TOP2A gene in bladder cancer. Furthermore, HER2 Homology overexpression and amplification in urothelial carcinoma of the bladder is found associated with MYC Homolog to avian erythroblastic leukemia viral (v-erb- co-amplification. b) oncogen 2.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 958 ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma Braccioli L, et al. derived oncogene homolog (avian))

Breast carcinoma detrimental in patients with HER2-positive tumors. In Paget's disease of breast, HER2 protein overexpression Prognosis is caused by amplification of the erbB-2 gene. HER2 Normal tissues have a low content of HER2 membrane has a role in this disease of the breast, where the protein. Overexpression of HER2 is seen in 20% of epidermis of the nipple is infiltrated by large neoplastic breast and it confers worse biological behavior and cells of glandular origin. It seems that binding of clinical aggressiveness in breast cancer. Breast cancers heregulin-alpha to the receptor complex on Paget cells can have up to 25 to 50 copies of the HER2 gene and results in chemotaxis of these breast cancer cells. The up to a 40- to 100-fold increase in HER2 protein isoforms HER2p95 and HER2 ∆16 are found in some resulting in 2 million receptors expressed at the tumor breast cancers and the expression of these hyperactive cell surface. The differential HER2 expression between forms of HER2 may contribute to the malignant normal tissues and tumors helps to define HER2 as an progression. ideal treatment target. Trastuzumab, the first treatment targeting HER2, is well tolerated in patients and has Cervical cancer little toxicity because its effects are relatively specific Prognosis for cancer cells overexpressing HER2. HER2 HER2 may be activated in the early stage of amplification is a relatively early event in human breast pathogenesis of cervical carcinoma in geriatric patients tumorigenesis, occurring in almost 50% of in situ and is frequently amplified in squamous cell carcinoma carcinomas. HER2 status is maintained during of the uterine cervix. progression to invasive disease and to nodal and distant metastasis. The fact that only 20% of invasive breast Childhood medulloblastoma cancers are HER2 amplified suggests that many HER2- Prognosis amplified in situ cancers never progress to the invasive Overexpression of HER2 in medulloblastoma is stage. HER2 amplification defines a subtype of breast associated with poor prognosis and metastasis and cancer with a unique signature of genes and this is HER2-HER4 receptor heterodimerization is of maintained during progression. Some tumors lose particular biological significance in this disease. HER2 expression following treatment with Colorectal cancer trastuzumab, presumably by selection of a HER2- negative clone not killed by treatment. Conversely, Prognosis HER2 may become positive in some initially negative Overexpression of HER2 occurs in a significant tumors over time, especially after endocrine therapy number of colorectal cancers. It was significantly targeting ER. Indeed, estrogen receptor has been shown associated with poor survival and related to tumor to downregulate HER2 and, conversely, HER2 is able progression in colorectal cancer. to downregulate ER expression. Therefore, it is not Oral squamous cell carcinoma surprising that blocking ER might upregulate HER2 and that blocking HER2 might upregulate ER. HER2- Prognosis amplified breast cancers have unique biological and E6/E7 proteins of HPV type 16 and HER2 cooperate to clinical characteristics. They have increased sensitivity induce neoplastic transformation of primary normal to certain cytotoxic agents such as doxorubicin, relative oral epithelial cells. Overexpression of HER2 receptor resistance to hormonal agents, and propensity to is a frequent event in oral squamous cell carcinoma and metastasize to the brain and viscera. HER2-amplified is correlated with poor survival. tumors have an increased sensitivity to doxorubicin Gastric cancer possibly due to coamplification of the topoisomerase-2 Prognosis gene, which is near the HER2 locus on chromosome 17 HER2 amplification/overexpression does not seem to and is the target of the drug. Half of HER2-positive play a role in the molecular pathogenesis of most breast cancers are ER positive but they generally have gastrinomas. However, mild gene amplification occurs lower ER levels, and many have p53 alterations. These in a subset of them, and overexpression of this receptor tumors have higher proliferation rates and more is associated with aggressiveness of the disease. HER2 aneuploidy and are associated with poorer patient overexpression in patients with gastric cancer, and it prognosis. The poor outcome is dramatically improved has been solidly correlated to poor outcomes and a with appropriate chemotherapy combined with the more aggressive disease. The overall HER2 positive HER2-targeting drug trastuzumab. Overexpression of rate is about 22%. HER2 overexpression rate in gastric the erbB-2 gene is associated with tumor cancer varies according to the site of the tumor. A aggressiveness, and with patient responsiveness to higher overexpression rate (36%) was shown in doxorubicin, cyclophosphamide, methotrexate, gastroesophageal junction (GEJ) tumors in comparison fluorouracil (CMF), and to paclitaxel, whereas to 21% in gastric tumors. tamoxifen was found to be ineffective and even

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 959 ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma Braccioli L, et al. derived oncogene homolog (avian))

Germ-cell testicular tumor Pancreatic adenocarcinoma Prognosis Prognosis A significant correlation was observed between HER2 Overexpression of HER-2 in pancreatic overexpression and clinical outcome in germ-cell adenocarcinoma seems to be a result of increased testicular tumors. transcription rather than gene amplification. The Cholangiocarcinoma coexpression of HER2 oncogene protein, epidermal growth factor receptor, and TGF-beta1 in pancreatic Prognosis ductal adenocarcinoma is related to the Data are still controversial about HER2 role in this histopathological grades and clinical stages of tumors. carcinoma. Increased HER2 expression contributes to The blockade of HER2 inhibits the growth of the development of cholangiocarcinogenesis into an pancreatic cancer cells in vitro. HER2 overexpression advanced stage associated with tumor metastasis. In was reported to accumulate in well differentiated addition, overexpression of HER2 and COX-2 pancreas adenocarcinomas whereas it is only correlated directly with tumor differentiation. However, infrequently found in poorly differentiated or other studies report that HER2 expression is associated undifferentiated tumors, in vivo and in vitro analyses with more favorable clinical features, such as a have suggested that targeting HER2 might increase polypoid macroscopic type and absence of other organ treatment effects of conventional chemotherapies of involvement, and has been reported that the proportion pancreas adenocarcinoma. However, unlike in breast of HER2-positive cases in papillary adenocarcinoma is cancer, the application of antibodies directed against higher than in other histological types and is associated HER2 has not yet become an established therapy for with an early disease stage. HER2 is preferentially pancreas adenocarcinoma. expressed in well differentiated component, and it is also expressed in dedifferentiated components in Prostate cancer progressive cases. Prognosis Lung cancer HER2 plays pivotal roles in prostate cancer. Studies have shown that 25% of untreated primary tumors, Prognosis 59% of localized tumors after neoadjuvant hormone HER2 is overexpressed in less than 20% of patients therapy, and 78% of metastatic tumors overexpressed with non-small cell lung cancer (NSCLC) and studies HER2. Several lines of evidence have implicated HER2 have shown that overexpression of this receptor is as a key mediator in the recurrence of prostate cancer to correlated with a poor prognosis in both resected and a hormone-refractory, androgen-independent tumor, advanced NSCLC. HER2 overexpression has an which is the hallmark of prostate cancer progress. The important function in the biology of NSCLC and may driving force for prostate cancer recurrence is the have a prognostic value for patients with metastatic reactivation of androgen receptor (AR), which is a type NSCLC. of nuclear receptors, activated by steroid hormone but Osteosarcoma ablated in hormonal therapy. Phosphorylation and reactivation of AR stimulate cancer cell growth and Prognosis trigger tumor progression. It has been observed that Higher frequency of HER2 expression has been overexpression of HER2 kinase enhanced AR function observed in samples from patients with metastatic and hormone-independent growth in prostate tumor disease at presentation and at the time of relapse, and it cells. HER2 activated AR through the MAPK pathway. correlates with worse histologic response and decreased Additionally, the HER2/HER3 dimmer increases AR event-free survival. HER2 could be an effective target protein stability and promotes the binding of AR to the for the immunotherapy of osteosarcoma, especially the promoter region of its target genes, resulting in AR type with high metastatic potential. activation in an androgen-depleted environment. Ovarian cancer Salivary gland tumor Prognosis Prognosis HER2 overexpression varies from 9% to 32% of all Several results demonstrated significant positive cases of ovarian cancer and its overexpression is more staining of HER2 in the salivary tumorigenic tissue but frequent in advanced stage of ovarian cancer. not in the surrounding non-tumorigenic tissue, pointing Overexpression of HER2 in ovarian cancer cells leads to a biological role in the tumorigenic process. HER2 to faster cell growth, higher abilities in DNA repair and amplification is present predominantly in tumors with colony formation. A cross-talk between HER2 and high HER2 expression and seems to be the dominant estrogen receptor (ER) was identified in ovarian cancer mechanism for HER2 overexpression in this tumor cells. Estrogen has been proven to induce the type. phosphorylation of HER2, and initiate the HER2's signaling pathway.

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in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Mini Review

KIAA0101 (KIAA0101) Shannon Joseph, Lingbo Hu, Fiona Simpson University of Queensland Diamantina Institute, University of Queensland, Brisbane, Australia (SJ, LH, FS)

Published in Atlas Database: May 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/KIAA0101ID41058ch15q22.html DOI: 10.4267/2042/46054 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Hosokawa et al., 2007). KIAA0101 was also reported Identity to be down-regulated in colon cancer cells (Simpson et Other names: FLJ58702; NS5ATP9; OEATC-1; al., 2006) and human hepatocellular carcinoma (Guo et OEATC1; PAF; p15(PAF); p15PAF al., 2006). Nuclear protein NF-kappaB (p50) (Li et al., HGNC (Hugo): KIAA0101 2008), the Hepatitis C virus protein non-structural protein 5A (NS5A) (Shi et al., 2008) and ATF3 (Turchi Location: 15q22.31 et al., 2009) bind to the promoter region upstream of the KIAA0101 transcription initiation site promoting DNA/RNA transcription in response to DNA damage. Note Pseudogene Murine gene embryonic expression shows highly None. restricted expression of KIAA0101 in facial prominences, limbs, somites, brain, spinal cord and hair Protein follicles. It has a suggested role in embryonic development (van Beuren et al., 2007). Note Description NS5ATP9, Hepatitis C virus NS5A-transactivated protein 9, HCV NS5A-transactivated protein 9, The gene is composed of 4 exons. Overexpressed in anaplastic thyroid carcinoma-1, Transcription OEATC-1, OEATC1, p15(PAF), L5. One transcript. RNA was expressed as a 1.1 kb Description message in liver, pancreas and placenta at high levels The KIAA0101 gene encodes for a 111 amino acid 15 (Yu et al., 2001). RNA profiling shows it is highly kDa protein. It contains a conserved proliferating cell expressed in a number of tumors, specifically in nuclear antigen (PCNA)-binding motif (Yu et al., esophageal tumors, anaplastic thyroid carcinomas, 2001). pancreatic cancer and non-small-cell lung cancer lines (Yu et al., 2001;

DNA diagram. KIAA0101 9768 chr: 62444265-62460755. One transcript, 4 exons.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 965 KIAA0101 (KIAA0101) Joseph S, et al.

Protein diagram. 111 aa in length, single transcript, mutation I-A at position 65 and mutation F-A at position 68 results in loss of PCNA binding.

Expression Implicated in Predominant expression in liver, pancreas and brain. Not detected in heart or liver (Yu et al., 2001). The Hepatocellular carcinoma KIAA0101 protein was down-regulated in human Disease hepatocellular carcinoma (Guo et al., 2006; Yuan et al., KIAA0101 expression was proposed to promote 2007). Increased protein levels have been detected in growth advantage and hypoxic insult resistance and be pancreatic cancer cells (Hosokawa et al., 2007). associated with promoting cell proliferation (Yuan et Localisation al., 2007). KIAA0101 overexpression was associated with concomitant p53 mutation and vascular invasion Nucleus, mitochondrion (Yu et al., 2001; Guo et al., (Yuan et al., 2007). This study suggested that high 2006; Simpson et al., 2006; Yuan et al., 2007). expression in hepatocellular carcinoma was indicative Function of tumour recurrence, metastatic potential and poor The KIAA0101 protein binds to PCNA through a prognosis (Yuan et al., 2007). KIAA0101 was also conserved PCNA binding domain. PCNA is required reported to be downregulated in hepatocellular for DNA replication or repair as a supplementary factor carcinoma (Guo et al., 2006). This study suggested that for DNA polymerase (Paunesku et al., 2001). Proteins KIAA0101 had a growth inhibitory effect. bound to PCNA can prevent its binding to DNA Astrocytomas polymerase, in turn leading to inhibition of DNA Disease synthesis, cell cycle progression and G1 cell cycle arrest (Yuan et al., 2007). PCNA binding proteins also Grade IV (glioblastoma multiforme) astrocytomas had interact with each other to modulate this regulation. For 5 times higher expression levels when compared to example, KIAA0101 also interacts in a complex with Grade I (pilocytic) astrocyomas suggesting that p33ING1 isoform 2, another PCNA binding protein KIAA0101 abundance correlates with malignancy which is a potential tumor suppressor and regulator of grade in human astrocytes (Marie et al., 2008). p53 (Simpson et al., 2006). UV irradiation caused Pancreatic cancer increased association of KIAA0101 with PCNA Disease suggesting that this association occurs in response to Pancreatic cells overexpress KIAA0101 both at cDNA DNA damage. KIAA0101 also competes with and protein level. Knock down of KIAA0101 by p21WAF for binding to PCNA (Yu et al., 2001). siRNA attenuated proliferation and DNA replication KIAA0101 most recently been shown to act in concert whereas overexpression enhanced cell growth in with ATF3 to control genomic integrity after UV stress pancreatic cancer cell lines (Hosokawa et al., 2007). (Turchi et al., 2009). KIAA0101 expression levels are also regulated by NF-kappaB, this protein family Anaplastic thyroid carcinoma having significant roles in apoptosis, cell cycle Disease regulation and onocgenesis (Hosokawa et al., 2007; Li Anaplastic thyroid carcinoma cell lines had significant et al., 2008). Together this data suggests a likely role overexpression of KIAA0101. Cell growth was for KIAA0101 in DNA repair and in protection from inhibited by silencing KIAA0101 expression using UV-induced cell death. siRNA. KIAA0101 may be oncogenic or cell growth- promoting but the mechanism for this is not understood Mutations (Mizutani et al., 2005). Note Follicular lymphoma Experimentally mutation I-A at position 65 and F-A at Disease position 68 result in loss of PCNA binding (Yu et al., High expression of KIAA0101 (along with CCNB1 2001). No other mutations have been described. (cyclin B1), CDC2, CDKN3A, CKS1B, ANP32E) was Screening of colon tumour samples identified a associated with better survival/response rate in a polymorphism in the intronic region just prior to the univariate analysis following CHOP start of exon 2 (982-15delT) (Simpson et al., 2006). (cyclophosphamide, vincristine, doxorubicin,

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 966 KIAA0101 (KIAA0101) Joseph S, et al.

prednisone) chemotherapy for follicular lymphoma KIAA0101/p15(PAF) binds the potential tumor suppressor treatment. Identification of these proteins aims to product p33ING1b. Exp Cell Res. 2006 Jan 1;312(1):73-85 develop a follicular lymphoma international prognostic Collado M, Garcia V, Garcia JM, Alonso I, Lombardia L, Diaz- index to aid in informing a successful treatment Uriarte R, Fernández LA, Zaballos A, Bonilla F, Serrano M. Genomic profiling of circulating plasma RNA for the analysis of strategy (Bjorck et al., 2005). cancer. Clin Chem. 2007 Oct;53(10):1860-3 Oncogenesis Hosokawa M, Takehara A, Matsuda K, Eguchi H, Ohigashi H, This gene is thought to be oncogenic through Ishikawa O, Shinomura Y, Imai K, Nakamura Y, Nakagawa H. modulation of DNA repair pathways via interaction Oncogenic role of KIAA0101 interacting with proliferating cell with PCNA. nuclear antigen in pancreatic cancer. Cancer Res. 2007 Mar 15;67(6):2568-76 References van Bueren KL, Bennetts JS, Fowles LF, Berkman JL, Simpson F, Wicking C. Murine embryonic expression of the Nagase T, Miyajima N, Tanaka A, Sazuka T, Seki N, Sato S, gene for the UV-responsive protein p15(PAF). Gene Expr Tabata S, Ishikawa K, Kawarabayasi Y, Kotani H. Prediction of Patterns. 2007 Jan;7(1-2):47-50 the coding sequences of unidentified human genes. III. The coding sequences of 40 new genes (KIAA0081-KIAA0120) Yuan RH, Jeng YM, Pan HW, Hu FC, Lai PL, Lee PH, Hsu HC. deduced by analysis of cDNA clones from human cell line KG- Overexpression of KIAA0101 predicts high stage, early tumor 1. DNA Res. 1995;2(1):37-43 recurrence, and poor prognosis of hepatocellular carcinoma. Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5368-76 Paunesku T, Mittal S, Proti ć M, Oryhon J, Korolev SV, Joachimiak A, Woloschak GE. Proliferating cell nuclear antigen Li K, Ma Q, Shi L, Dang C, Hong Y, Wang Q, Li Y, Fan W, (PCNA): ringmaster of the genome. Int J Radiat Biol. 2001 Zhang L, Cheng J. NS5ATP9 gene regulated by NF-kappaB Oct;77(10):1007-21 signal pathway. Arch Biochem Biophys. 2008 Nov 1;479(1):15- 9 Yu P, Huang B, Shen M, Lau C, Chan E, Michel J, Xiong Y, Payan DG, Luo Y. p15(PAF), a novel PCNA associated factor Marie SK, Okamoto OK, Uno M, Hasegawa AP, Oba-Shinjo with increased expression in tumor tissues. Oncogene. 2001 SM, Cohen T, Camargo AA, Kosoy A, Carlotti CG Jr, Toledo S, Jan 25;20(4):484-9 Moreira-Filho CA, Zago MA, Simpson AJ, Caballero OL. Maternal embryonic leucine zipper kinase transcript Björck E, Ek S, Landgren O, Jerkeman M, Ehinger M, abundance correlates with malignancy grade in human Björkholm M, Borrebaeck CA, Porwit-MacDonald A, astrocytomas. Int J Cancer. 2008 Feb 15;122(4):807-15 Nordenskjöld M. High expression of cyclin B1 predicts a favorable outcome in patients with follicular lymphoma. Blood. Shi L, Zhang SL, Li K, Hong Y, Wang Q, Li Y, Guo J, Fan WH, 2005 Apr 1;105(7):2908-15 Zhang L, Cheng J. NS5ATP9, a gene up-regulated by HCV NS5A protein. Cancer Lett. 2008 Feb 8;259(2):192-7 Mizutani K, Onda M, Asaka S, Akaishi J, Miyamoto S, Yoshida A, Nagahama M, Ito K, Emi M. Overexpressed in anaplastic Turchi L, Fareh M, Aberdam E, Kitajima S, Simpson F, Wicking thyroid carcinoma-1 (OEATC-1) as a novel gene responsible C, Aberdam D, Virolle T. ATF3 and p15PAF are novel for anaplastic thyroid carcinoma. Cancer. 2005 May gatekeepers of genomic integrity upon UV stress. Cell Death 1;103(9):1785-90 Differ. 2009 May;16(5):728-37 Guo M, Li J, Wan D, Gu J. KIAA0101 (OEACT-1), an Miller WR, Larionov A. Changes in expression of oestrogen expressionally down-regulated and growth-inhibitory gene in regulated and proliferation genes with neoadjuvant treatment human hepatocellular carcinoma. BMC Cancer. 2006 Apr highlight heterogeneity of clinical resistance to the aromatase 29;6:109 inhibitor, letrozole. Breast Cancer Res. 2010;12(4):R52 Simpson F, Lammerts van Bueren K, Butterfield N, Bennetts This article should be referenced as such: JS, Bowles J, Adolphe C, Simms LA, Young J, Walsh MD, Leggett B, Fowles LF, Wicking C. The PCNA-associated factor Joseph S, Hu L, Simpson F. KIAA0101 (KIAA0101). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):965-967.

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Gene Section Review

PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8) Nikki Minnebo, Nele Van Dessel, Monique Beullens, Aleyde van Eynde, Mathieu Bollen Laboratory of Biosignaling & Therapeutics, Dept Molecular Cell Biology, University of Leuven, Herestraat 49 box 901, 3000 Leuven, Belgium (NM, NV, MB, Av, MB)

Published in Atlas Database: May 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/PPP1R8ID41811ch1p35.html DOI: 10.4267/2042/46055 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

form of NIPP1 encompassing residues 225-351 only. Identity This transcript has been shown to restore Other names: ARD-1; ARD1; NIPP-1; NIPP1; endoribonuclease activity to E. coli rne gene mutants PRO2047 (Wang and Cohen, 1994; Claverie-Martin et al., 1997; HGNC (Hugo): PPP1R8 Chang et al., 1999; Jin et al., 1999; Van Eynde et al., 1999). Moreover, note that the name ARD1 is also used Location: 1p35.3 for a completely unrelated protein, TRIM23 (Mishima DNA/RNA et al., 1993). Description Note The entire PPP1R8 gene spans 20.9 kb on the forward ARD1 is a frequently used alias for NIPP1, however, strand of the long arm on chromosome 1. The gene this name actually corresponds to an alternative contains 7 exons of which exon 1 has 5'-alternative transcript (NIPP1gamma), which encodes a truncated splice sites.

Genomic organization of the PPP1R8 gene and the alternative splice variants with their corresponding coding sequences (black line). Exons and alternative splice sites are indicated by different colors.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 968 PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8) Minnebo N, et al.

Transcription thirds of all known PP1 interacting proteins (Beullens et al., 1999; Beullens et al., 2000; Hendrickx et al., The PPP1R8 gene contains 7 exons which give rise to 5 2009). In addition, the C-terminal 22 residues can alternative splice products (see diagram above). interact with nucleic acids (Jin et al., 1999). When speaking about NIPP1, one usually refers to the NIPP1alpha isoform (39 kDa, 351 residues) which is Expression by far the most abundant isoform in all examined NIPP1 is ubiquitously expressed (Van Eynde et al., mammalian tissues. When visualized by 1995). immunoblotting with C-terminal antibodies (which recognize all isoforms except NIPP1epsilon), also Localisation smaller polypeptides are visualized albeit at a much NIPP1 is a nuclear protein and is enriched in splicing lower intensity as compared to the alpha-isoform. factor storage sites called speckles (Trinkle-Mulcahy et However, it is not clear yet whether these represent al., 1999; Jagiello et al., 2000). Although largely some of the other NIPP1 isoforms or simply nuclear, some data suggest that there also exists a degradation products of NIPP1alpha (Van Eynde et al., cytoplasmic pool of NIPP1 (Boudrez et al., 1999; 1999; Chang et al., 1999; Fardilha et al., 2004). Jagiello et al., 1997). Pseudogene Function A processed pseudogene, termed PPP1R8P, has been NIPP1 is a scaffold protein and exerts its functions via mapped to chromosome 1p33-32 (48790762-48791795 its interacting proteins. NIPP1 was discovered as a bp from pter according to hg19 - Feb 2009). Consistent potent inhibitor and a major nuclear interactor of the with this notion, it is only 1034 bp in size, contains no phosphatase PP1 (Beullens et al., 1999). PP1 functions introns and encodes an incomplete NIPP1-transcript as a holoenzyme in which the interacting proteins due to the presence of various premature stop codons confine substrate specificity, activity and/or (Van Eynde et al., 1999). localization of PP1 (Bollen et al., 2010). For NIPP1, it has been shown that it acts as a physiological PP1 Protein inhibitor for some substrates, while functioning as an activator towards other substrates (Parker et al., 2002; Note Lesage et al., 2004; Comerford et al., 2006; Shi and Nuclear Inhibitor of PP1 (NIPP1) was first identified in Manley, 2007). bovine thymus nuclei as a potent inhibitor of the Also, the interaction between NIPP1 and PP1 can be protein Ser/Thr phosphatase PP1 (Beullens et al., 1992; regulated by phosphorylation (Beullens et al., 1993; Beullens et al., 1993). Later on, it became clear that Van Eynde et al., 1994; Jagiello et al., 1995; Vulsteke NIPP1 exerts various functions in the eukaryotic cell by et al., 1997; Beullens et al., 1999). NIPP1 is also serving as a kind of scaffold protein onto which a involved in 3 other major cellular processes: splicing, variety of proteins can bind. These interaction partners transcription and development. Firstly, NIPP1 is range from protein kinase MELK, protein phosphatase associated with spliceosomes and splicing factor PP1 (PPP1C-a/PPP1C-b/PPP1C-c), the pre-mRNA storage sites called "speckles", probably mediated by splicing factors SAP155 (SF3B1) and CDC5L to the its interaction with the splicing factors CDC5L and chromatin modifiers EED and EZH2. SAP155 (Boudrez et al., 2000; Deckert et al., 2006). Description Pre-mRNA splicing assays showed that NIPP1 is required for late stage spliceosome formation (Beullens NIPP1 consists of 351 amino acids and has a molecular and Bollen, 2002). Recently it was published that mass of 39 kDa. However, it migrates at a size of about NIPP1 directs associated PP1 to dephosphorylate 45 kDa on SDS-PAGE. NIPP1 contains an N-terminal SAP155 (Tanuma et al., 2008). Secondly, NIPP1 is a ForkHead Associated (FHA) domain. transcriptional repressor via its interaction with EED Via this established phosphothreonine-binding domain, and EZH2 (Jin et al., 2003; Roy et al., 2007), two core NIPP1 interacts with protein kinase MELK, the components of the Polycomb repressive complex 2 splicing factors SAP155 and CDC5L and the histone (PRC2). Through its interaction with PRC2, NIPP1 methyltransferase EZH2. Moreover, it was shown that directs it to a subset of Polycomb target genes, where the NIPP1 FHA-domain binds to its ligands via the methyltransferase EZH2 will mark genes proned for phosphorylated TP-dipeptide motifs, present in the silencing by trimethylating histone 3 on lysine 27 interacting proteins (Boudrez et al., 2000; Boudrez et (Nuytten et al, 2008). In 2010, Van Dessel et al. al., 2002; Vulsteke et al., 2004; Nuytten et al., 2008). showed that this targeting function of NIPP1 is Two additional interactors, PP1 and EED, have two dependent on associated PP1. Finally, NIPP1 is separate binding sites on NIPP1: one in the central essential for embryonic development as a NIPP1 knock domain and the other at the C-terminus. In the central out mouse is embryonically lethal at the onset of domain, the binding of NIPP1 to PP1 is mediated by a gastrulation (Van Eynde et al., 2004). so called RVXF-motif, which is present in about two

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 969 PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8) Minnebo N, et al.

A schematic representation of the domain structure of NIPP1 and its interactor binding sites. The FHA-domain (red) binds the indicated interactors via a phosphorylated TP dipeptide motif. NIPP1 binds PP1 via the indicated RVXF-motif and via a C-terminal binding site (green). EED and RNA binding sites are colored blue and orange, respectively. Known phosphorylation sites are indicated in black (in vivo validated) or grey (in vitro data).

The splice variant NIPP1gamma or ARD1 displays a phosphorylation with protein kinase A and casein kinase-2. site-specific Mg 2+ -dependent endoribonuclease activity, Biochem J. 1994 Feb 1;297 ( Pt 3):447-9 in contrast to the NIPP1alpha isoform, which does not Wang M, Cohen SN. ard-1: a human gene that reverses the possess this function (Wang and Cohen, 1994; effects of temperature-sensitive and deletion mutations in the Escherichia coli rne gene and encodes an activity producing Claverie-Martin et al., 1997; Chang et al., 1999; Jin et RNase E-like cleavages. Proc Natl Acad Sci U S A. 1994 Oct al., 1999; Van Eynde et al., 1999). 25;91(22):10591-5 Homology Jagiello I, Beullens M, Stalmans W, Bollen M. Subunit structure and regulation of protein phosphatase-1 in rat liver nuclei. J NIPP1 is highly conserved in all multicellular Biol Chem. 1995 Jul 21;270(29):17257-63 organisms. Van Eynde A, Wera S, Beullens M, Torrekens S, Van Leuven F, Stalmans W, Bollen M. Molecular cloning of NIPP-1, a Implicated in nuclear inhibitor of protein phosphatase-1, reveals homology with polypeptides involved in RNA processing. J Biol Chem. Hepatoma 1995 Nov 24;270(47):28068-74 Disease Claverie-Martin F, Wang M, Cohen SN. ARD-1 cDNA from Cancer. human cells encodes a site-specific single-strand endoribonuclease that functionally resembles Escherichia coli Prognosis RNase E. J Biol Chem. 1997 May 23;272(21):13823-8 An increase in NIPP1 mRNA is correlated with a Jagiello I, Beullens M, Vulsteke V, Wera S, Sohlberg B, malignant phenotype in rats (Kim et al., 2000). Stalmans W, von Gabain A, Bollen M. NIPP-1, a nuclear inhibitory subunit of protein phosphatase-1, has RNA-binding References properties. J Biol Chem. 1997 Aug 29;272(35):22067-71 Vulsteke V, Beullens M, Waelkens E, Stalmans W, Bollen M. Beullens M, Van Eynde A, Stalmans W, Bollen M. The isolation Properties and phosphorylation sites of baculovirus-expressed of novel inhibitory polypeptides of protein phosphatase 1 from nuclear inhibitor of protein phosphatase-1 (NIPP-1). J Biol bovine thymus nuclei. J Biol Chem. 1992 Aug Chem. 1997 Dec 26;272(52):32972-8 15;267(23):16538-44 Beullens M, Van Eynde A, Vulsteke V, Connor J, Shenolikar S, Mishima K, Tsuchiya M, Nightingale MS, Moss J, Vaughan M. Stalmans W, Bollen M. Molecular determinants of nuclear ARD 1, a 64-kDa guanine nucleotide-binding protein with a protein phosphatase-1 regulation by NIPP-1. J Biol Chem. carboxyl-terminal ADP-ribosylation factor domain. J Biol Chem. 1999 May 14;274(20):14053-61 1993 Apr 25;268(12):8801-7 Boudrez A, Evens K, Beullens M, Waelkens E, Stalmans W, Beullens M, Van Eynde A, Bollen M, Stalmans W. Inactivation Bollen M. Identification of MYPT1 and NIPP1 as subunits of of nuclear inhibitory polypeptides of protein phosphatase-1 protein phosphatase 1 in rat liver cytosol. FEBS Lett. 1999 Jul (NIPP-1) by protein kinase A. J Biol Chem. 1993 Jun 16;455(1-2):175-8 25;268(18):13172-7 Chang AC, Sohlberg B, Trinkle-Mulcahy L, Claverie-Martin F, Van Eynde A, Beullens M, Stalmans W, Bollen M. Full Cohen P, Cohen SN. Alternative splicing regulates the activation of a nuclear species of protein phosphatase-1 by production of ARD-1 endoribonuclease and NIPP-1, an

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 970 PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8) Minnebo N, et al.

inhibitor of protein phosphatase-1, as isoforms encoded by the Van Eynde A, Nuytten M, Dewerchin M, Schoonjans L, same gene. Gene. 1999 Nov 15;240(1):45-55 Keppens S, Beullens M, Moons L, Carmeliet P, Stalmans W, Bollen M. The nuclear scaffold protein NIPP1 is essential for Jin Q, Beullens M, Jagiello I, Van Eynde A, Vulsteke V, early embryonic development and cell proliferation. Mol Cell Stalmans W, Bollen M. Mapping of the RNA-binding and Biol. 2004 Jul;24(13):5863-74 endoribonuclease domains of NIPP1, a nuclear targeting subunit of protein phosphatase 1. Biochem J. 1999 Aug 15;342 Vulsteke V, Beullens M, Boudrez A, Keppens S, Van Eynde A, ( Pt 1):13-9 Rider MH, Stalmans W, Bollen M. Inhibition of spliceosome assembly by the cell cycle-regulated protein kinase MELK and Trinkle-Mulcahy L, Ajuh P, Prescott A, Claverie-Martin F, involvement of splicing factor NIPP1. J Biol Chem. 2004 Mar Cohen S, Lamond AI, Cohen P. Nuclear organisation of 5;279(10):8642-7 NIPP1, a regulatory subunit of protein phosphatase 1 that associates with pre-mRNA splicing factors. J Cell Sci. 1999 Comerford KM, Leonard MO, Cummins EP, Fitzgerald KT, Jan;112 ( Pt 2):157-68 Beullens M, Bollen M, Taylor CT. Regulation of protein phosphatase 1gamma activity in hypoxia through increased Van Eynde A, Pérez-Callejón E, Schoenmakers E, Jacquemin interaction with NIPP1: implications for cellular metabolism. J M, Stalmans W, Bollen M. Organization and alternate splice Cell Physiol. 2006 Oct;209(1):211-8 products of the gene encoding nuclear inhibitor of protein phosphatase-1 (NIPP-1). Eur J Biochem. 1999 Apr;261(1):291- Deckert J, Hartmuth K, Boehringer D, Behzadnia N, Will CL, 300 Kastner B, Stark H, Urlaub H, Lührmann R. Protein composition and electron microscopy structure of affinity- Beullens M, Vulsteke V, Van Eynde A, Jagiello I, Stalmans W, purified human spliceosomal B complexes isolated under Bollen M. The C-terminus of NIPP1 (nuclear inhibitor of protein physiological conditions. Mol Cell Biol. 2006 Jul;26(14):5528- phosphatase-1) contains a novel binding site for protein 43 phosphatase-1 that is controlled by tyrosine phosphorylation and RNA binding. Biochem J. 2000 Dec 15;352 Pt 3:651-8 Roy N, Van Eynde A, Beke L, Nuytten M, Bollen M. The transcriptional repression by NIPP1 is mediated by Polycomb Boudrez A, Beullens M, Groenen P, Van Eynde A, Vulsteke V, group proteins. Biochim Biophys Acta. 2007 Sep-Oct;1769(9- Jagiello I, Murray M, Krainer AR, Stalmans W, Bollen M. 10):541-5 NIPP1-mediated interaction of protein phosphatase-1 with CDC5L, a regulator of pre-mRNA splicing and mitotic entry. J Shi Y, Manley JL. A complex signaling pathway regulates Biol Chem. 2000 Aug 18;275(33):25411-7 SRp38 phosphorylation and pre-mRNA splicing in response to heat shock. Mol Cell. 2007 Oct 12;28(1):79-90 Kim SE, Ishita A, Shima H, Nakamura K, Yamada Y, Ogawa K, Kikuchi K. Increased expression of NIPP-1 mRNA correlates Nuytten M, Beke L, Van Eynde A, Ceulemans H, Beullens M, positively with malignant phenotype in rat hepatomas. Int J Van Hummelen P, Fuks F, Bollen M. The transcriptional Oncol. 2000 Apr;16(4):751-5 repressor NIPP1 is an essential player in EZH2-mediated gene silencing. Oncogene. 2008 Feb 28;27(10):1449-60 Beullens M, Bollen M. The protein phosphatase-1 regulator NIPP1 is also a splicing factor involved in a late step of Tanuma N, Kim SE, Beullens M, Tsubaki Y, Mitsuhashi S, spliceosome assembly. J Biol Chem. 2002 May Nomura M, Kawamura T, Isono K, Koseki H, Sato M, Bollen M, 31;277(22):19855-60 Kikuchi K, Shima H. Nuclear inhibitor of protein phosphatase-1 (NIPP1) directs protein phosphatase-1 (PP1) to Boudrez A, Beullens M, Waelkens E, Stalmans W, Bollen M. dephosphorylate the U2 small nuclear ribonucleoprotein Phosphorylation-dependent interaction between the splicing particle (snRNP) component, spliceosome-associated protein factors SAP155 and NIPP1. J Biol Chem. 2002 Aug 155 (Sap155). J Biol Chem. 2008 Dec 19;283(51):35805-14 30;277(35):31834-41 Hendrickx A, Beullens M, Ceulemans H, Den Abt T, Van Parker L, Gross S, Beullens M, Bollen M, Bennett D, Alphey L. Eynde A, Nicolaescu E, Lesage B, Bollen M. Docking motif- Functional interaction between nuclear inhibitor of protein guided mapping of the interactome of protein phosphatase-1. phosphatase type 1 (NIPP1) and protein phosphatase type 1 Chem Biol. 2009 Apr 24;16(4):365-71 (PP1) in Drosophila: consequences of over-expression of NIPP1 in flies and suppression by co-expression of PP1. Bollen M, Peti W, Ragusa MJ, Beullens M. The extended PP1 Biochem J. 2002 Dec 15;368(Pt 3):789-97 toolkit: designed to create specificity. Trends Biochem Sci. 2010 Aug;35(8):450-8 Jin Q, van Eynde A, Beullens M, Roy N, Thiel G, Stalmans W, Bollen M. The protein phosphatase-1 (PP1) regulator, nuclear Van Dessel N, Beke L, Görnemann J, Minnebo N, Beullens M, inhibitor of PP1 (NIPP1), interacts with the polycomb group Tanuma N, Shima H, Van Eynde A, Bollen M. The protein, embryonic ectoderm development (EED), and phosphatase interactor NIPP1 regulates the occupancy of the functions as a transcriptional repressor. J Biol Chem. 2003 Aug histone methyltransferase EZH2 at Polycomb targets. Nucleic 15;278(33):30677-85 Acids Res. 2010 Nov;38(21):7500-12

Fardilha M, Wu W, Sá R, Fidalgo S, Sousa C, Mota C, da Cruz This article should be referenced as such: e Silva OA, da Cruz e Silva EF. Alternatively spliced protein variants as potential therapeutic targets for male infertility and Minnebo N, Van Dessel N, Beullens M, van Eynde A, Bollen M. contraception. Ann N Y Acad Sci. 2004 Dec;1030:468-78 PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):968- Lesage B, Beullens M, Nuytten M, Van Eynde A, Keppens S, 971. Himpens B, Bollen M. Interactor-mediated nuclear translocation and retention of protein phosphatase-1. J Biol Chem. 2004 Dec 31;279(53):55978-84

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Gene Section Mini Review

SMYD2 (SET and MYND domain containing 2) Hitoshi Tsuda, Shuhei Komatsu Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan (HT), Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan (SK)

Published in Atlas Database: May 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/SMYD2ID47098ch1q32.html DOI: 10.4267/2042/46056 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Localisation Cytoplasmic and nucleus (Brown et al., 2006). Other names: HSKM-B; KMT3C; MGC119305; ZMYND14 Function HGNC (Hugo): SMYD2 Regulation of transcription as a lysine methyltransferase for histone 3, lysine 36 (H3K36) and Location: 1q32.3 inhibition of p53's transactivation activity as a lysine methyltransferase for lysine 370 (K370) of p53 through DNA/RNA the SET domain (Brown et al., 2006; Huang et al., Description 2006). Possibly promotion of cell proliferation and/or differentiation through its overexpression/activation- 55913 bp, 12 exons. induced inhibition of p53's transactivation activity. Transcription Methylation of retinoblastoma (RB) tumor suppressor 1689 bp mRNA. at lysine 860, that is regulated during cell cycle progression, cellular differentiation ,and in response to Protein DNA damage (Saddic et al., 2010). RB monomethylation at lysine 860 provides a direct binding site for the transcription repressor L3MBTL1. Through interaction with HSP90alpha, SMYD2 histone methyltransferase activity and specificity for histone Description H3 at lysine 4 (H3K4) are enhanced in vitro (Abu- 433 amino acids. The protein contains SET domain, Farha et al., 2008). SMYD2 gain of function is MYND domain/zinc-finger motif, and cysteine-rich correlated with the upregulation of 37 and down post-SET domain. The SET domain is split into two regulation of 4 genes, the majority of which are segments by a MYND domain. involved in the cell cycle, chromatin remodelling, and transcriptional regulation (Abu-Farha et al., 2008). Expression Homology Wide, highly expressed in heart, brain, liver, kidney, thymus, ovary, embryonic tissues (heart, Xenopus laevis, Zebrafish, Chicken, Gray short-tailed hypothalamus) (Brown et al., 2006). opossum, Mouse, Rat, Rabbit, Pig, Horse, Cattle, Dog, White-tufted-ear marmoset, Rhesus monkey, Sumatran orangutan, Chimpanzee.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 972 SMYD2 (SET and MYND domain containing 2) Tsuda H, Komatsu S

and SMYD2) evaluated by real-time PCR was shown Mutations to be a potential candidate to predict response to Note neoadjuvant chemotherapy (4 cycles of doxorubicin Not found. and cyclophosphamide) in breast cancer patients (Barros Filho et al., 2010). Implicated in References Esophageal squamous cell carcinoma Brown MA, Sims RJ 3rd, Gottlieb PD, Tucker PW. Identification (ESCC) and characterization of Smyd2: a split SET/MYND domain- containing histone H3 lysine 36-specific methyltransferase that Note interacts with the Sin3 histone deacetylase complex. Mol Frequent overexpression of SMYD2 mRNA and Cancer. 2006 Jun 28;5:26 protein was observed in KYSE150 cells with Huang J, Perez-Burgos L, Placek BJ, Sengupta R, Richter M, remarkable amplification at 1q32-q41.1 and other Dorsey JA, Kubicek S, Opravil S, Jenuwein T, Berger SL. ESCC cell lines (11/43 lines, 25.6%). Overexpression Repression of p53 activity by Smyd2-mediated methylation. of SMYD2 protein was frequently detected in primary Nature. 2006 Nov 30;444(7119):629-32 tumor samples of ESCC (117/153 cases, 76.5%) as well Abu-Farha M, Lambert JP, Al-Madhoun AS, Elisma F, Skerjanc and significantly correlated with gender, venous IS, Figeys D. The tale of two domains: proteomics and invasion, the pT category in the tumor-lymph node- genomics analysis of SMYD2, a new histone metastasis classification and status of recurrence. methyltransferase. Mol Cell Proteomics. 2008 Mar;7(3):560-72 Patients with SMYD2-overexpressing tumors had a Komatsu S, Imoto I, Tsuda H, Kozaki KI, Muramatsu T, worse overall rate of survival than those with non- Shimada Y, Aiko S, Yoshizumi Y, Ichikawa D, Otsuji E, Inazawa J. Overexpression of SMYD2 relates to tumor cell expressing tumors. Knockdown of SMYD2 expression proliferation and malignant outcome of esophageal squamous inhibited and ectopic overexpression of SMYD2 cell carcinoma. Carcinogenesis. 2009 Jul;30(7):1139-46 promoted the proliferation of ESCC cells in a TP53 Barros Filho MC, Katayama ML, Brentani H, Abreu AP, mutation-independent but SMYD2 expression Barbosa EM, Oliveira CT, Góes JC, Brentani MM, Folgueira dependent manner (Komatsu et al., 2009). MA. Gene trio signatures as molecular markers to predict response to doxorubicin cyclophosphamide neoadjuvant Thyroid carcinoma and benign thyroid chemotherapy in breast cancer patients. Braz J Med Biol Res. nodule 2010 Dec;43(12):1225-31 Note Saddic LA, West LE, Aslanian A, Yates JR 3rd, Rubin SM, Gozani O, Sage J. Methylation of the retinoblastoma tumor Using differential display-polymerase chain reaction suppressor by SMYD2. J Biol Chem. 2010 Nov method, the gene expression differences between 26;285(48):37733-40 benign thyroid nodules (BTNs) and follicular and Igci YZ, Arslan A, Akarsu E, Erkilic S, Igci M, Oztuzcu S, classic variants of papillary thyroid carcinoma (PTC) Cengiz B, Gogebakan B, Cakmak EA, Demiryurek AT. were evaluated in a group of 42 patients (15 BTNs, 14 Differential expression of a set of genes in follicular and classic follicular variant of PTC and 13 classic variant of variants of papillary thyroid carcinoma. Endocr Pathol. 2011 PTC). SMYD2 had lower expression in both carcinoma Jun;22(2):86-96 groups than in BTNs (Igci et al., 2011). This article should be referenced as such: Breast cancer Tsuda H, Komatsu S. SMYD2 (SET and MYND domain Note containing 2). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):972-973. Expression of a group of three genes (MTSS1, RPL37,

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Leukaemia Section Mini Review t(1;9)(p34;q34) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: May 2011 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0109p34q34ID2143.html DOI: 10.4267/2042/46057 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

association of HNRNPL and SFPQ drives the change in Clinics and pathology PTPRC (CD45) splicing (CD45 undergoes alternative Disease splicing in response to T-cell activation). DNA damage: DNA double-strand breaks are repaired B cell progenitor acute lymphoid leukemia (B-ALL) via nonhomologous DNA end joining and homologous Epidemiology recombination. The SFPQ/NONO heterodimer Only one case to date, a 22-year-old male patient enhances DNA strand break rejoining. SFPQ has (Hidalgo-Curtis et al., 2008). homologous recombination and non-homologous end joining activities. SFPQ is associated with the RAD51 Prognosis protein complex. Complete remission was obtained, a relapse occured. Role in transcriptional regulation: SFPQ and PTK6 The patient was in complete remission 6 years after (protein tyrosine kinase 6, also called BRK) play a role diagnosis. downstream of the EGF receptor (EGFR). SFPQ and NONO form complexes with the androgen receptor Cytogenetics (AR) and modulate its transcriptional activity (Huret, 2011). Cytogenetics morphological ABL1 The translocation was found solely in the main clone, and a subclone also showed a +21. Location 9q34 Genes involved and proteins Protein ABL1, when localized in the nucleus, induces SFPQ apoptosis after DNA damage. Cytoplasmic ABL1 has a Location possible function in adhesion signalling (Turhan, 1p34.3 2008). Protein DNA- and RNA binding protein; pre-mRNA splicing Result of the chromosomal factor; binds specifically to intronic polypyrimidine anomaly tracts. Role in transcription and RNA splicing: SFPQ, often Hybrid gene called PSF, is a coactivator of Fox proteins, which bind Description the RNA element UGCAUG and regulate alternative Break in the 3' of SFPQ exon 10 and reunion with pre-mRNA splicing. SFPQ and NONO are part of a ABL1 intron 3; a further mRNA splicing gives rise to a large complex with all the snRNPs. SFPQ is chimeric SFPQ exons 1 to 9 (nucleotide 2072) fused to phosphorylated by GSK3, which prevents SFPQ from ABL1 exon 4 to end. binding PTPRC (CD45 antigen) pre-mRNA. The

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 974 t(1;9)(p34;q34) Huret JL

Fusion protein References Description Huret JL.. SFPQ (splicing factor proline/glutamine-rich). Atlas 1609 amino acids fusion protein of 174 kDa; retains Genet Cytogenet Oncol Haematol. January 1999. most of SFPQ, including the RNA recognition motifs http://atlasgeneticsoncology.org/Genes/PSFID167.html and the coiled-coil domain (dimerization domain), Hidalgo-Curtis C, Chase A, Drachenberg M, Roberts MW, fused to the SH2 domain of ABL1; the fusion protein Finkelstein JZ, Mould S, Oscier D, Cross NC, Grand FH.. The also includes the SH1 domain (tyrosine kinase activity), t(1;9)(p34;q34) and t(8;12)(p11;q15) fuse pre-mRNA the nuclear localization domain, and the actin binding processing proteins SFPQ (PSF) and CPSF6 to ABL and FGFR1. Genes Chromosomes Cancer. 2008 May;47(5):379- domain of ABL1. 85. Oncogenesis Turhan AG.. ABL1 (v-abl Abelson murine leukemia viral Constitutive tyrosine kinase activation is likely, oncogene homolog 1). Atlas Genet Cytogenet Oncol through dimerization of the fusion protein. Haematol. August 2008. http://atlasgeneticsoncology.org/Genes/ABL.html This article should be referenced as such:

Huret JL. t(1;9)(p34;q34). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):974-975.

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Deep Insight Section

Understanding the structure and function of ASH2L Paul F South, Scott D Briggs Department of Biochemistry and Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA (PFS, SDB)

Published in Atlas Database: June 2011 Online updated version : http://AtlasGeneticsOncology.org/Deep/ASH2LFunctionID20097.html DOI: 10.4267/2042/46058 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Introduction genes (LaJeunesse and Shearn, 1995). Mammalian ASH2L is known to be important for development ASH2L (Absent, Small, or Homeotic-Like) encodes the because ASH2L -null mice exhibit an embryonic lethal protein ASH2L which was named after the Drosophila phenotype (Stoller et al., 2010). Work has established protein Ash2 a known regulator of HOX genes ASH2L as a core component of the H3K4 (Ikegawa et al., 1999). ASH2L is known to be a methyltransferase complexes MLL1-4 and SET1A and component of histone H3 lysine 4 (H3K4) SET1B. Furthermore, ASH2L containing methyltransferase complexes and H3K4 methylation is methyltransferase complexes are shown to be important commonly associated with active gene transcription for the maintenance of HOX gene expression by (Ikegawa et al., 1999; Hughes et al., 2004; Dou et al., binding to HOX gene promoters and by adding H3K4 2006; Steward et al., 2006; Cho et al., 2007). Previous di- and trimethylation (Fig. 1) (Hughes et al., 2004; Tan studies have shown that disruption of ASH2L leads to a et al., 2008; Yates et al., 2010). HOX gene expression decrease in H3K4 trimethylation, which negatively is important for proper development and affects gene expression (Dou et al., 2006; Steward et differentiation, and disruption in H3K4 methylation al., 2006). Furthermore, disruption of ASH2L or the leads to defects in HOX gene expression and the methyltransferases involved in H3K4 methylation can development of cancer (Tan et al., 2008; Hess, 2006; lead to oncogenesis mostly through the regulation of Rampalli et al., 2007; MacConaill et al., 2006; Hughes HOX gene expression (Hughes et al., 2004; Lüscher- et al., 2004). Firzlaff et al., 2008). Interestingly, overexpression of Biochemical data has shown that ASH2L is found in a ASH2L leads to tumor proliferation and knock-down of methyltransferase core complex composed of ASH2L, ASH2L inhibits tumorigenesis, which is the reason why RBBP5, DPY30, WDR5, and the catalytic SET domain ASH2L is thought to be an oncoprotein (Lüscher- containing protein (Fig. 1). This core complex is highly Firzlaff et al., 2008). Understanding the role that conserved and similar to the budding yeast Set1 ASH2L plays in facilitating proper H3K4 methylation complex that consists of Set1 (MLL/SET1), Bre2 may provide insight into how disruption of ASH2L can (ASH2L), Swd1 (RBBP5), Swd3 (WDR5), Swd2 lead to abnormal cell proliferation and oncogenesis. (WDR82), Sdc1 (DPY-30), Spp1 (CFP1/CGBP). ASH2L function ASH2L is also known to associate with numerous Genetic information and sequence alignments additional factors listed in Table 1. Many of these identified ASH2L to be homologous to the additional factors are thought to associate with ASH2L transcriptional activator Drosophila Ash2 (Wang et al., and the H3K4 methyltransferase complexes to target 2001; Ikegawa et al., 1999). Drosophila Ash2 (Absent, the complex to specific sites within the genome (Stoller small, and homeotic discs) is a member of the Trithorax et al., 2010; Cho et al., 2007; Steward et al., 2006; Dou family, known regulators of developmental homeotic et al., 2006; Hughes et al., 2004).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 976 Understanding the structure and function of ASH2L South PF, Briggs SD

Figure 1. ASH2L functions in a histone methyltransferase complex. The role of ASH2L within the MLL histone H3K4 methyltransferase complex. ASH2L interacts with RBBP5 and DPY-30 increasing the activity of the MLL complex. Histone H3K4 methylation in mammals peaks at the start sight of open reading frames and is important in active transcription. Knock-down of ASH2L in mammalian cells results in a decrease in H3K4 trimethylation and changes in gene expression.

ASH2L interacting protein Function MLL1 -4/ SET1 A and B Catalytic core; Histone methyltransferase (HMT) RBBP5 Component of HMT complex DPY -30 Component of HMT complex WDR5 Component of HMT complex CXXC1 Component of HMT complex C16orf53/PA1 Glutamate rich coactivator C17orf49 Unknown CHD8 Chromatin remodeling factor

E2F6 Transcription factor HCFC1 Host cell factor IN080C Unknown KDM6A H3K27 demethylase KIAA1267 Unknown LAS1L Unknown MAX Transcription factor MCRS1 Transcriptional repressor

MEN1 Tumor suppressor MYST1/MOF Histone acetyltransferase NCOA6 Transcriptional co-activator PAXIP1/PTIP Transcription factor PELP1 Transcription factor PHF20 Unknown PRP31 Component of spliceosome RING2 E3-ligase SENP3 Sumo-specific protease TAF1, 4, 6, 7, 9 TATA-box binding proteins TEX10 Unknown TBX1 Transcription factor Table 1.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 977 Understanding the structure and function of ASH2L South PF, Briggs SD

ASH2L and Bre2 subunits are important for proper Isoform 3 is missing the amino acids 1-94 from isoform histone methylation. Studies done in yeast show that 1 (Fig. 2) (Wang et al., 2001). There are four identified deletion of the ASH2L homolog BRE2 leads to a domains within ASH2L which include a N-terminus complete loss of H3K4 trimethylation and reductions in containing a PHD finger and a winged helix motif mono- and dimethylation (Dehé et al., 2006; South et (WH) and the C-terminus containing a SPRY domain al., 2010; Roguev et al., 2001). In addition, knock- and a newly identified Sdc1 DPY-30 Interacting down of ASH2L using siRNA globally decreases domain (SDI) (Fig. 2) (Wang et al., 2001; Roguev et H3K4 trimethylation (Steward et al., 2006; Dou et al., al., 2001; South et al., 2010; Sarvan et al., 2011; Chen 2006). These data suggest that ASH2L may act in a et al., 2011). Interestingly, the domains with known similar manner to yeast Bre2. From these studies it is biological function are the C-terminal SDI domain, clear that ASH2L is playing an important role in which is responsible for the interaction with another histone methyltransferase complexes in order to histone methyltransferase component DPY-30 and the maintain proper H3K4 methylation and gene winged helix motif which binds to DNA (South et al., expression (Patel et al., 2009; Roguev et al., 2001). 2010; Sarvan et al., 2011; Chen et al., 2011). Alternative to ASH2L's function in H3K4 methylation The function of the SDI domain was determined using ASH2L may also be playing a role in endosomal in vitro binding experiments. ASH2L was shown to trafficking (Xu et al., 2009). ASH2L, DPY-30 and directly interact with DPY-30 without any additional WDR5 were originally implicated in endosomal MLL or Set1 complex components (South et al., 2010). trafficking when siRNA knock-down of these genes The function of the SDI domain is conserved from increased the amount of internalized CD8-CIMPR and yeast to humans because the yeast ASH2L homolog overexpression increased the amount of cells displaying Bre2 was also shown to interact with the DPY-30 a altered CIMPR distribution (Xu et al., 2009). This homolog Sdc1 (South et al., 2010). There are conserved affect was limited to components of H3K4 hydrophobic residues in both the SDI domain of methyltransferases and not to other methyl marks such ASH2L and the Dpy-30 domain of DPY-30 that are as lysine 9 (Xu et al., 2009). The mechanism in which important for binding, which suggests that the ASH2L and other components of H3K4 interaction between the SDI domain of ASH2L and the methyltransferase complexes modulate endosomal DPY-30 domain of DPY-30 is through hydrophobic trafficking remains unclear. However, two possible interactions (South et al., 2010). In addition, binding mechanisms have been suggested, one is that the H3K4 affinities between ASH2L and DPY-30, as well as methyltransferase components are part of an unknown ASH2L and RBBP5 have been determined by complex that regulates trafficking, or that changes in sedimentation velocity analytical ultracentrifugation H3K4 methylation lead to changes in expression of showing dissociation constants of 0.1 µM and 0.75 µM another regulating factor (Xu et al., 2009). respectively (Patel et al., 2009). Interestingly, in yeast ASH2L structure the ASH2L homolog Bre2 must interact with Sdc1 through the SDI domain to interact with the yeast Set1 One way to better understand the function of ASH2L is histone methyltransferase complex (South et al., 2010). to determine the role of specific domains within In contrast, in vitro experiments have shown ASH2L ASH2L in facilitating H3K4 methylation. There are does not require DPY-30 to interact with MLL three known isoforms of ASH2L (Wang et al., 2001). complex. To better understand how ASH2L interacts Isoform 1 is considered the canonical sequence and with MLL, in vivo studies must be done to determine if consists of 628 amino acids (Wang et al., 2001). DPY-30 is required for ASH2L interaction. However, it Isoform 2 is missing amino acids 1-94 and 541-573 is quite possible that the yeast and human complexes from isoform 1 (Wang et al., 2001). assemble differently.

Figure 2. ASH2L has three known isoforms. Schematic model of the three known isoforms of ASH2L and the amino acid sequence changes compared to the canonical isoform 1 (aa 1-628). The positions of known domains within ASH2L are displayed. PHD finger (aa 95-161), WH motif (aa 162-273), SPRY domain (aa 360-583), and SDI domain (aa 602-628). Isoform 2 and 3 are numbered according to isoform 1.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 978 Understanding the structure and function of ASH2L South PF, Briggs SD

The N-terminal winged helix (WH) motif was recently al., 2008; van Ingen et al., 2008; Champagne and discovered when the crystal structure of the N-terminus Kutateladze, 2009). PHD fingers generally form a of ASH2L was solved (Sarvan et al., 2011; Chen et al., globular fold, consisting of a two-stranded beta-sheet 2011). Using in vitro DNA binding analyses as well as and an alpha-helix. Loop regions of PHD fingers tend chromatin immunoprecipitation, it was determined that to vary giving rise to specificity of the domain. Some ASH2L can bind DNA at the HS2 promoter region and PHD fingers are considered to be readers of epigenetic the β-globin locus as well as non-specific DNA marks by binding to specific modifications or sites on sequence (Sarvan et al., 2011; Chen et al., 2011). The histones to stabilize or localize an interaction (Mellor, DNA binding activity of ASH2L promotes H3K4 2006). Primarily, PHD fingers have been shown to methylation and gene expression at the β-globin locus interact with trimethylated histone residues such as by 50% when overexpressed in a cell line where trimethylated histone H3 lysine 4 and lysine 9 (Mellor, ASH2L is knocked-down by siRNA (Sarvan et al., 2006). There is no known function attributed to the 2011). In addition, chromatin immunoprecipitation PHD finger in ASH2L, though in conjunction with the followed by a tiling array (ChIP-chip) analysis shows winged helix motif it may be necessary for DNA that disruption of the winged helix motif causes mis- binding. However, the PHD finger may also be needed localization of ASH2L (Chen et al., 2011). It was also in binding to MLL, other MLL/SET1 components, or shown that the DNA binding activity of the N-terminus recognizing a specific histone modification or for of ASH2L increases when the C-terminal SPRY and binding to a histone tail. Additional studies are needed SDI domains are present (Chen et al., 2011). to determine how the PHD finger of ASH2L and the Altogether, these data suggests that multiple domains in SPRY domain may help the MLL and Set1 ASH2L may contribute to its ability to bind chromatin. methyltransferase complexes interact and catalyze However, more work will be needed to clearly establish H3K4 methylation. the function of each domain. Conclusion The largest of the three identified domains within ASH2L is the SPRY domain, which is also conserved Currently, relatively little is known about the from yeast to humans. SPRY domains were originally contribution of ASH2L to facilitate and or regulate the named after the SP Ia kinase and the RY anodine degree of methylation along the eukaryotic genome, but receptor proteins in which it was first identified disruption of ASH2L and H3K4 methylation both (Rhodes et al., 2005). Multiple crystal structures have appear to play a key role in oncogenesis (Lüscher- been solved for proteins that contain an SPRY domain. Firzlaff et al., 2008; Hess, 2006). Interestingly, recent Crystal structures of SPRY domain containing proteins work has suggested that ASH2L in combination with show primarily a β-sandwich structure with extending WDR5 and RBBP5 exhibits H3K4 methyltransferase loops (Woo et al., 2006b; Kuang et al., 2009; activity (Cao et al., 2010; Patel et al., 2009; Patel et al., Filippakopoulos et al., 2010; Simonet et al., 2007). The 2011). In addition, this catalytic activity is not SPRY domain is thought to be a specific protein- dependent on the SET domain containing proteins such protein interaction domain with specific partners, but as MLL1 (Patel et al., 2009; Cao et al., 2010; Patel et instead of recognizing a particular motif or interaction al., 2011). One report shows the catalytic activity of the domain the SPRY domain binds to interaction partners ASH2L, WDR5, RBBP5, DPY-30 complex in an in using non-conserved binding loops (Filippakopoulos et vitro histone methyltransferase assay is observed but al., 2010; Woo et al., 2006b; Woo et al., 2006a). SPRY only after eight hours of incubation (Patel et al., 2009; domain-containing proteins are involved in a wide Patel et al., 2011). In contrast, more methyltransferase array of functions including RNA metabolism, calcium activity and much shorter incubation times are required release, and developmental processes (Woo et al., when these components are incubated with the MLL1 2006b; Kuang et al., 2009; Filippakopoulos et al., 2010; SET domain containing methyltransferase (Patel et al., Simonet et al., 2007; Woo et al., 2006a). Recent work 2009; Patel et al., 2011). This indicates the sub- has shown that the C-terminus of ASH2L that contains complex has poor catalytic activity when the main the SPRY domain and the SDI domain are able to catalytic SET domain-containing subunit is not present interact with the other MLL complex member RBBP5 in the reaction. However, Cao et al. shows that only in vitro (Avdic et al., 2011). This interaction is most ASH2L/RBBP5 heterodimer is needed for weak H3K4 likely through the SPRY domain and not the SDI methyltransferase activity (Cao et al., 2010). Because domain, though further work would need to be done to ASH2L, WDR5, RBBP5, and better map this interaction. DPY-30 complex does not contain a known ASH2L also contains a putative Plant Homeo Domain methyltransferase domain, more work needs to be done (PHD) finger in its N-terminus (Wang et al., 2001). to determine if a new class of methyltransferase has PHD fingers are a family of zinc finger domains that been identified and whether or not this are known to bind to both modified and unmodified methyltransferase activity is biologically relevant. histone tails (Bienz, 2006; Mellor, 2006). The structure ASH2L is found to be over abundant in many cancer of PHD fingers shows that conserved cysteine cell lines and knock-down of ASH2L by siRNA can and histidine residues bind to Zn 2+ ions (Champagne et prevent tumorigenesis (Lüscher-Firzlaff et al., 2008).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 979 Understanding the structure and function of ASH2L South PF, Briggs SD

ASH2L is important for proper H3K4 methylation but MacConaill LE, Hughes CM, Rozenblatt-Rosen O, Nannepaga how ASH2L contributes to the distribution and degree S, Meyerson M.. Phosphorylation of the menin tumor suppressor protein on serine 543 and serine 583. Mol Cancer of methylation and its role in gene expression remains Res. 2006 Oct;4(10):793-801. unclear. To better understand the role of ASH2L in Mellor J.. It takes a PHD to read the histone code. Cell. 2006 methylation and gene expression several questions need Jul 14;126(1):22-4. (REVIEW) to be addressed. What is the mechanism of interaction that contributes to ASH2L's interaction with histone Steward MM, Lee JS, O'Donovan A, Wyatt M, Bernstein BE, Shilatifard A.. Molecular regulation of H3K4 trimethylation by methyltransferase complexes? What is ASH2L's role in ASH2L, a shared subunit of MLL complexes. Nat Struct Mol regulating the degree of methylation along genes and Biol. 2006 Sep;13(9):852-4. Epub 2006 Aug 6. what genes are affected by changes in ASH2L? Woo JS, Imm JH, Min CK, Kim KJ, Cha SS, Oh BH.. Structural Additional structural studies will help address the and functional insights into the B30.2/SPRY domain. EMBO J. mechanism of how ASH2L interacts with other 2006a Mar 22;25(6):1353-63. Epub 2006 Feb 23. methyltransferase complex members and microarray Woo JS, Suh HY, Park SY, Oh BH.. Structural basis for protein experiments will be needed to determine the genes that recognition by B30.2/SPRY domains. Mol Cell. 2006b Dec are affected by changes in ASH2L expression levels. 28;24(6):967-76. Addressing these questions could provide valuable Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski information for the development specific inhibitors for T, Dressler GR, Copeland TD, Kalkum M, Ge K.. PTIP the treatment of various cancers. associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. 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Roguev A, Schaft D, Shevchenko A, Pijnappel WW, Wilm M, Champagne KS, Saksouk N, Pena PV, Johnson K, Ullah M, Aasland R, Stewart AF. The Saccharomyces cerevisiae Set1 Yang XJ, Cote J, Kutateladze TG.. The crystal structure of the complex includes an Ash2 homologue and methylates histone ING5 PHD finger in complex with an H3K4me3 histone 3 lysine 4. EMBO J. 2001 Dec 17;20(24):7137-48 peptide. Proteins. 2008 Sep;72(4):1371-6. Wang J, Zhou Y, Yin B, Du G, Huang X, Li G, Shen Y, Yuan J, Luscher-Firzlaff J, Gawlista I, Vervoorts J, Kapelle K, Qiang B. ASH2L: alternative splicing and downregulation Braunschweig T, Walsemann G, Rodgarkia-Schamberger C, during induced megakaryocytic differentiation of multipotential Schuchlautz H, Dreschers S, Kremmer E, Lilischkis R, Cerni C, leukemia cell lines. J Mol Med (Berl). 2001 Jul;79(7):399-405 Wellmann A, Luscher B.. The human trithorax protein hASH2 functions as an oncoprotein. Cancer Res. 2008 Feb Hess JL.. MLL: Deep Insight. Atlas Genet Cytogenet Oncol 1;68(3):749-58. Haematol. August 2003 . Tan CC, Sindhu KV, Li S, Nishio H, Stoller JZ, Oishi K, Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD, Puttreddy S, Lee TJ, Epstein JA, Walsh MJ, Gelb BD.. Levine SS, Lee JC, Hayes DN, Shanmugam KS, Bhattacharjee Transcription factor Ap2delta associates with Ash2l and ALR, a A, Biondi CA, Kay GF, Hayward NK, Hess JL, Meyerson M.. trithorax family histone methyltransferase, to activate Hoxc8 Menin associates with a trithorax family histone transcription. Proc Natl Acad Sci U S A. 2008 May methyltransferase complex and with the hoxc8 locus. Mol Cell. 27;105(21):7472-7. Epub 2008 May 21. 2004 Feb 27;13(4):587-97. van Ingen H, van Schaik FM, Wienk H, Ballering J, Rehmann Rhodes DA, de Bono B, Trowsdale J.. Relationship between H, Dechesne AC, Kruijzer JA, Liskamp RM, Timmers HT, SPRY and B30.2 protein domains. Evolution of a component of Boelens R.. Structural insight into the recognition of the immune defence? Immunology. 2005 Dec;116(4):411-7. H3K4me3 mark by the TFIID subunit TAF3. Structure. 2008 (REVIEW) Aug 6;16(8):1245-56. Bienz M.. The PHD finger, a nuclear protein-interaction Champagne KS, Kutateladze TG.. Structural insight into domain. Trends Biochem Sci. 2006 Jan;31(1):35-40. Epub histone recognition by the ING PHD fingers. Curr Drug 2005 Nov 16. (REVIEW) Targets. 2009 May;10(5):432-41. (REVIEW) Dehe PM, Dichtl B, Schaft D, Roguev A, Pamblanco M, Lebrun Kuang Z, Yao S, Xu Y, Lewis RS, Low A, Masters SL, Willson R, Rodriguez-Gil A, Mkandawire M, Landsberg K, Shevchenko TA, Kolesnik TB, Nicholson SE, Garrett TJ, Norton RS.. SPRY A, Shevchenko A, Rosaleny LE, Tordera V, Chavez S, Stewart domain-containing SOCS box protein 2: crystal structure and AF, Geli V.. Protein interactions within the Set1 complex and residues critical for protein binding. J Mol Biol. 2009 Feb their roles in the regulation of histone 3 lysine 4 methylation. J 27;386(3):662-74. Epub 2009 Jan 6. Biol Chem. 2006 Nov 17;281(46):35404-12. Epub 2006 Aug 18. Patel A, Dharmarajan V, Vought VE, Cosgrove MS.. On the mechanism of multiple lysine methylation by the human mixed Dou Y, Milne TA, Ruthenburg AJ, Lee S, Lee JW, Verdine GL, lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. Allis CD, Roeder RG.. Regulation of MLL1 H3K4 2009 Sep 4;284(36):24242-56. Epub 2009 Jun 25. methyltransferase activity by its core components. Nat Struct Mol Biol. 2006 Aug;13(8):713-9. Epub 2006 Jul 30.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 980 Understanding the structure and function of ASH2L South PF, Briggs SD

Xu Z, Gong Q, Xia B, Groves B, Zimmermann M, Mugler C, Mu remodeling enzyme CHD8. FEBS Lett. 2010 Feb D, Matsumoto B, Seaman M, Ma D.. A role of histone H3 lysine 19;584(4):689-93. Epub 2010 Jan 17. 4 methyltransferase components in endosomal trafficking. J Cell Biol. 2009 Aug 10;186(3):343-53. Epub 2009 Aug 3. Avdic V, Zhang P, Lanouette S, Groulx A, Tremblay V, Brunzelle J, Couture JF.. Structural and biochemical insights Cao F, Chen Y, Cierpicki T, Liu Y, Basrur V, Lei M, Dou Y.. An into MLL1 core complex assembly. Structure. 2011 Jan Ash2L/RbBP5 heterodimer stimulates the MLL1 12;19(1):101-8. methyltransferase activity through coordinated substrate interactions with the MLL1 SET domain. PLoS One. 2010 Nov Chen Y, Wan B, Wang KC, Cao F, Yang Y, Protacio A, Dou Y, 23;5(11):e14102. Chang HY, Lei M.. Crystal structure of the N-terminal region of human Ash2L shows a winged-helix motif involved in DNA Filippakopoulos P, Low A, Sharpe TD, Uppenberg J, Yao S, binding. EMBO Rep. 2011 Jun 10;12(8):797-803. doi: Kuang Z, Savitsky P, Lewis RS, Nicholson SE, Norton RS, 10.1038/embor.2011.101. Bullock AN.. Structural basis for Par-4 recognition by the SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, Patel A, Vought VE, Dharmarajan V, Cosgrove MS.. A novel and SPSB4. J Mol Biol. 2010 Aug 20;401(3):389-402. Epub non-SET domain multi-subunit methyltransferase required for 2010 Jun 16. sequential nucleosomal histone H3 methylation by the mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. South PF, Fingerman IM, Mersman DP, Du HN, Briggs SD.. A 2011 Feb 4;286(5):3359-69. Epub 2010 Nov 24. conserved interaction between the SDI domain of Bre2 and the Dpy-30 domain of Sdc1 is required for histone methylation and Sarvan S, Avdic V, Tremblay V, Chaturvedi CP, Zhang P, gene expression. J Biol Chem. 2010 Jan 1;285(1):595-607. Lanouette S, Blais A, Brunzelle JS, Brand M, Couture JF.. Epub 2009 Nov 6. Crystal structure of the trithorax group protein ASH2L reveals a forkhead-like DNA binding domain. Nat Struct Mol Biol. 2011 Stoller JZ, Huang L, Tan CC, Huang F, Zhou DD, Yang J, Gelb Jun 5;18(7):857-9. doi: 10.1038/nsmb.2093. BD, Epstein JA.. Ash2l interacts with Tbx1 and is required during early embryogenesis. Exp Biol Med (Maywood). 2010 This article should be referenced as such: May;235(5):569-76. South PF, Briggs SD. Understanding the structure and function Yates JA, Menon T, Thompson BA, Bochar DA.. Regulation of of ASH2L. Atlas Genet Cytogenet Oncol Haematol. 2011; HOXA2 gene expression by the ATP-dependent chromatin 15(11):976-981.

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Case Report Section Paper co-edited with the European LeukemiaNet

A new case of t(4 ;12)(q12 ;p 13) in a secondary acute myeloid leukemia with review of literature Sarah M Heaton, Frederick Koppitch, Anwar N Mohamed Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine, Detroit Medical Center, Detroit MI, USA (SMH, FK, ANM) Published in Atlas Database: March 2011 Online updated version : http://AtlasGeneticsOncology.org/Reports/t0412HeatonID100051.html DOI: 10.4267/2042/46059 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics Immunophenotype Flow cytometry (FCM) revealed that the blasts were of Age and sex myeloid lineage expressing CD13, CD33, CD34, 57 years old male patient. CD117, HLA-DR, and CD56. Previous history Diagnosis No preleukemia. Previous malignancy Hodgkin's Acute myeloid leukemia (AML) with dysplastic Lymphoma, stage IVA at age 25 year, treated with changes. ABVD for 12 months. Tumor mass in the upper cervical spine diagnosed at age 27 year, treated with Survival laminectomy and five doses of radiation. No inborn Date of diagnosis: 08-2007 condition of note. Treatment Organomegaly He was treated with Idarubicin+Ara-c (3+7) regimen. No hepatomegaly, no splenomegaly, no enlarged lymph Because of 15% residual blasts in bone marrow, patient nodes, no central nervous system involvement. received additional 2+5 therapy, and then he underwent consolidation with Ara-C. Result of karyotype: Blood 46,XY[20]. On April 2008, the patient received a 9 WBC : 0.8X 10 /l matched unrelated female donor stem cell transplant HB : 9.7g/dl (SCT). 30 days post transplant; bone marrow revealed 9 Platelets : 21.0X 10 /l no morphological evidence of leukemia and the Blasts : 18% karyotype was 46,XX[20]. On June 2008; patient Bone marrow : Variably cellular with 20% developed pancytopenia; WBC: 2.2 x 10 9/l; Hb: 11.6 myeloblasts and dysplastic changes in the erythroid and g/dl; platelets: 18.0 x 10 3/l. His bone marrow showed myeloid cell lines. an increased dysplastic changes and <5% blasts, suggestive of possible early relapse. The karyotype Cyto-Pathology became abnormal (see below). On June 2010; bone marrow was hypocellular with 20% blasts and Classification dysplastic changes in the erythroid and myeloid Cytology lineages. FCM revealed myeloblasts expressing CD4, His bone marrow showed 60% blasts, and dysplastic CD7, CD33, CD34, CD56, CD117 and HLA-DR. changes were noted in the erythroid and myeloid cell myeloperoxidase was negative. Non-specific esterase lines. was positive in occasional blasts. Cytology: AML possibly of monocytic origin (AML-M5). Treatment related death : no

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 982 A new case of t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature Heaton SM, et al.

Figure 1. G-banded karyotype showing the balanced t(4;12)(q12;p13) translocation.

Figure 2. FISH on abnormal metaphases; (A) Metaphase hybridized with LSI 4q12 tricolor DNA probe showed a translocation of PDGFRA (SA) to derivative chromosome 12 (arrow), with the dual fusion of spectrunOrange (SO) and spectrunGreen (SG) remained on derivative 4. (B) Metaphase hybridized with LSI ETV6/RUNX1 ES dual color probe revealed a split of ETV6 (SG) with the smaller signal being translcated to derivative 4 (arrows). (C) Metaphase hybridized with both LSI 4q12 and ETV6/RUNX1 probes showed PDGFRA (SA) translocted to derivative 12 adjacent to ETV6 locus (arrows).

Phenotype at relapse: M5-AML Other molecular cytogenetics results Status: Alive. Last follow up: 06-2010. Translocation of the PDGFRA gene in Toto, Survival: 24 months spectrunAqua (SA), to derivative 12 and colocalized with centromeric region of ETV6; Break within ETV6 Karyotype gene locus, sepctrunGreen (SG) and the telomeric region of ETV6 translocated to derivative 4 (Figure 2 Sample: Bone marrow A-C). Culture time: 24 and 48h with 10% conditioned medium Comments Banding: GTG Acute leukemia with t(4;12)(q11-q12;p13) is a rare, Results nonrandom event with an estimated incidence of 0.6% 46,XY,t(4;12)(q12;p13)[6]/46,XX[14] in June 2008 among adults according to Harada et al. (Harada et al., (post transplant) 1997). This translocation is seen mostly in adult AML but less frequent in pediatric ALL (Hamaguchi et al., Karyotype at Relapse 1999). A review of the literature revealed at least 46,XY,t(4;12)(q12;p13)[12]/ twenty-two additional cases with a t(4;12)(q11- 46,idem,del(7)(q22q36)[4]/ 47,idem,+19[2]/ 46,XX[2], q12;p13); eighteen adults and four children. The male consistent with the recurrence and clonal evolution of to female ratio is 1.5:1 (1.7:1 in adults and 1:1 in the leukemic clone. children). The majority of patients are adults, aged 18 Other molecular cytogenetics technics to 82 with the mean being 58.9 years old (Harada et al., Fluorescence in situ hybridization (FISH) using LSI 1995; Harada et al., 1997; Ma et al., 1997; Cools et al., 4q12 tricolor and LSI ETV6/RUNX1 ES dual color 1999; Hamaguchi et al., 1999; Chaufaille et al., 2003; DNA probes were performed (Abbott Molecular. Manabe et al., 2010). Four children have been reported, Downers Grove, IL) on the abnormal metaphase cells. aged 3-14 years old, of which three had ALL and the oldest had AML (Harada et al., 1997).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 983 A new case of t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature Heaton SM, et al.

Among the 23 cases including our case with t(4;12) leukemia; 19 had AML; 3 ALL, and one unclassified References leukemia. Common features to t(4;12) AML include Harada H, Asou H, Kyo T, Asaoku H, Iwato K, Dohy H, Oda K, dysplasia of three hematopoietic lineages (erythroid, Harada Y, Kita K, Kamada N. A specific chromosome abnormality of t(4;12)(q11-12;p13) in CD7+ acute leukaemia. myeloid and megakaryocytic), low or absent Br J Haematol. 1995 Aug;90(4):850-4 myeloperoxidase activity, basophilia and a pseudo- lymphoid morphology. The surface markers of the Harada H, Harada Y, Eguchi M, Dohy H, Kamada N. Characterization of acute leukemia with t(4;12). Leuk blasts show positivity for CD7, CD13, CD33, CD34 Lymphoma. 1997 Mar;25(1-2):47-53 and HLA DR, suggesting that the leukemic cells have an immature myeloid stem cell origin (Harada et al., Ma SK, Lie AK, Au WY, Wan TS, Chan LC. CD7+ acute myeloid leukaemia with 'mature lymphoid' blast morphology, 1995; Ma et al., 1997; Hamaguchi et al., 1999). Of the marrow basophilia and t(4;12)(q12;p13) Br J Haematol. 1997 reported t(4;12) AML cases; seven were characterized Dec;99(4):978-80 as AML-M0 and four AML-M1. Previous reports Wlodarska I, La Starza R, Baens M, Dierlamm J, Uyttebroeck suggest that less than 50% of cases achieve remission A, Selleslag D, Francine A, Mecucci C, Hagemeijer A, Van den with intensive induction chemotherapy. Of the patients Berghe H, Marynen P. Fluorescence in situ hybridization who do not achieve morphologic remission, none characterization of new translocations involving TEL (ETV6) in a wide spectrum of hematologic malignancies. Blood. 1998 survived beyond six months (Hamaguchi et al., 1999; Feb 15;91(4):1399-406 Chaufaille et al., 2003; Manabe et al., 2010). The breakpoint at 12p13 in t(4;12) AML is located Cools J, Bilhou-Nabera C, Wlodarska I, Cabrol C, Talmant P, Bernard P, Hagemeijer A, Marynen P. Fusion of a novel gene, within or near the ETV6 gene locus. The ETV6 gene BTL, to ETV6 in acute myeloid leukemias with a t(4;12)(q11- has been implicated in both myeloid and lymphoid q12;p13). Blood. 1999 Sep 1;94(5):1820-4 malignancies (Wlodarska et al., 1998). ETV6 belongs Hamaguchi H, Nagata K, Yamamoto K, Kobayashi M, to the ETS family of transcription factors and has two Takashima T, Taniwaki M. A new translocation, important domains: HLH and an ETS DNA binding t(2;4;12)(p21;q12;p13), in CD7-positive acute myeloid domain. Cools et al, found the t(4;12) caused the ETV6 leukemia: a variant form of t(4;12). Cancer Genet Cytogenet. gene recombined to CHIC2 (formerly BLT) (Cools et 1999 Oct 15;114(2):96-9 al., 1999). A number of genes have been mapped to the Chauffaille Mde L, Fermino FA, Pelloso LA, Silva MR, Bordin band 4q12 including mac25, PDGFRA, AFP, and a JO, Yamamoto M. t(4;12)(q11;p13): a rare chromosomal translocation in acute myeloid leukemia. Leuk Res. 2003 beta-sarcoglycan gene (Hamaguchi et al., 1999). Apr;27(4):363-6 The case reported here shared some features to those reported in the literature including positivity for CD7, Manabe M, Nakamura K, Inaba A, Fujitani Y, Kosaka S, Yamamura R, Inoue A, Hino M, Senzaki H, Ohta K. A rare CD33, CD34, CD117 and HLA-DR, lack of t(4;12)(q12;p13) in an adolescent patient with acute myeloid myeloperoxidase activity and dysplastic bone marrow. leukemia. Cancer Genet Cytogenet. 2010 Jul 1;200(1):70-2 Unlike other reported cases, bone marrow basophilia and high platelets were not found. Clearly in our case, This article should be referenced as such: FISH showed a break within ETV6/12p13 gene, and Heaton SM, Koppitch F, Mohamed AN. A new case of colocalization of PDGFR1 gene to derivative 12 next to t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature. Atlas Genet Cytogenet Oncol Haematol. 5’ ETV6 region. 2011; 15(10):982-984.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 984 Atlas of Genetics and Cytogenetics

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Case Report Section Paper co-edited with the European LeukemiaNet

Unbalanced rearrangement, der(9;18)(p10 ;q 10) in a patient with myelodysplastic syndrome: Case 0002M Kavita S Reddy Kaiser Permanente Southern California, 4580 ElectronicPlace, Los Angeles, CA 90039, USA (KSR)

Published in Atlas Database: March 2011 Online updated version : http://AtlasGeneticsOncology.org/Reports/der918Case2ReddyID100053.html DOI: 10.4267/2042/46060 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics Survival Age and sex Date of diagnosis: 03-2005 85 years old male patient. Treatment: not on any treatment Previous history Complete remission : None Preleukemia. Previous malignancy Bladder cancer, Treatment related death : NA status post removal and BCG treatment. No inborn Relapse : no condition of note. Phenotype at relapse: NA Organomegaly Status: Alive. Last follow up: 12-2010 No hepatomegaly, no splenomegaly, no enlarged lymph Survival: 66 months. nodes, no central nervous system involvement. Blood Karyotype Sample: 3/2005 BM, 6/2007 BM and 12/2010 BM WBC : 1.9X 10 9/l HB : 10.9g/dl Culture time : 24 and 72 hours with overnight Platelets : 57X 10 9/l Colcemid Banding: GTW at 400 bands Cyto-Pathology Results Classification 3/2005 BM 45,X,-Y[5]/46,XY,+9, der(9;18)(p10;q10)[11]/46,XY[4]; Cytology 6/2007 BM 45,X,-Y[5][4]/46,XY[16]; MDS (normocellular marrow with 12/2010 BM 46,XY,+9, dysmegakaryopoiesis and dysgranulopoiesis; consistent der(9;18)(p10;q10)[15]/46,XY[5] with myelodysplastic syndrome) Karyotype at Relapse: NA Immunophenotype: NA Other molecular cytogenetics technics: None Rearranged Ig Tcr: NA Diagnosis: MDS

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 985 Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myelodysplastic syndrome. Case 0002M. Reddy KS

4) and one had sAML after ET. The JAK2V617F is a gain in function mutation on chromosome 9. Hence, the extra copy of 9p may exacerbate the MPN as observed in 0001M case. The patient had splenomegaly and also myelofibrosis when the patient was found with the der(9;18). Der(9;18) is the sole abnormality in most reported cases, balanced translocations or complex aberrant karyotypes were reported as additional abnormalities. Our patient had del(13) in a sideline and this abnormality is observed in MPN. Among the 9 patients with der(9;18) two arose post treatment (present case 0001M and Andrieux et al 2003). and the other were at diagnosis. The der(9;18) supports progression of the disease in case 0001M but in case 0002M with MDS it reappears when there is suspicion of transformation and its role is less uncertain. References

Chen Z, Notohamiprodjo M, Guan XY, Paietta E, Blackwell S, Case 0002M : two partial karyotypes with a normal Stout K, Turner A, Richkind K, Trent JM, Lamb A, Sandberg chromosome 9 pair, a der(9;18)and a normal chromosome 18 AA. Gain of 9p in the pathogenesis of polycythemia vera. and arrow) Genes Chromosomes Cancer. 1998 Aug;22(4):321-4 Andrieux J, Demory JL, Caulier MT, Agape P, Wetterwald M, Comments Bauters F, Laï JL. Karyotypic abnormalities in myelofibrosis following polycythemia vera. Cancer Genet Cytogenet. 2003 Both the cases described in this study were followed Jan 15;140(2):118-23 for >5 years. Case 0001M, had thrombocytosis and Bacher U, Haferlach T, Schoch C. Gain of 9p due to an could not tolerate Interferon or Hydrea treatment and unbalanced rearrangement der(9;18): a recurrent clonal hence was treated with Busulfan. The patient was abnormality in chronic myeloproliferative disorders. Cancer positive for JAK2 mutation (on chromosome 9). A Genet Cytogenet. 2005 Jul 15;160(2):179-83 recent study was to rule out transformation of MPN as Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, there was myelofibrosis, splenomegaly and apparent Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of- progression of the disease. The der(9;18) was first function mutation of JAK2 in myeloproliferative disorders. N identified in the stem line and a sideline had partial Engl J Med. 2005 Apr 28;352(17):1779-90 deletion of chromosome 13q. Case 0002M was a MDS Xu X, Chen X, Rauch EA, Johnson EB, Thompson KJ, Laffin case with a der(9;18) detected in the initial study and JJS, Raca G, Kurtycz DF.. Unbalanced rearrangement again when the patient was suspected to be der(9;18)(p10;q10) in a patient with polycythemia vera. Atlas Genet Cytogenet Oncol Haematol. April 2010. URL : transforming >5 years later. This patient had very little http://AtlasGeneticsOncology.org/Reports/der0918XuID100044 symptoms and was not treated. .html In this report for the first time a long standing MDS case was found to have the der(9;18) at initial diagnosis This article should be referenced as such: and after over 5 years . Others reported with Reddy KS. Unbalanced rearrangement, der(9;18)(p10;q10) in der(9;18)(n 7) had PV (n 3) or post PV myelofibrosis (n a patient with myelodysplastic syndrome. Case 0002M.. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(10):985-986.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 986 Atlas of Genetics and Cytogenetics

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Case Report Section Paper co-edited with the European LeukemiaNet

Unbalanced rearrangement, der(9;18)(p10 ;q 10) in a patient with myeloproliferative neoplasm: Case 0001M Kavita S Reddy Kaiser Permanente Southern California, 4580 ElectronicPlace, Los Angeles, CA 90039, USA (KSR)

Published in Atlas Database: March 2011 Online updated version : http://AtlasGeneticsOncology.org/Reports/der918Case1ReddyID100052.html DOI: 10.4267/2042/46061 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics Survival Age and sex Date of diagnosis: 10-2004 71 years old male patient. Treatment: Could tolerate Interferon or Hydrea and is Previous history on regulated dose of Busulfan. Preleukemia. No previous malignancy. No inborn Complete remission : None condition of note. Treatment related death : NA Organomegaly Relapse : no No hepatomegaly, splenomegaly (Spleen appears Phenotype at relapse: NA enlarged measures 15.8 cm in length), no enlarged Status: Alive. Last follow up: 12-2010. lymph nodes, no central nervous system involvement. Survival: 74 months Blood Karyotype 9 WBC : 112.7X 10 /l Sample: 10/2004 BM, 6/2007 PB and 12/2010 BM HB : 13.3g/dl Platelets : 42X 10 9/l Culture time: 24 and 72 hours with overnight Colcemid Cyto-Pathology Banding: GTW at 400 bands Classification Results 10/2004 BM 46,XY[20]; Cytology 6/2007 PB 46,XY[10]; MPN (near 100% cellular marrow with granulocytic 12/2010 BM 46,XY,+9,der(9;18)(p10;q10) and megakaryocytic hyperplasia consistent with [8]/46,sl,del(13)(q12q14)[cp6]/46,XY[6] chronic myeloproliferative neoplasm). Karyotype at Relapse: NA Immunophenotype: NA Other molecular cytogenetics technics: None Rearranged Ig Tcr: NA Diagnosis: CMPN Other Molecular Studies Technics: PCR

Results: JAK2V617F mutation

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 987 Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myeloproliferative neoplasm. Case 0001M. Reddy KS

again when the patient was suspected to be transforming > 5 years later. This patient had very little symptoms and was not treated. In this report for the first time a long standing MDS case was found to have the der(9;18) at initial diagnosis and after over 5 years . Others reported with der(9;18)(n 7) had PV (n 3) or post PV myelofibrosis (n 4) and one had sAML after ET. The JAK2V617F is a gain in function mutation on chromosome 9. Hence, the extra copy of 9p may exacerbate the MPN as observed in 0001M case. The patient had splenomegaly and also myelofibrosis when the patient was found with the der(9;18). Der(9;18) is the sole abnormality in most reported cases, balanced translocations or complex aberrant karyotypes were reported as additional abnormalities. Our patient had del(13) in a sideline and this abnormality is observed in MPN. Among the 9 patients with der(9;18) two arose post treatment (present case 0001M and Andrieux et al 2003). and the other were at diagnosis. The der(9;18) supports progression of the disease in case 0001M but in case 0002M with MDS it reappears when there is suspicion of transformation and its role is less uncertain. References Chen Z, Notohamiprodjo M, Guan XY, Paietta E, Blackwell S, Stout K, Turner A, Richkind K, Trent JM, Lamb A, Sandberg AA. Gain of 9p in the pathogenesis of polycythemia vera. Genes Chromosomes Cancer. 1998 Aug;22(4):321-4 Andrieux J, Demory JL, Caulier MT, Agape P, Wetterwald M, Bauters F, Laï JL. Karyotypic abnormalities in myelofibrosis following polycythemia vera. Cancer Genet Cytogenet. 2003 Case 0001M : two partial karyotypes of the stemline (row1-2) Jan 15;140(2):118-23 with 2 normal chromosomes 9 a der(9;18), 13 pairs, a one Bacher U, Haferlach T, Schoch C. Gain of 9p due to an normal chromosome 18 and arrow). Two partial karyotpes of unbalanced rearrangement der(9;18): a recurrent clonal the sideline (row 3-4) with a normal chromosome 9 pair, a abnormality in chronic myeloproliferative disorders. Cancer der(9;18), a normal chromosome 13 and a deleted 13 (arrow) Genet Cytogenet. 2005 Jul 15;160(2):179-83 and a normal 18 (arrow). Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of- Comments function mutation of JAK2 in myeloproliferative disorders. N Both the cases described in this study were followed Engl J Med. 2005 Apr 28;352(17):1779-90 for > 5 years. Case 0001M, had thrombocytosis and Xu X, Chen X, Rauch EA, Johnson EB, Thompson KJ, Laffin could not tolerate Interferon or Hydrea treatment and JJS, Raca G, Kurtycz DF.. Unbalanced rearrangement der(9;18)(p10;q10) in a patient with polycythemia vera. Atlas hence was treated with Busulfan. The patient was Genet Cytogenet Oncol Haematol. April 2010. URL : positive for JAK2 mutation (on chromosome 9). A http://AtlasGeneticsOncology.org/Reports/der0918XuID100044 recent study was to rule out transformation of MPN as .html there was myelofibrosis, splenomegaly and apparent progression of the disease. The der(9;18) was first This article should be referenced as such: identified in the stem line and a sideline had partial Reddy KS. Unbalanced rearrangement, der(9;18)(p10;q10) in deletion of chromosome 13q. Case 0002M was a MDS a patient with myeloproliferative neoplasm. Case 0001M.. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(10):987-988. case with a der(9;18) detected in the initial study and

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Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myeloproliferative neoplasm. Case 0001M. Reddy KS

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 990