Volume 1 - Number 1 May - September 1997
Volume 24 - Number 4 April 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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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 is made for and by: clinicians and researchers in cytogenetics, molecular biology, oncology, haematology, and pathology. One main scope of the Atlas is to conjugate the scientific information provided by cytogenetics/molecular genetics to the clinical setting (diagnostics, prognostics and therapeutic design), another is to provide an encyclopedic knowledge in cancer genetics. The Atlas deals with cancer research and genomics. It is at the crossroads of research, virtual medical university (university and post-university e-learning), and telemedicine. It contributes to "meta-medicine", this mediation, using information technology, between the increasing amount of knowledge and the individual, having to use the information. Towards a personalized medicine of cancer.
It presents structured review articles ("cards") on: 1- Genes, 2- Leukemias, 3- Solid tumors, 4- Cancer-prone diseases, and also 5- "Deep insights": more traditional review articles on the above subjects and on surrounding topics. It also present 6- Case reports in hematology and 7- Educational items in the various related topics for students in Medicine and in Sciences. The Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles.
See also: http://documents.irevues.inist.fr/bitstream/handle/2042/56067/Scope.pdf
Editorial correspondance
Jean-Loup Huret, MD, PhD, [email protected]
Editor, Editorial Board and Publisher See:http://documents.irevues.inist.fr/bitstream/handle/2042/48485/Editor-editorial-board-and-publisher.pdf
The Atlas of Genetics and Cytogenetics in Oncology and Haematology 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. The Atlas is hosted by INIST-CNRS (http://www.inist.fr) Staff: Vanessa Le Berre Philippe Dessen is the Database Directorof the on-line version (Gustave Roussy Institute – Villejuif – France).
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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
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Editors-in-Chief Jesús María Hernández Rivas (Salamanca, Spain) Paola Dal Cin (Boston, Massachusetts) Jean-Loup Huret (Poitiers, France) Hematology Section Editor Ana E. Rodríguez, Teresa Gonzalez (Salamanca, Spain) Bone Tumors Section Editor Judith Bovee (Leiden, Netherlands) Head and Neck Tumors Section Editor Cécile Badoual (Paris, France) Urinary Tumors Section Editor Paola Dal Cin (Boston, Massachusetts) Pediatric Tumors Section Editor Frederic G. Barr (Bethesda, Maryland) Cancer Prone Diseases Section Editor Gaia Roversi (Milano, Italy) Cell Cycle Section Editor João Agostinho Machado-Neto (São Paulo, Brazil) DNA Repair Section Editor Godefridus Peters (Amsterdam, Netherlands) Epigenetics Section Editor Roberto Piergentili (Rome, Italy) Hematopoeisis Section Editor Olga Weinberg (Boston, Massachusetts) Hormones and Growth factors Section Editor Gajanan V. Sherbet (Newcastle upon Tyne, UK) Mitosis Section Editor Patrizia Lavia (Rome, Italy) Oxidative stress Section Editor Thierry Soussi (Stockholm, Sweden/Paris, France) WNT pathway Section Editor Alessandro Beghini (Milano, Italy) B-cell activation Section Editors Anette Gjörloff Wingren, Barnabas Nyesiga (Malmö, Sweden) Board Members Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Alessandro Beghini Department of Health Sciences, University of Milan, Italy; [email protected] Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Antonio Cuneo Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; [email protected] Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected] IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212, 91223 François Desangles Bretigny-sur-Orge, France; [email protected] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, OX37BN, UK Enric Domingo [email protected] Ayse Elif Erson- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Bensan Ad Geurts van Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB Nijmegen, Kessel The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer Research Oskar A. Haas Institute Vienna, Vienna, Austria. [email protected] Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; [email protected] Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA; Nyla Heerema [email protected] Sakari Knuutila Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; [email protected] Lidia Larizza Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; l.larizza@auxologico Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Roderick Mc Leod Germany; [email protected] Cristina Mecucci Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Fredrik Mertens [email protected] Konstantin Miller Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Felix Mitelman [email protected] Hossain Mossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected] Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Stefan Nagel Germany; [email protected] Florence Pedeutour Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; [email protected] Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Memphis, Tennessee 38105- Susana Raimondi 3678, USA; [email protected] Clelia Tiziana Department of Biology, University of Bari, Bari, Italy; [email protected] Storlazzi Sabine Strehl CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; [email protected] Nancy Uhrhammer Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; [email protected] Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected] Roberta Vanni Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Italy; [email protected]
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4) Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Volume 24, Number 4, April 2020
Table of contents
Gene Section
CEACAM19 (carcinoembryonic antigen related cell adhesion molecule 19) 152 Dimitra Tsouraki; Christos K. Kontos PRXL2C (Peroxiredoxin like 2C) 156 Jean Loup Huret PYGO2 (pygopus family PHD finger 2) 159 Ilaria Esposito, Adriana Cassaro EEF1DP3 (Eukaryotic translation elongation factor 1 delta pseudogene 3) 164 Luigi Cristiano
Leukaemia Section
Breast implant-associated anaplastic large cell lymphoma 170 Diego Conde Royo, Luis Miguel Juárez Salcedo, Samir Dalia Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2: Overview 2019 174 Sheng Xiao Juvenile myelomonocytic leukemia (JMML) 180 Karen M. Chisholm
Solid Tumor Section
EEF1G/PPP6R3 (11q12-13) 185 Luigi Cristiano
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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CEACAM19 (carcinoembryonic antigen related cell adhesion molecule 19) Dimitra Tsouraki; Christos K. Kontos Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece / [email protected]
Published in Atlas Database: June 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/CEACAM19ID53540ch19q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70693/06-2019-CEACAM19ID53540ch19q13.pdf DOI: 10.4267/2042/70693 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
downstream of the PVR gene (poliovirus receptor Abstract cell adhesion molecule) and upstream of the CEACAM16 gene at the chromosomal location CEACAM19 is a member of the CEACAM 19q13.31. subfamily of genes, described for the first time by Scorilas et al. (2003). Very few studies have been Transcription conducted so far concerning the CEACAM19 gene. CEACAM19 pre-mRNA is subjected to alternative Consequently, very little is known about it, and its splicing. According to UniProt, three main splice function in either physiological or pathological variants of the gene have been described. The first cellular processes remains poorly elucidated. Here, one, which is referred to as the "canonical" one, we present a review on the DNA, mRNA and protein consists of 903 nt and encodes for a 300-amino-acid level of the gene and on its implication in various (aa) polypeptide chain (Scorilas et al., 2003). The types of human malignancies. second splice variant contains one more exon (exon Keywords 3) of 134 bp and encodes for a polypeptide chain of Carcinoembryonic antigen; Immunoglobulin 142 aa residues (Scorilas et al., 2003). The third superfamily; ovarian cancer; breast cancer; gastric splice variant consists of 900 nt and encodes for a cancer; penile cancer; lung adenocarcinoma. polypeptide chain of 299 aa residues. However, according to the Human Protein Atlas, another five Identity splice variants have also been described. Other names Pseudogene CEACM19, CEAL1 Not identified so far. HGNC (Hugo): CEACAM19 Protein Location: 19q13.31 Local order: Centromere to telomere Description The canonical polypeptide isoform that is encoded DNA/RNA by the CEACAM19 gene (isoform 1) consists of 300 aa residues and has a putative molecular weight of Description 32.6 kDa. (Scorilas et al., 2003). This polypeptide The CEACAM19 gene belongs to the CEACAM corresponds to a protein with an N-terminal subfamily of the CEA gene family, which in turn extracellular domain consisting of the aa residues belongs to the Immunoglobulin Superfamily (IgS) 33-157 and one Ig-like helical transmembrane (Scorilas et al., 2003). It has a total length of 12,904 domain, similar to other members of the same gene nucleotides and consists of 8 exons and 7 intervening family (CEA family), composed of the aa residues introns (Scorilas et al., 2003). It is located 158-178 (Scorilas et al., 2003). The protein carries a
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4) 152 CEACAM19 (carcinoembryonic antigen related cell adhesion Tsouraki D, Kontos CK molecule 19)
hydrophobic N-terminal sequence, which is thought protein isoform is derived from a splice variant of to act as a signal peptide and which is comprised on 900 nt and consists of 299 aa residues. In this case, its whole of the aa residues 1-32 (Scorilas et al., the glutamine residue in position 282 of the 2003). The signal peptide of the protein is removed. canonical form is missing. aa residues 179-300 represent the cytoplasmic part As described above, the Human Protein Atlas of this protein (Figure 1). The CEACAM19 protein mentions the existence of another five splice variants bears no constant C2-like domains like the ones seen of the CEACAM19 gene, which encode for secreted in other members of the same family (Beauchemin polypeptides and not transmembrane ones (contrary et al., 2013). The protein bears a 9-aa sequence to the three main isoforms described earlier). Four of (SAMGQRDIV - from position 92 to 100) that is these polypeptides consist of 56 aa residues and present in the eIF5A domain of a variety of share a common molecular weight of 6.1 kDa each, transcription factors in eukaryotes (Scorilas et al., while one of them consists of 54 amino acids and has 2003). Moreover, the CEACAM19 polypeptide is a a molecular weight of 6 kDa. All these polypeptide heavily glycosylated glycoprotein, which carries an chains bear a signal peptide consisting of the amino ITAM motif (Immunoreceptor Tyrosine-based acids 1-33. Activation Motif) in its cytoplasmic tail (as most of the members of the same subfamily) (Beauchemin et Expression al., 2013). Moreover, several putative sites for post- The CEACAM19 gene is widely expressed in a translational modifications, such as O-/N- variety of tissues. Based on RNA-seq experiments glycosylation, phosphorylation, N-myristoylation, (Fagerberg et al., 2014), higher expression levels are have been described (Scorilas et al., 2003). mainly seen in skin and testis. However, moderate to The alternative splicing of CEACAM19 pre-mRNA high expression levels have also been described in leads to the production of two other protein isoforms. the prostate, adrenal gland, endometrium, lung, and As described previously, the second splice variant ovary. encodes for a polypeptide of 142 aa residues, shorter than the one described as the canonical form of the Localisation protein. Besides the fact that the aa residues from The three main CEACAM19 protein isoforms that position 143 to 300 are missing, this isoform also bear a transmembrane domain are characterized as differs from the canonical one in that the glutamic single-pass type-I membrane proteins. These are acid residue in position 142 is replaced by an aspartic proteins that traverse the membrane only once with acid residue. The third their N-terminal domain on the extracellular side of it and their signal peptide being removed.
Figure 1. Alignment of the three main protein isoforms (CLUSTAL O 1.2.4) that arise as a result of the CEACAM19 pre-mRNA alternative splicing procedure. The N-terminal signal peptide and the eIF5A domain that are present in all three protein isoforms are shown in red and light blue, respectively. The Ig-like transmembrane domain is underlined. The ITAM motif present in the two of the three isoforms is shown in green .
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However, according to the Human Protein Atlas, the negative breast cancer patients, with higher mRNA rest of the protein isoforms, which lack levels in the latter (Estiar et al., 2016). transmembrane domains, are predicted to be Gastric cancer secreted. Prognosis Function It has been shown that CEACAM19 protein levels The functions of the CEACAM19 protein (either are significantly elevated in gastric cancer tissues physiological or pathological) have not been and cancerous cell lines, compared to normal ones. elucidated, yet. Similarly, the same study showed that the expression of matrix metallopeptidases 2 and 9 ( MMP2 and Implicated in MMP9) was also upregulated in gastric cancer cell lines and that knockdown of CEACAM19 via Ovarian cancer siRNA in the same cells led to the inhibition of their Prognosis expression. Knockdown of CEACAM19 was also CEACAM19 mRNA expression is higher in ovarian shown to lead to a decrease in proliferation, invasion, cancer tissues, particularly in patients with late stage and migration of gastric cancer cells. Furthermore, it (stage III) of the disease and patients having been has been suggested that knockdown of CEACAM19 subjected to suboptimal cytoreduction. The sizes of leads to the inactivation of PI3K/Akt and NF-kB the residual tumors were found to present a signaling pathways and to the inhibition of tumor statistically significant difference between growth in vivo, as measured by xenograft CEACAM19 mRNA-positive and -negative tumors, experiments in mice (Zhao et al., 2018). with the positive ones exhibiting larger dimensions. Penile cancer No statically significant association has been observed between the expression status of Prognosis CEACAM19 and patients' age (Scorilas et al., 2003). Differential expression levels of CEACAM19 have been shown in penile cancer cases, with some Breast cancer cancerous tissues exhibiting low and others Prognosis exhibiting higher expression levels, compared to CEACAM19 has been shown to be overexpressed in normal ones. Overexpression of CEACAM19 has malignant breast tissue sections, compared to normal been associated with distant and lymph node counterparts derived from the same patients metastasis in penile cancer and with unfavorable (Michaelidou et al., 2013), and in breast tumor cancer-specific survival of patients, but its samples compared to samples derived from normal prognostic significance is not independent from individuals (Estiar et al., 2016). Furthermore, higher other predictors of survival. Moreover, it has been mRNA levels of CEACAM19 have been associated shown that knockdown of CEACAM19 in penile with increased risk of breast cancer in women. The cancer cell lines leads to decreased cell growth and association between CEACAM19 mRNA that it suppresses colony formation. CEACAM19 expression and various clinicopathological knockdown has also been related to the decrease of parameters linked to aggressive tumor behavior and SMAD2/3 signaling pathway activity and inhibition poor prognosis has also been examined in the of MMP2 and MMP9 secretion, which are both aforementioned study. In particular, elevated associated with invasion and metastasis. expression levels have been observed in higher grade Consequently, it has been observed that migration (grade III) tumors and those with a high proliferation and invasion abilities of the Pen11 cancerous cells index. Moreover, it has been shown that the were suppressed after CEACAM19 knockdown (Hu expression of CEACAM19 is elevated in estrogen et al., 2019). receptor (ER)-negative tumors and those of Lung adenocarcinoma premenopausal patients; both these features are associated with poor prognosis (Michaelidou et al., Prognosis 2013). On the other hand, another study by Estiar et Kobayashi et al. (2012) examined whether some al. (2016) did not support the positive association members of the CEACAM gene family could be between CEACAM19 expression and tumor grade, used as surrogate markers for tyrosine kinase observed by Michaelidou et al. (2013), as described inhibitor (TKI) sensitivity in lung adenocarcinoma above. In the study of Estiar et al., no significant patients. The examined members of the family association was shown between CEACAM19 included CEACAM3, CEACAM5, CEACAM6, mRNA expression status and tumor grade. CEACAM7, and CEACAM19. The expression Moreover, the study of Estiar et al. revealed a patterns of all these genes were found to be statistically significant difference in the expression associated with TKI sensitivity, in microarray of CEACAM19 between ER/PR-positive and - analysis. Moreover, the immunoreactivity of the CEACAMs examined was shown to be significantly
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higher in patients carrying EGFR mutations than in Hu X, Chen M, Li Y, Wang Y, Wen S, Jun F. Aberrant those carrying the wild-type gene. CEACAM19 CEACAM19 expression is associated with metastatic phenotype in penile cancer. Cancer Manag Res. immunoreactivity was not found to present 2019;11:715-725 statistically significant association with Kobayashi M, Miki Y, Ebina M, Abe K, Mori K, Narumi S, clinicopathological parameters of lung Suzuki T, Sato I, Maemondo M, Endo C, Inoue A, adenocarcinoma patients, such as age, sex, tumor Kumamoto H, Kondo T, Yamada-Okabe H, Nukiwa T, size, stage of the disease, and lymph node metastasis. Sasano H. Carcinoembryonic antigen-related cell adhesion molecules as surrogate markers for EGFR inhibitor sensitivity in human lung adenocarcinoma Br J Cancer References 2012 Nov 6;107(10):1745-53 Beauchemin N, Arabzadeh A. Carcinoembryonic antigen- Michaelidou K, Tzovaras A, Missitzis I, Ardavanis A, related cell adhesion molecules (CEACAMs) in cancer Scorilas A. The expression of the CEACAM19 gene, a novel progression and metastasis. Cancer Metastasis Rev. 2013 member of the CEA family, is associated with breast cancer Dec;32(3-4):643-71 progression Int J Oncol 2013 May;42(5):1770-7 Estiar MA, Esmaeili R, Zare AA, Farahmand L, Fazilaty H, Scorilas A, Chiang PM, Katsaros D, Yousef GM, Diamandis Zekri A, Jafarbeik-Iravani N, Majidzadeh-A K. High EP. Molecular characterization of a new gene, CEAL1, expression of CEACAM19, a new member of encoding for a carcinoembryonic antigen-like protein with a carcinoembryonic antigen gene family, in patients with highly conserved domain of eukaryotic translation initiation breast cancer. Clin Exp Med. 2017 Nov;17(4):547-553 factors Gene 2003 May 22;310:79-89 Fagerberg L, Hallström BM, Oksvold P, Kampf C, Zhao H, Xu J, Wang Y, Jiang R, Li X, Zhang L, Che Y. Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Knockdown of CEACAM19 suppresses human gastric Danielsson A, Edlund K, Asplund A, Sjöstedt E, Lundberg cancer through inhibition of PI3K/Akt and NF-κB Surg Oncol E, Szigyarto CA, Skogs M, Takanen JO, Berling H, Tegel H, 2018 Sep;27(3):495-502 Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson F, Mardinoglu A, Sivertsson A, von Feilitzen K, Forsberg M, This article should be referenced as such: Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten F, Uhlén M. Analysis of the human tissue-specific Tsouraki D, Kontos CK. CEACAM19 (carcinoembryonic expression by genome-wide integration of transcriptomics antigen related cell adhesion molecule 19). Atlas Genet and antibody-based proteomics. Mol Cell Cytogenet Oncol Haematol. 2020; 24(4):152-155. Proteomics. 2014 Feb;13(2):397-406
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Gene Section Review
PRXL2C (Peroxiredoxin like 2C) Jean Loup Huret [email protected]
Published in Atlas Database: November 2018 Online updated version : http://AtlasGeneticsOncology.org/Genes/PRXL2CID60014ch9q22.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70694/11-2018-PRXL2CID60014ch9q22.pdf DOI: 10.4267/2042/70694 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
selenocysteines (Sec), with an atom of selenium Abstract SHE taking the place of the sulfur SH of the cysteine. Decoding of UGA into a selenocysteine (Sec) is Review on PRXL2C, with data on DNA, on the alternative to the stop signal in the canonical genetic protein encoded, and where the gene is implicated. code. Keywords The human selenoproteins (SelU family) are PRXL2C; oxidation; reduction; Mutation; composed of three Cys-containing members, one of Overexpression; Cancer; Gastric cancer; Attention- which being PRXL2C (Ensembl deficit/hyperactivity disorder ENSG00000158122) (Castellano et al., 2004). PRXL2C amino acids 68-71 are: CYIC, a CXXC Identity motif. According to InterPro http://www.ebi.ac.uk/interpro/protein/Q7RTV5, Other names: C9orf21, AAED1 PRXL2C signature matches with thioredoxin-like HGNC (Hugo): AAED1 superfamily in amino acids 35-135 (or 21-90) (with Location: 9q22.33 a thioredoxin CXXC motif at aa 68-71 (CYIC); the two cysteines can forms a disulfide bond), and also DNA/RNA matches with peroxiredoxin-like 2A/B/C in aa 86- 196 (or 40-150). Peroxiredoxins and thioredoxins Description are involved in oxidation-reduction process Six exons, four splice forms, one of which codes for (antioxidants). Peroxiredoxins form a family of thiol a protein: oxidoreductases and play a role in peroxides detoxification (see Figure2). A peroxidatic cysteine Transcription reduces the peroxide to water. Thioredoxin system Coding transcript: 2863bp reduce peroxiredoxins restoring to them their catalytically active form (West et al., 2018). Protein Expression Description PRXL2C is widely expressed (The Human Protein A selenoprotein is a protein containing Atlas).
Figure 1 PRXL2C gene
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4) 156 PRXL2C (Peroxiredoxin like 2C) Huret JL
Figure 2 Peroxides detoxification by Peroxiredoxins motifs -C-X-X-C-
Function cancer cells. Silencing of PRXL2C inhibited cancer cell proliferation in vitro in gastric cancer cell lines. Aaed1 was found to be one of the few primitive Possibly though MAPK signaling, PRXL2C endoderm transition markers in preimplantation upregulates HIF1A (hypoxia inducible factor 1 mouse embryos (Gerovska and Arauzo-Bravo, subunit alpha), a transcriptional activator of many 2016). genes, including glycolytic enzymes and glucose transporters in aerobic glycolysis (Zhang et al., Mutations 2018). Somatic Renal cancer According to Cosmic PRXL2C High expression is related with an Glioma astrocytoma grade IV amino acid (aa) unfavourable prognosis according to the Human mutation: p.V91A from CDS mutation c.272T>C Protein Atlas Papillary thyroid carcinomas aa mutation p.I81S https://www.proteinatlas.org/ENSG00000158122- (c.242T>G) AAED1/pathology Thyroid carcinomas NOS aa mutations: p.V95L Attention-deficit/hyperactivity (c.283G>T); p.G183V (c.548G>T) disorder (ADHD) Lung small cell carcinoma aa mutation: p.E136K (c.406G>A) (Rudin et al. 2012) A rare variant of PRXL2C (rs151326868) amino Lung adenocarcinoma aa mutations: p.H145N acid p.H200D (c.598C>G) was found to segregate (c.433C>A) (Imielinski et al. 2012); p.S152L with ADHD in one of the families with an apparent (c.455C>T) dominant inheritance that was studied (Corominas et Skin melanoma aa mutations: p.M131I (c.393G>A); al., 2018). p.S148L (c.443C>T); p.W159* (c.476G>A) PRXL2C binds PICK1 (Protein Kinase C-Alpha- Colon adenocarcinoma aa mutations: p.E76D Binding Protein) and PICK1 binds SLC6A3 (solute (c.228G>T); p.L110Q (c.329T>A) (Giannakis et al. carrier family 6 member 3, also known as DAT, the 2016); p.S143I (c.428G>T) (Giannakis et al. 2016); dopamine transporter 1), regulating SLC6A3 p.Q208H (c.624G>T) (Wood et al. 2007); p.P221H trafficking in presynaptic sites of dopaminergic (c.662C>A) neurons, and DRD3 (dopamine D3 receptor 3). Duodenum adenoma aa mutations: p.K201N PICK1 also has a role in glutamate receptor (c.603A>C) (Yachida et al. 2016); p.T218A regulation (Corominas et al., 2018). (c.652A>G) (Yachida et al. 2016) Disease Prostate adenocarcinoma aa mutation: p.H214R ADHD is characterized by of lack of attention, (c.641A>G) impulsivity, hyperactivity and distractibility. It is a highly heritable (80%-90%) childhood Implicated in behavioral disorder with a prevalence estimated at 5- 7% in children, male predominance, and half of them Gastric cancer have persisting symptoms in adulthood. (AhpC/TSA antioxidant enzyme domain containing In addition to genetic factors, environmental factors 1), which is upregulated in gastric (adverse circumstances in maternal or children life) have been implicated in the etiology of ADHD.
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Z, Shames DS, Bergbower EA, Guan Y, Shin J, Guillory J, References Rivers CS, Foo CK, Bhatt D, Stinson J, Gnad F, Haverty PM, Gentleman R, Chaudhuri S, Janakiraman V, Jaiswal Castellano S, Novoselov SV, Kryukov GV, Lescure A, BS, Parikh C, Yuan W, Zhang Z, Koeppen H, Wu TD, Stern Blanco E, Krol A, Gladyshev VN, Guigó R. Reconsidering HM, Yauch RL, Huffman KE, Paskulin DD, Illei PB, Varella- the evolution of eukaryotic selenoproteins: a novel Garcia M, Gazdar AF, de Sauvage FJ, Bourgon R, Minna nonmammalian family with scattered phylogenetic JD, Brock MV, Seshagiri S. Comprehensive genomic distribution. EMBO Rep. 2004 Jan;5(1):71-7 analysis identifies SOX2 as a frequently amplified gene in Corominas J, Klein M, Zayats T, Rivero O, Ziegler GC, small-cell lung cancer Nat Genet 2012 Oct;44(10):1111-6 Pauper M, Neveling K, Poelmans G, Jansch C, Svirin E, West JD, Roston TJ, David JB, Allan KM, Loberg MA. Geissler J, Weber H, Reif A, Arias Vasquez A, Galesloot TE, Piecing Together How Peroxiredoxins Maintain Genomic Kiemeney LALM, Buitelaar JK, Ramos-Quiroga JA, Stability Antioxidants (Basel) 2018 Nov 28;7(12) Cormand B, Ribasés M, Hveem K, Gabrielsen ME, Hoffmann P, Cichon S, Haavik J, Johansson S, Jacob CP, Wood LD, Parsons DW, Jones S, Lin J, Sjöblom T, Leary Romanos M, Franke B, Lesch KP. Identification of ADHD RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo risk genes in extended pedigrees by combining linkage S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, analysis and whole-exome sequencing. Mol Psychiatry. Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, 2018 Aug 16; Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger Gerovska D, Araúzo-Bravo MJ. Does mouse embryo DG, Sparks AB, Hartigan J, Smith DR, Suh E, primordial germ cell activation start before implantation as Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani suggested by single-cell transcriptomics dynamics? Mol G, Kinzler KW, Velculescu VE, Vogelstein B. The genomic Hum Reprod. 2016 Mar;22(3):208-25 landscapes of human breast and colorectal cancers Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Science 2007 Nov 16;318(5853):1108-13 Nishihara R, Bahl S, Cao Y, Amin-Mansour A, Yamauchi M, Yachida S, Wood LD, Suzuki M, Takai E, Totoki Y, Kato M, Sukawa Y, Stewart C, Rosenberg M, Mima K, Inamura K, Luchini C, Arai Y, Nakamura H, Hama N, Elzawahry A, Nosho K, Nowak JA, Lawrence MS, Giovannucci EL, Chan Hosoda F, Shirota T, Morimoto N, Hori K, Funazaki J, AT, Ng K, Meyerhardt JA, Van Allen EM, Getz G, Gabriel Tanaka H, Morizane C, Okusaka T, Nara S, Shimada K, SB, Lander ES, Wu CJ, Fuchs CS, Ogino S, Garraway LA. Hiraoka N, Taniguchi H, Higuchi R, Oshima M, Okano K, Genomic Correlates of Immune-Cell Infiltrates in Colorectal Hirono S, Mizuma M, Arihiro K, Yamamoto M, Unno M, Carcinoma. Cell Rep. 2016 Apr 26;15(4):857-865 Yamaue H, Weiss MJ, Wolfgang CL, Furukawa T, Imielinski M, Berger AH, Hammerman PS, Hernandez B, Nakagama H, Vogelstein B, Kiyono T, Hruban RH, Shibata Pugh TJ, Hodis E, Cho J, Suh J, Capelletti M, Sivachenko T. Genomic Sequencing Identifies ELF3 as a Driver of A, Sougnez C, Auclair D, Lawrence MS, Stojanov P, Ampullary Carcinoma Cancer Cell 2016 Feb 8;29(2):229- Cibulskis K, Choi K, de Waal L, Sharifnia T, Brooks A, 40 Greulich H, Banerji S, Zander T, Seidel D, Leenders F, Zhang B, Wu J, Cai Y, Luo M, Wang B, Gu Y. AAED1 Ansén S, Ludwig C, Engel-Riedel W, Stoelben E, Wolf J, modulates proliferation and glycolysis in gastric cancer Goparju C, Thompson K, Winckler W, Kwiatkowski D, Oncol Rep 2018 Aug;40(2):1156-1164 Johnson BE, Jänne PA, Miller VA, Pao W, Travis WD, Pass HI, Gabriel SB, Lander ES, Thomas RK, Garraway LA, This article should be referenced as such: Getz G, Meyerson M. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing Cell Huret JL. PRXL2C (Peroxiredoxin like 2C). Atlas Genet 2012 Sep 14;150(6):1107-20 Cytogenet Oncol Haematol. 2020; 24(4):156-158. Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan
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Gene Section Review
PYGO2 (pygopus family PHD finger 2) Ilaria Esposito, Adriana Cassaro Department of Health Sciences, University of Milan, via A. Di Rudinò, 8 20142, Milan (Italy); [email protected], [email protected]
Published in Atlas Database: June 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/PYGO2ID45884ch1q21.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70695/06-2019-PYGO2ID45884ch1q21.pdf DOI: 10.4267/2042/70695 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Identity Other names PYGO2 is member of a conserved family of plant Pygopus Homolog 2 (Drosophila), Pygopus homeo domain (PHD)-containing proteins and takes Homolog 2, 190004M21 Rik, Pygopus 2 part in a wide range of developmental and transcriptional processes. HGNC (Hugo) PYGO2 The most relevant role played by PYGO2 is in Wnt Location signaling pathway, where it is required for β- 1q21.3 [link to chromosomal band 1q21. catenin/TCF-dependent transcription, even if it has [http://atlasgeneticsoncology.org/Bands/1q21.html ] showed to have a crucial role also in absence of β- Local order catenin in tissues such as eye and testis. Starts at 154957026 and ends at 154961782 from PYGO2 is also known as a chromatin effector pter (according to hg38-Dec_2013) because of its implication in chromatin remodelling processes through regulation of histones methylation. DNA/RNA Keywords Note PYGO2, Pygopus, Wnt signaling pathway, The PYGO2 gene (6828 bp) contains a total of 3 transcription factor, chromatin remodelling exons and the PYGO2 transcript is 3146 bp.
Figure 1: A) Location of PYGO2 gene on chr1. B) Schematic representation of PYGO2 gene, with its three exons.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4) 159 PYGO2 (pygopus family PHD finger 2) Esposito I, Cassaro A
Figure 2: Schematic representation of PYGO2 gene.
Figure 3: Schematic illustration of domains of PYGO2 protein.
Description PHD-BCL9-HD1 complex formation (Miller et al., 2010). Genomic size: 6828 bp. Exons count: 3. This gene has 3 transcript (splice variants), 112 orthologues Expression and 1 paralogue The first molecular cloning and expression analysis of a mouse pygopus gene, mpygo2, were described Transcription by Li et al. (2004). Its transcripts were expressed in 3 transcript variants have been found for this gene various adult mouse tissues, such as brain, heart, (font. www.ensembl.org). kidney, liver, lung, skin, small intestine, spleen, PYGO2-202 ENST00000368457.2 : mRNA 3146 stomach, testis tissue and thymus; at the same bp, protein 406 aa manner, mpygo2 transcripts were detected in all PYGO2-201 ENST00000368456.1 : mRNA 1306 embryos stages examined. The majority of tissues in bp, protein 369 aa which mpygo2 is expressed requires Wnt signaling PYGO2-203 ENST00000483463.1 : mRNA 594 bp, activation for development, morphogenesis and no protein. maintenance and this is in line with the involvement of this gene in the Wnt signaling. Interestingly, since Protein the hair follicle development is a well-known system which involves Wnt signaling, mpygo2 expression Description was detected both in developing and adult hair PYGO2 protein, composed by 406 aa with a follicle (Li et al; 2004). The homologous Drosophila molecular mass of 41244 Da, is one of mammalian pygo gene is necessary to the binding with Lgs homologs of Drosophila Pygopus, essential for early (legless) and for this reason Drosophila embryos embryonic development, moreover is known to be homozygous for a pygo mutation, with any Pygo co-activator of the Wnt/β-catenin pathway activity, die with a severe segment polarity transcriptional complex. phenotype (Kramps et al., 2002); this lethality is not PYGO2 has two conserved domains, an N-terminal found in mice. Mammals have two Pygopus homology domain (NHD) and a C-terminal PHD homologues, Pygo1 and Pygo2, and the latter seems zinc finger motif. The NHD domain plays an to be dominant (Schwab et al., 2007). The hPygo is important role in transcriptional activation, taking expressed in a Wnt-dependent manner, in tissues part in the recruitment of histone modification such as kidney (Schwab et al., 2007), pancreas factors and being involved in histone methylation (Jonckheere et al., 2008), brain (Lake and Kao, (Gu et al., 2009). Deletion of NHD domain has been 2003) and mammary gland (Gu et al., 2012); while associated with 50% reduction of transcriptional is expressed in a Wnt-independent fashion for eye activity (Liang et al., 2018). Moreover, in the N- development (Song et al., 2007), spermiogenesis terminal region, there is its nuclear localization (Nair et al., 2008) and embryonic brain patterning signal-NLS (from aa 41 to aa 47) and a NPF (Lake and Kao, 2003). hPYGO2 shows high (asparagine-proline-phenylalanine) sequence, which expression levels also in several types of cancer, in takes part in interactions with several proteins particular in epithelial ovarian cancer cell lines involved in chromatin remodelling. PYGO2 contains (Popadiuk et al., 2006), in several breast malignant a plant homeodomain (PHD) finger, from aa 327 to tumours (Andrews et al., 2007), in gliomas and aa 385, composed by 60 aminoacids organized in glioblastoma cells (Wang et al., 2010 14; Chen et al., C4HC3 motives, which is important for the PYGO2 2011); recently hPYGO2 has been associated also
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with adenomas and colon tumours (Brembeck et al., 2011) and esophageal squamous cell carcinoma Mutations (Moghbeli et al., 2013). Somatic Localisation Some somatic mutations have been identified and PYGO2 is localized in the nucleus (UniProt Pygo2) described by COSMIC (Catalogue of Somatic Mutation In Cancer) and they are listed mostly as Function substitutions and frameshift insertion or deletions; PYGO2 protein is known to be implicated in their role in disease has not yet been clarified. chromatin remodelling and binding to methylated residues on lysine 4 of histone H3 (H3K4me), relevant for active transcription (Aasland et al., 1995). Has also been demonstrated that PYGO2 is involved in promoting trimethylation of the same residue (H3K4) and acetylation of H3K9/K14 (Gu et al., 2009; Chen et al., 2010). In addition, PYGO2 seems to act as scaffold protein between CTNNB1 (β-catenin), HNMT, TMPRSS11D (HAT) and the chromatin (Chen et al., 2010). This protein is also involved in signal transduction through the Wnt pathway and it showed a role in nuclear retention of β-catenin. Several studies reported that the NHD domain of Pygo regulates the transactivation activity, instead the PHD domain is responsible for the binding, through adaptor proteins, to the N- terminal domain of β-catenin (Townsley et al., 2004; Stadeli and Basler, 2005). Several studies reported Figure 4: Overview of the major types of mutations not only the association with β-catenin to act as co- occurring in PYGO2. activators of the β-catenin/ LEF1/TCF complex (Kramps et al., 2002, Stadeli and Basler, 2005), but Implicated in also the β-catenin independent association with Metastatic prostate cancer LEF/TCF target genes (de la Roche and Bienz, 2007). In two of the most extensively characterized Prostate cancer (PrCa) is the most common PYGO2-requiring tissues, testis and eye, its function malignancy in men. Since PYGO2 mRNA and is β-catenin independent. In the developing kidney protein show elevated levels in many androgen- PYGO2 shows wide expression in the ureteric bud dependent and androgen-independent PrCa cell lines and PYGO2 mutant phenotype resulted in reduced (Kao et al., 2018), there could be evidences of his branching morphogenesis of this (Schwab et al., involvement in tumor progression. PYGO2 2007). Similarly, a mutant phenotype has been overexpression promotes prostate tumor growth and observed also in pancreas, where lack of PYGO2 moreover regional lymph nodes invasion; instead its results in pancreas hypoplasia and defective depletion results in cell cycle arrest, decreasing of endocrine cell differentiation (Jonckheere et al., cell proliferation and reduction of cell invasion (Lu 2008). PYGO2 demonstrated to play a role in et al., 2018). development also in lung morphogenesis, because Glioma mpygo2-/- showed lungs pale and smaller than the Glioma is one of the most common type of tumor wild type and with airways defects (Boan et al., that occurs in brain and spinal cord. Zhou et al (2016) 2007). Concerning the tissues where PYGO2 is not found PYGO2 mRNA expression in the majority of linked to the Wnt signalling, it showed to play a role primary glioma tissue of patients and this was in lens development, because of its expression in increased compared to control. Interestingly, this tissues of early eye such as optic vesicle and overexpression correlates with some clinic- presumptive lens (Song et al., 2007), and during pathological features, such as the age and the tumor spermatogenesis, as a matter of fact its block leads to grade: it is present in patients over 50 years and in spermiogenesis arrest and infertility (Nair et al., advanced tumors. Knockdown of PYGO2, in human 2008). brain glioma cell lines, leads to decreased mRNA Homology and protein levels of some Wnt/β-catenin pathway PYGO2 is conserved in human, mouse, rat, downstream targets, acting through regulation of chimpanzee, cattle, dog and chicken. H2K4me3 level on their promoters.
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Hepatic carcinoma receptor which is broadly involved in various squamous cell carcinomas. Apparently, PYGO2 Hepatic carcinoma (HCC) is a primary malignancy could act as transcriptional activator of EGFR, of the liver. There are evidences (Zhang et al., 2015) promoting the ESCC tumorigenesis that in HCC tissues PYGO2 mRNA and protein are highly expressed and it could play a role in HCC Epithelial ovarian cancer development and progression, showing positive Epithelial ovarian cancer is the most common type regulation on cell migration. This positive regulation of ovarian cancer, almost 90% of ovarian cancers are could be explained considering the fact that PYGO2 epithelial. PYGO2 shows overexpression in six can bind to the promoter of CDH1 (E-cadherin) malignant epithelial ovarian cancer cell lines, regulating its expression. Zhang and colleagues compared to control. Interestingly it is demonstrated that down-modulation of PYGO2 overexpressed in both ovarian cancer tumors increased E-cadherin expression, resulting in endometrioid and non-endometrioid, that differ from increased cellular adhesion; indeed, a weak presence each other, respectively, for the activation and of PYGO2, and a subsequently wider presence of E- inactivation of Wnt pathway. Popadiuk et al. cadherin, leads to decreased invasion capability and demonstrated that knockdown of Pygo2 results in metastasis formation. reduction of mRNA and protein levels and it causes Colon cancer growth's inhibition. Colon cancer affects the large intestine and the Breast cancer primary source for the development of this type of Breast cancer is the leading malignant female cancer is the deregulation of Wnt/β-catenin signaling disease with a high percentage of chemoresistance. pathway, resulting in an overactivation of the entire Watanabe et al. (2014) demonstrated that PYGO2 pathway. Brembeck and colleagues (2011) plays an important role in mammary tumorigenesis demonstrated a PYGO2 overexpression in human and its loss leads to delays in mammary tumors colon cancer and for this reason has been formation in mice, acting via both Wnt-dependent investigated his oncogenic role. There are evidences and independent mechanism. PYGO2 seems to play that PYGO2 deletion decelerates tumor formation in a role also in the onset of chemoresistance, activating chemically induced colon cancer, decreasing in a a drug efflux transporter, ABCB1 (MDR1). To significant manner tumor number and size. This confirm this hypothesis, Zhang et al. (2016) delay is caused by inhibition of Wnt signaling, demonstrated that knockdown of PYGO2 results in because of the capability of PYGO2 to reduce restoring sensitivity for chemotherapeutic drug. overexpression of some Wnt/β-catenin target genes (Talla and Brembeck, 2016). Idiopathic azoospermia Non-small cell lung carcinoma Idiopathic azoospermia is a medical condition which implies the absence of sperm in semen. Two non- Non-small cell lung carcinoma (NSCLC) represents synonymous SNP mutations in PYGO2 have been about 80% to 85% of lung cancers. Liu et al. (2013) reported to be implicated in this disease: demonstrated PYGO2 nuclear accumulation in more rs61758740, M141I, has no effect on protein than half of the lung cancer samples analysed and structure, and rs141722381, N240I, disrupts the determined a correlation between PYGO2 protein structure and so it can be disease causing (Ge expression and some NSCLC clinic-pathological et al., 2015). These SNPs are reported in the National features, such as stages of tumor and survival. Center for Biotechnology Information SNP database Moreover, viability assays demonstrated that (NCBI SNPdb). PYGO2 silencing results in inhibition of lung cancer cells proliferation, via regulation of cell cycle and References apoptosis. Aasland R, Gibson TJ, Stewart AF. The PHD finger: Esophageal squamous cell implications for chromatin-mediated transcriptional carcinoma regulation. Trends Biochem Sci. 1995 Feb;20(2):56-9 Esophageal squamous cell carcinoma (ESCC) is a Andrews PG, Lake BB, Popadiuk C, Kao KR. Requirement of Pygopus 2 in breast cancer. Int J Oncol. 2007 type of esophageal carcinoma that usually affects the Feb;30(2):357-63 upper or middle third part. For the first time Moghbeli et al. reported an association between the Brembeck FH, Wiese M, Zatula N, Grigoryan T, Dai Y, Fritzmann J, Birchmeier W. BCL9-2 promotes early stages overexpression of PYGO2 and clinic-pathological of intestinal tumor progression. Gastroenterology. 2011 features of ESCC, such as the grade of tumor Oct;141(4):1359-70, 1370.e1-3 differentiation, the tumor size and the age of patients. Chen J, Luo Q, Yuan Y, Huang X, Cai W, Li C, Wei T, Zhang The exact role of PYGO2 in ESCC is unclear, but it L, Yang M, Liu Q, Ye G, Dai X, Li B. Pygo2 associates with has been demonstrated to have a significant MLL2 histone methyltransferase and GCN5 histone correlation with EGFR, a type I transmembrane acetyltransferase complexes to augment Wnt target gene
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expression and breast cancer stem-like cell expansion. Association of PYGO2 and EGFR in esophageal squamous Molecular and cellular biology 30.24 (2010): 5621-5635. cell carcinoma. Medical Oncology 30.2 (2013): 516. Chen Y Y, Li B A, Wang H D, Liu X Y, Tan G W, Ma Y H, Nair M, Nagamori I, Sun P, Mishra DP, Rhéaume C, Li B, Shen S H, Zhu H W, Wang Z X. The role of Pygopus 2 in rat Sassone-Corsi P, Dai X. Nuclear regulator Pygo2 controls glioma cell growth. Medical Oncology 28.2 (2011): 631-640. spermiogenesis and histone H3 acetylation. Developmental biology 320.2 (2008): 446-455. Ge SQ, Grifin J, Liu LH, Aston KI, Simon L, Jenkins TG, Emery BR, Carrell DT. Associations of single nucleotide Popadiuk CM, Xiong J, Wells MG, Andrews PG, Dankwa K, polymorphisms in the Pygo2 coding sequence with Hirasawa K, Lake BB, Kao KR. Antisense suppression of idiopathic oligospermia and azoospermia Genet Mol Res pygopus2 results in growth arrest of epithelial ovarian 14.3 (2015): 9053-9061 cancer. Clinical Cancer Research 12.7 (2006): 2216-2223. Gu B, Sun P, Yuan Y, Moraes RC, Li A, Teng A, Agrawal A, Schwab KR, Patterson LT, Hartman HA, Song N, Lang RA, Rhéaume C, Bilanchone V, Veltmaat JM, Takemaru K, Lin X, Potter SS. Pygo1 and Pygo2 roles in Wnt signaling in Millar S, Lee EY, Lewis MT, Li B, Dai X. Pygo2 expands mammalian kidney development. BMC biology 5.1 (2007): mammary progenitor cells by facilitating histone H3 K4 15. methylation. The Journal of cell biology 185.5 (2009): 811- 826. Song N, Schwab KR, Patterson LT, Yamaguchi T, Lin X, Potter SS, Lang RA. pygopus 2 has a crucial, Wnt pathway- Gu B, Watanabe K, Dai X. Pygo2 regulates histone gene independent function in lens induction. Development 134.10 expression and H3 K56 acetylation in human mammary (2007): 1873-1885. epithelial cells. Cell cycle 11.1 (2012): 79-87. Städeli R, Basler K. Dissecting nuclear Wingless signalling: Jonckheere N, Mayes E, Shih HP, Li B, Lioubinski O, Dai X, recruitment of the transcriptional co-activator Pygopus by a Sander M. Analysis of mPygo2 mutant mice suggests a chain of adaptor proteins. Mechanisms of development requirement for mesenchymal Wnt signaling in pancreatic 122.11 (2005): 1171-1182. growth and differentiation. Developmental biology 318.2 (2008): 224-235. Talla SB, Brembeck FH. The role of Pygo2 for Wnt/β- catenin signaling activity during intestinal tumor initiation Kao KR, Popadiuk P, Thoms J, Aoki S, Anwar S, Fitzgerald and progression. Oncotarget 7.49 (2016): 80612. E, Andrews P, Voisey K, Gai L, Challa S, He Z, Gonzales- Aguirre P, Simmonds A, Popadiuk C. PYGOPUS2 Townsley FM, Thompson B, Bienz M. Pygopus residues expression in prostatic adenocarcinoma is a potential risk required for its binding to Legless are critical for transcription stratification marker for PSA progression following radical and development. Journal of Biological Chemistry 279.7 prostatectomy. Journal of clinical pathology 71.5 (2018): (2004): 5177-5183. 402-411. Wang ZX, Chen YY, Li BA, Tan GW, Liu XY, Shen SH, Zhu Kramps T, Peter O, Brunner E, Nellen D, Froesch B, HW, Wang HD. Decreased pygopus 2 expression Chatterjee S, Murone M, Züllig S, Basler K. Wnt/wingless suppresses glioblastoma U251 cell growth. Journal of signaling requires BCL9/legless-mediated recruitment of neuro-oncology 100.1 (2010): 31-41. pygopus to the nuclear β-catenin-TCF complex. Cell 109.1 Watanabe K, Fallahi M, Dai X. Chromatin effector Pygo2 (2002): 47-60. regulates mammary tumor initiation and heterogeneity in Lake BB, Kao KR. Pygopus is required for embryonic brain MMTV-Wnt1 mice. Oncogene 33.5 (2014): 632. patterning in Xenopus. Developmental biology 261.1 Zhang S, Li J, Liu P, Xu J, Zhao W, Xie C, Yin Z, Wang X. (2003): 132-148. Pygopus-2 promotes invasion and metastasis of hepatic Li B, Mackay DR, Ma J, Dai X. 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Scientific reports 6 communication and signaling (2018): 1-10. (2016): 22066. Liu Y, Dong QZ, Wang S, Fang CQ, Miao Y, Wang L, Li MZ, de la Roche M, Bienz M. Wingless-independent association Wang EH. Abnormal expression of Pygopus 2 correlates of Pygopus with dTCF target genes. Current biology 17.6 with a malignant phenotype in human lung cancer. BMC (2007): 556-561. cancer 13.1 (2013): 346. This article should be referenced as such: Lu X, Pan X, Wu CJ, et al. An in vivo screen identifies PYGO2 as a driver for metastatic prostate cancer. Cancer Esposito I., Cassaro A. PYGO2 (pygopus family PHD research (2018): canres-3564. finger 2). Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4):159-163. Miller TC, Rutherford TJ, Johnson CM, Fiedler M, Bienz M. Allosteric remodelling of the histone H3 binding pocket in the Pygo2 PHD finger triggered by its binding to the B9L/BCL9 co-factor. Journal of molecular biology 401.5 (2010): 969-984. 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Gene Section Review EEF1DP3 (Eukaryotic translation elongation factor 1 delta pseudogene 3) Luigi Cristiano Aesthetic and medical biotechnologies research unit, Prestige, Terranuova Bracciolini, Italy; [email protected]; [email protected]
Published in Atlas Database: June 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/EEF1DP3ID62732ch13q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70696/06-2019-EEF1DP3ID62732ch13q13.pdf DOI: 10.4267/2042/70696
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Location : 13q13.1 Eukaryotic translation elongation factor 1 delta DNA/RNA pseudogene 3, alias EEF1DP3, is a pseudogene. This review collects the data about its DNA/RNA and on Description the diseases where it is involved. EEF1DP3, alias eukaryotic translation elongation Keywords factor 1 delta pseudogene 3, is a pseudogene and it EEF1DP3; eukaryotic translation elongation factor 1 is located on chromosome 13 that is known to bring delta pseudogene 3; ankylosing spondylitis; cancer; some putative oncogenes involved in cancer oncogenesis including the breast cancer type 2 (BRCA2) and the retinoblastoma (RB1) genes (Dunham et al., 2004). Identity The related functional gene is the "eukaryotic translation elongation factor 1 delta" (EEF1D) that is Other names located on chromosome 8 (8q24.3). EEF1DP3-201, MGC149669, MGC149670, EEF1DP3 starts at 31,846,783 nt and ends at Putative Elongation Factor 1-Delta-Like Protein, 31,959,584 from pter. It has a length of 112,802 bp Putative EF-1-Delta-Like Pseudogene 3 Protein and the current reference sequence is NC_000013.11 HGNC (Hugo) : EEF1DP3 (Dunham et al., 2004).
Figure. 1. EEF1DP3 gene. The figure shows the locus on chromosome 13 of the EEF1DP3 gene (reworked from https://www.ncbi.nlm.nih.gov/gene; http://grch37.ensembl.org; www.genecards.org)
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4) 164 EEF1DP3 (Eukaryotic translation elongation factor 1 delta Cristiano L pseudogene 3)
It is proximal to the 'relaxin family peptide receptor protein EF1DL can be displayed or not, its presence 2' (RXFP2) gene and FRY microtubule binding should be not excluded. This protein should be 133 protein (FRY) gene. Curiously, closer to the amino acids long and should have a molecular genomic sequence of EEF1DP3 there is a promoter weight of 14,137 kDa and a theoretical pI of 5.94. element that is located at -0.1 kb. This promoter Curiously, EF1DL shows 90% of identity with an element exercises its influence also on genes closer uncharacterized protein (H2NJJ9_PONAB) of to EEF1DP3, i.e. FRY and RXFP2. similar mass and length present in Sumatran EEF1DP3 is classified as a transcribed unprocessed orangutan (Pongo pygmaeus abelii) and linked to its pseudogene. In the genomic sequence there are 4 chromosome 13. Bioinformatic analysis of the non-coding exons. comparison between EF1DL protein and eEF1D Transcription isoforms (pblast) revealed that there is an 85% of identity between EF1DL (1-90 aa) and a fragment of EEF1DP3 pseudogene is transcribed and produces a the long isoform of eEF1D (367-458 aa) and that is long non-coding RNA (lncRNA) of 575 nt (Kimura included a little portion of the second leucine-zipper et al., 2006) with a reference sequence domain of eEF1D. A similar result is obtained NR_027062.1. It is still unknown if it is subjected to between EF1DL (1-90 aa) and the short form of post-transcriptional modifications, such as 5'- eEF1D (1-92 aa) with the inclusion of a little portion capping, 3'-polyadenylation or splicing. However, of the unique leucine-zipper domain of the short other alternative transcripts are reported: EEF1DP3- form of eEF1D. 001, a processed transcript of 1309 nt, EEF1DP3- EF1DL could take a significant aspect in relation to 002, a retained intron of 3283 nt and EEF1DP3-003, cellular alterations observed in cancer that frequently a transcribed unprocessed pseudogene of 782 nt juxtapose genomic elements next to strong promotor (http://phase3browser.1000genomes.org). It seems elements to produce unusual proteins that contribute that EEF1DP3 is overexpressed in heart, in particular to its malignant behavior and its aggressiveness. In in the left ventricle (https://www.genecards.org) and fact, it is reported the involvement of EEF1DP3 in also expressed in normal trachea, liver, testis, some genomic rearrangements and although there kidney, bladder and brain (http://source- are no sufficient data yet to clarify these phenomena search.princeton.edu/). On the contrary, a low it cannot be excluded that EEF1DP3 can bring to a expression is detected in adrenal gland, colon and protein product after significative genomic pituitary gland alterations. (https://amp.pharm.mssm.edu/Harmonizome/gene/ EEF1DP3). It is known that lncRNAs, as Mutations pseudogenes as well as the others ncRNAs, may modulate the gene expression both at the Have been discovered a large number of mutations transcriptional level, interacting with the promotor and alterations in the genomic sequence for of parental gene o other genes, and post- EEF1DP3. The genomic alterations observed transcriptional level, acting as microRNA decoys include copy number variations, translocations and and so they may play key roles in cellular biological interchromosomal translocations with the formation processes (Chan and Tay, 2018; Hu et al., 2018; of novel fusion genes. However, there are no Kovalenko and Patrushev, 2018). Nowadays, is still sufficient experimental data yet to understand the unknown the exact role of EEF1DP3 in healthy repercussions on cellular behavior of these fusion tissues. genes. Protein Implicated in EEF1DP3 seems to be able to produce a lncRNA but Top note there are no proofs about the existence of a codified It is known that the aberrant expression of lncRNAs, protein. However, is reported in some databases as pseudogenes as well as the others ncRNAs, could (UniProtKB; InterPro) a protein product also for this have an important role in cancer development and pseudogene, called "putative elongation factor 1- progression (Chan and Tay, 2018; An et al., 2017). delta-like protein", alias EF1DL (accession number: EEF1DP3 was found highly expressed in some Q658K8). healthy tissue types and also in many cancer types Until recently, it was believed that pseudogenes were and this suggests that it could act as a positive not able to encode a protein, but recent regulator of gene expression, with high probability transcriptomic and proteomic analyses seem to for its parental gene EEF1D and maybe also for other demonstrate not only the presence of pseudogene- genes. In fact, it is known that the pseudogenes may derived transcripts but also of pseudogene-derived act as positive regulators or negative regulators of proteins (Chan and Tay, 2018; Kim et al., 2014; gene expression (Hu et al., 2008). However, its role Djebali et al., 2012). Although it is still unclear if the is still to be determined.
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Name 5' end 3' end Loc1 Loc2 Description Type Disease Organ Code Ref.< 5q22. 13q13. t(5;13)(q22;q13) Translocatio APC/EEF1DP3 APC EEF1DP3 (?) - - - 2 1 n EEF1DP3/BLVR 13q13. 19q13. t(13;19)(q13;q1 Translocatio Soft SAR EEF1DP3 BLVRB Sarcoma - B 1 2 3) n tissue C Alaei- EEF1DP3/CLDN1 13q13. 13q32. t(13;13)(q13;q3 Adenocarcino BRC Mahabad EEF1DP3 CLDN10 Fusion gene Breast 0 1 1 2) ma A i et al., 2016 Adenocarcino BRC Kim et Breast ma A al., 2015 Burkitt Blood BL - lymphoma Adenocarcino LUA Lung - ma D Malignant SKC Skin - melanoma M Nonneoplastic Adrenal epithelial - gland disorder/lesion Nonneoplastic epithelial Bladder - disorder/lesion Bone - - marrow EEF1DP 13q13. 13q13. Readthrough Embryoni EEF1DP3/FRY FRY Fusion gene 3 1 1 transcription c stem - ESC cells (cell line) Nonneoplastic Babicean mesenchymal Heart - u et al., disorder/lesion 2016 Nonneoplastic epithelial Skin - disorder/lesion Nonneoplastic epithelial Stomach - disorder/lesion Nonneoplastic epithelial Testis - disorder/lesion Nonneoplastic epithelial Thyroid - disorder/lesion EEF1DP3/N4BP2 13q13. 13q13. t(13;13)(q13;q1 Adenocarcino BRC EEF1DP3 N4BP2L1 Fusion gene Breast - L1 1 1 3) ma A 13q13. 13q12. t(13;13)(q13;q1 Adenocarcino BRC EEF1DP3/TEX26 EEF1DP3 TEX26 Fusion gene Breast - 1 3 2) ma A 13q13. 2q31. t(2;13)(q31;q13) Translocatio Burkitt EEF1DP3/TLK1 EEF1DP3 TLK1 Blood BL - 1 1 n lymphoma EEF1DP 13q13. 13q13. t(13;13)(q13;q1 NCL/EEF1DP3 NCL Fusion gene (?) - - - 3 1 1 3)
Table.1 EEF1DP3 rearrangements: translocations and fusion genes (reworked from https://cgap.nci.nih.gov/Chromosomes; http://atlasgeneticsoncology.org//Bands/13q13.html#REFERENCES; https://fusionhub.persistent.co.in/home.html; https://ccsm.uth.edu/FusionGDB/index.html)[(?)] unknown; [-] no reference
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EEF1DP3 (Eukaryotic translation elongation factor 1 delta Cristiano L pseudogene 3)
Research Network et al., 2013; https://amp.pharm.mssm.edu/Harmonizome/gene/E EF1DP3). Breast Cancer Some fusion genes caused by intrachromosomal translocations were reported for EEFDP3 in breast cancer (Alaei-Mahabadi et al., 2016; Babiceanu et al., 2016; Kim et al., 2015; https://fusionhub.persistent.co.in/home.html). Hybrid/Mutated gene All fusion genes reported until now between EEF1DP3 and other partner genes are due to intrachromosomal translocations except the more known fusion gene EEF1DP3/FRY that is the result of a fusion between EEF1DP3 at 5'-end and "FRY microtubule binding protein" ( FRY) gene at 3'-end Figure.2 Circos plot for fusion events involving EEF1DP3. (Kim et al., 2015) and it is due to a readthrough The picture summarizes all fusion events concerning transcription. This fusion gene was found also in EEF1DP3 and its fusion partners (from https://fusionhub.persistent.co.in/search_genewise.html). nonneoplastic epithelial disorders or in healthy tissues, so its presence in the cell seems to be not EEF1DP3/FRY read-through fusion only linked with neoplastic transformation. Its EEF1DP3/FRY is a recurrent read-through fusion biological significance needs to be clarified as well transcript that is found in some types of as its role in the cells and in cancer cells. nonneoplastic disorders and in some types of tumors Other fusion genes are reported such as such as malignant melanoma, Burkitt lymphoma, EEF1DP3/CLDN10 that is originated by fusion of lung cancer and breast cancer (Babiceanu et al., EEF1DP3 at 5'-end with "claudin 10" ( CLDN10) 2016; Kim et al., 2015; Kim et al., 2011; gene at 3'-end (Alaei-Mahabadi et al., 2016), https://fusionhub.persistent.co.in/ home.html; EEF1DP3/N4BP2L1 that is originated by fusion of https://ccsm.uth.edu/FusionGDB/ index.html). EEF1DP3 at 5'-end with "NEDD4 binding protein 2 The off-frame fusion of these two adjacent genes like 1" ( N4BP2L1) gene at 3'-end and finally brings to the formation of a novel transcript formed EEF1DP3/TEX26 that is originated by fusion of by the 1 and 2 exons of EEF1DP3 joined with the EEF1DP3 at 5'-end with "testis expressed 26" ( exons from 2 to 61 of FRY. TEX26) gene at 3'-end. The significance of these This results in an insertion of a stop codon in the genomic alterations is still poorly understood. nucleotidic sequence with an early truncation with Colorectal cancer loss-of-function of the FRY gene (Kim et al., 2015). EEF1DP3 is reported to be highly expressed in Adrenal carcinoma rectum adenocarcinoma (READ) samples (Cancer EEF1DP3 is reported to be highly expressed Genome Atlas Research Network et al., 2013; inadrenocortical carcinoma (ACC) and https://amp.pharm.mssm.edu/Harmonizome/gene/E pheochromocytoma and other paraganglioma EF1DP3). (PCPG) samples (Cancer Genome Atlas Research Gynaecological cancers Network et al., 2013; https://amp.pharm.mssm.edu/ Harmonizome/gene/EEF1DP3). EEF1DP3 is reported to be highly expressed in cervical squamous cell carcinoma and endocervical Ankylosing Spondylitis adenocarcinoma (CESC) samples and also in uterine EEF1DP3 seems to be involved in some variants carcinosarcoma (UCS) (Cancer Genome Atlas associated with ankylosing spondylitis (AS), a Research Network et al., 2013; chronic and complex autoimmune disorder. In https://amp.pharm.mssm.edu/Harmonizome/gene/E particular, it was found a loss in EEF1DP3 due to its EF1DP3). deletion and this has been associated with an Head and neck squamous cell increased risk and predisposition for AS (Shahba et al., 2018; Yim et al., 2015; Jung et al., 2014). carcinoma (HNSC) Brain and central nervous system EEF1DP3 is reported to be highly expressed in head and neck squamous cell carcinoma (HNSC) samples (CNS) cancers (Cancer Genome Atlas Research Network et al., EEF1DP3 is reported to be highly expressed in brain 2013; https://amp.pharm.mssm.edu/ lower grade glioma (LGG) (Cancer Genome Atlas Harmonizome/gene/EEF1DP3).
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Liver cancer 2013; https://amp.pharm.mssm.edu/Harmonizome/ gene/EEF1DP3). EEF1DP3 is reported to be highly expressed in liver hepatocellular carcinoma samples (LIHC) (Cancer Prostate Cancer Genome Atlas Research Network et al., 2013; Erho and colleagues found that EEF1DP3 is https://amp.pharm.mssm.edu/Harmonizome/gene/E differentially expressed between normal prostate EF1DP3). tissues and primary and metastatic prostate cancer Lung cancer samples (Erho et al., 2012) and other authors confirm this overexpression in prostate adenocarcinoma EEF1DP3 is reported to be highly expressed in lung (PRAD) (Cancer Genome Atlas Research Network adenocarcinoma (LUAD), lung squamous cell et al., 2013; carcinoma (LUSC) and mesothelioma (MESO) https://amp.pharm.mssm.edu/Harmonizome/gene/E samples (Cancer Genome Atlas Research Network et EF1DP3). al., 2013; https://amp.pharm.mssm.edu/ Harmonizome/gene/EEF1DP3). Sarcoma Lymphoma, leukaemia and other EEF1DP3 is revealed to be highly expressed in blood cancers sarcoma (SARC) samples (Cancer Genome Atlas EEF1DP3 is reported to be highly expressed in acute Research Network et al., 2013; myeloid leukemia (AML) and lymphoid neoplasm https://amp.pharm.mssm.edu/Harmonizome/gene/E diffuse large B-cell lymphoma (DLBC) (Cancer EF1DP3) and was reported the translocation Genome Atlas Research Network et al., 2013; t(13;19)(q13;q13) EEF1DP3/BLVRB https://amp.pharm.mssm.edu/Harmonizome/gene/E (https://fusionhub.persistent.co.in/home.html). EF1DP3) and are reported the fusion gene EEF1DP3 Hybrid/Mutated gene /FRY and the translocation t(2;13)(q31;q13) The t(13;19)(q13;q13) EEF1DP3/BLVRB was EEF1DP3/TLK1 in Burkitt lymphoma found in sarcoma. This rearrangement is originated (https://fusionhub.persistent.co.in/home.html). by the fusion of EEF1D gene at 5'-end with Hybrid/Mutated gene 'biliverdin reductase B' (BLVRB) gene at 3' end. The t(2;13)(q31;q13) EEF1DP3/TLK1 and There are no data about the respective chimeric EEF1DP3/FRY fusion gene were found in Burkitt transcript or protein and the role of this genomic lymphoma. The first rearrangement is originated by alteration is unknown. the fusion of EEF1D gene at 5'-end with "tousled like Urinary tract cancers kinase 1" (TLK1) gene at 3' end while the EEF1DP3/FRY fusion gene is originated by the EEF1DP3 is reported to be highly expressed in fusion of EEF1D gene at 5'-end with "FRY bladder urothelial carcinoma (BLCA) samples and microtubule binding protein" (FRY) gene at 3' end also in chromophobe renal cell carcinoma (KICH), and it is probably due to readthrough transcription. clear cell renal cell carcinoma (KIRC) and papillary In fact, EEF1D and FRY are two neighboring genes renal cell carcinoma (KIRP) (Cancer Genome Atlas on the same chromosome. There are no data about Research Network et al., 2013; the chimeric transcripts or proteins and the role of https://amp.pharm.mssm.edu/Harmonizome/gene/E these genomic alterations are still unknown. EF1DP3). Melanoma References EEF1DP3 is reported to be highly expressed in skin Alaei-Mahabadi B, Bhadury J, Karlsson JW, Nilsson JA, cutaneous melanoma (SKCM) samples (Cancer Larsson E. Global analysis of somatic structural genomic Genome Atlas Research Network et al., 2013; alterations and their impact on gene expression in diverse https://amp.pharm.mssm.edu/Harmonizome/gene/E human cancers. Proc Natl Acad Sci U S A. 2016 Nov EF1DP3). 29;113(48):13768-13773 An Y, Furber KL, Ji S. Pseudogenes regulate parental gene Neurodegenerative disorders expression via ceRNA network. J Cell Mol Med. 2017 EEF1DP3 seems to be related to various Jan;21(1):185-192 neurodegenerative disorders as synucleinopathy and Babiceanu M, Qin F, Xie Z, Jia Y, Lopez K, Janus N, Parkinson's disease (https://amp.pharm.mssm.edu/ Facemire L, Kumar S, Pang Y, Qi Y, Lazar IM, Li H. Harmonizome/gene/EEF1DP3). Recurrent chimeric fusion RNAs in non-cancer tissues and cells. Nucleic Acids Res. 2016 Apr 7;44(6):2859-72 Pancreatic cancer Cancer Genome Atlas Research Network, Weinstein JN, EEF1DP3 is reported to be highly expressed in Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, pancreatic adenocarcinoma (PAAD) samples Shmulevich I, Sander C, Stuart JM. The Cancer Genome Atlas Pan-Cancer analysis project Nat Genet 2013 (Cancer Genome Atlas Research Network et al., Oct;45(10):1113-20
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Recurrent fusion transcripts detected by E, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood whole-transcriptome sequencing of 120 primary breast MJ, Gao H, Gonzalez D, Gordon A, Gunawardena H, cancer samples Genes Chromosomes Cancer 2015 Howald C, Jha S, Johnson R, Kapranov P, King B, Nov;54(11):681-91 Kingswood C, Luo OJ, Park E, Persaud K, Preall JB, Ribeca Kim MS, Pinto SM, Getnet D, Nirujogi RS, Manda SS, P, Risk B, Robyr D, Sammeth M, Schaffer L, See LH, Chaerkady R, Madugundu AK, Kelkar DS, Isserlin R, Jain Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, S, Thomas JK, Muthusamy B, Leal-Rojas P, Kumar P, Trout D, Walters N, Wang H, Wrobel J, Yu Y, Ruan X, Sahasrabuddhe NA, Balakrishnan L, Advani J, George B, Hayashizaki Y, Harrow J, Gerstein M, Hubbard T, Reymond Renuse S, Selvan LD, Patil AH, Nanjappa V, A, Antonarakis SE, Hannon G, Giddings MC, Ruan Y, Wold Radhakrishnan A, Prasad S, Subbannayya T, Raju R, B, Carninci P, Guigó R, Gingeras TR. Landscape of Kumar M, Sreenivasamurthy SK, Marimuthu A, Sathe GJ, transcription in human cells Nature 2012 Sep Chavan S, Datta KK, Subbannayya Y, Sahu A, Yelamanchi 6;489(7414):101-8 SD, Jayaram S, Rajagopalan P, Sharma J, Murthy KR, Dunham A, Matthews LH, Burton J, Ashurst JL, Howe KL, Syed N, Goel R, Khan AA, Ahmad S, Dey G, Mudgal K, Ashcroft KJ, Beare DM, Burford DC, Hunt SE, Griffiths- Chatterjee A, Huang TC, Zhong J, Wu X, Shaw PG, Freed Jones S, Jones MC, Keenan SJ, Oliver K, Scott CE, D, Zahari MS, Mukherjee KK, Shankar S, Mahadevan A, Ainscough R, Almeida JP, Ambrose KD, Andrews DT, Lam H, Mitchell CJ, Shankar SK, Satishchandra P, Ashwell RI, Babbage AK, Bagguley CL, Bailey J, Bannerjee Schroeder JT, Sirdeshmukh R, Maitra A, Leach SD, Drake R, Barlow KF, Bates K, Beasley H, Bird CP, Bray-Allen S, CG, Halushka MK, Prasad TS, Hruban RH, Kerr CL, Bader Brown AJ, Brown JY, Burrill W, Carder C, Carter NP, GD, Iacobuzio-Donahue CA, Gowda H, Pandey A. 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Diversification of transcriptional DA, Lloyd DM, Lloyd C, Loveland JE, Lovell J, Martin S, modulation: large-scale identification and characterization Mashreghi-Mohammadi M, McLaren SJ, McMurray A, Milne of putative alternative promoters of human genes Genome S, Moore MJ, Nickerson T, Palmer SA, Pearce AV, Peck AI, Res 2006 Jan;16(1):55-65 Pelan S, Phillimore B, Porter KM, Rice CM, Searle S, Sehra HK, Shownkeen R, Skuce CD, Smith M, Steward CA, Kovalenko TF, Patrushev LI. Pseudogenes as Functionally Sycamore N, Tester J, Thomas DW, Tracey A, Tromans A, Significant Elements of the Genome Biochemistry (Mosc) Tubby B, Wall M, Wallis JM, West AP, Whitehead SL, Willey 2018 Nov;83(11):1332-1349 DL, Wilming L, Wray PW, Wright MW, Young L, Coulson A, Durbin R, Hubbard T, Sulston JE, Beck S, Bentley DR, Shahba S, Jafari Shakib R, Jamshidi A, Vojdanian M, Rogers J, Ross MT. The DNA sequence and analysis of Akhtari M, Aslani S, Poursani S, Nikokar I, Mahmoudi M. human chromosome 13 Nature 2004 Apr 1;428(6982):522- Association study of copy number variation in BMP8A gene 8 with the risk of ankylosing spondylitis in Iranian population J Cell Biochem 2018 Nov 28 Erho N, Buerki C, Triche TJ, Davicioni E, Vergara IA. Transcriptome-wide detection of differentially expressed Yim SH, Jung SH, Chung B, Chung YJ. Clinical implications coding and non-coding transcripts and their clinical of copy number variations in autoimmune disorders Korean J Intern Med 2015 May;30(3):294-304 significance in prostate cancer J Oncol 2012;2012:541353 This article should be referenced as such: Hu X, Yang L, Mo YY. Role of Pseudogenes in Tumorigenesis Cancers (Basel) 2018 Aug 1;10(8) Cristiano L. EEF1DP3 (Eukaryotic translation elongation factor 1 delta pseudogene 3). Atlas Genet Cytogenet Jung SH, Yim SH, Hu HJ, Lee KH, Lee JH, Sheen DH, Lim Oncol Haematol. 2020; 24(4):164-169. 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Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4) 169 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Leukaemia Section Short Communication
Breast implant-associated anaplastic large cell lymphoma Diego Conde Royo, Luis Miguel Juárez Salcedo, Samir Dalia Principe de Asturias University Hospital, Madrid, Spain [email protected] (DCR); Gregorio Marañón University General Hospital, Madrid, Spain [email protected] (LMJS); Oncology and Hematology, Mercy Clinic Joplin, Joplin, MO, USA [email protected] (SD). Published in Atlas Database: July 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/BreastImplantALCLID1850.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70697/07-2019-BreastImplantALCLID1850.pdf DOI: 10.4267/2042/70697 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
the histologic and immunophenotypic features, Abstract which are similar to other ALK-negative anaplastic large cell lymphomas (ALCLs). The vast majority of Review on Breast implant-associated anaplastic malignant cells are CD30 positive and ALK- large cell lymphoma with clinics and the genes negative (Quesada AE et al., 2019). Surgery involved represents the optimal approach to the disease, Keywords reaching excellent results and high rates of overall Breast implant-associated anaplastic large cell survival (OS). Chemotherapy is reserved for lymphoma; Seroma-associated anaplastic large cell systemic cases, and anthracycline-based regimens lymphoma are preferred (Clemens MW, Horwitz SM, 2017). Identity Phenotype/cell stem origin Immunophenotype is similar to the cell expression of Other names systemic ALK-negative ALCLs. Thus is Seroma-associated anaplastic large cell lymphoma characterized by a strong positivity for CD30 and negativity for ALK. Several markers like CD43, Clinics and pathology CD45, CD4, TIA-1, granzyme B and EMA are frequently expressed; whereas CD3 and CD8 Disease expression are less prevalent. Epsetin-Barr virus Breast implant-associated anaplastic large cell small-encoded RNA is constantly negative, like lymphoma (BI-ALCL) is a new provisional entity CD1a, cyclin D1 and TdT (Quesada AE et al., 2019). described in the 2017 revision of the World Health Organization Classification of Tumors of Etiology Hematopoietic and Lymphoid Tissues (Swerdlow Pathogenesis is not clearly established, however, SH et al., 2016). This disorder represents an several mechanisms have been theorized based on uncommon form of slow-growing T-cell lymphoma chronic antigenic stimulation (Laurent C et al., where breast implants play a leading role in the 2018). This pathway triggers the recruitment, lymphomagenesis. For its diagnosis a high index of expansion, and proliferation of T cells leading to suspicion is warranted. The most common clinical clonality and malignant transformation (Roden AC presentation is an effusion around the implant, and et al., 2008). Local inflammation and fibrosis caused less common as a tumor mass. (Miranda RN et al., by the silicone and its degradation products sustain 2014) Imaging studies, ultrasound specifically, will T-cell proliferation (Bizjak M et al., 2015). help the clinician diagnose this malignancy (Adrada Microbiome studies have demonstrated a playing BE, 2014). Further tests are necessary to determinate role of the gram-negative bacteria Ralostonia
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4) 170 Breast implant-associated anaplastic large cell lymphoma Conde Royo D et al.
pickettii, stimulating Th1 cells by the release of 2018). Two staging systems are routinely used. Ann cytokines (Hu H et al., 2016). BI-ALCL cells present Arbor staging system, being the patients divided in a secretory profile similar to TH1/Th17 cells and are stage I (83%), II (10%) and III (7%) at diagnosis dependent on microenvironment cytokines like IL2, (Miranda RN et al., 2014). The National IL10, and IL6 (De Leval L, 2019). The content of the Comprehensive Cancer Network (NCCN) promotes implant (saline or silicone-filled) does not imply an the second one to determinate the degree of tumor increased risk of BI-ALCL (Miranda RN et al., infiltration into the capsule, a staging system 2014). However, the different outer shell of the proposed by the MD Anderson. Based on a T stage implants (textured or smooth) will play a leading role included in the clinical Tumor Node Metastasis in the pathogenesis. Some studies found a higher (TNM) solid tumor staging system. In the latter, the prevalence of BI-ALCL among patents with textured patients are divided in IA (35.6%), IB (11.5%), IC implants compared to smooth implants or the general (13.8%), IIA (25.3%), IIB (4.6%), III (9.2%) and IV population. This difference could be explained by (0-9%) (Clemens MW et al., 2016). the finding in textured implants of inflammation Diagnosis The diagnosis of BI-ALCL needs a high with a T-cell profile more frequently than in the index of suspicion since it is a low-growth neoplasm smooth ones (Meza Britez ME et al., 2012). and its most frequent clinical presentation (effusion) Activation of JAK/STAT3 signaling pathway and could be misdiagnosed as a benign seroma. The expression of cytotoxic molecules are also involved NCCN has established diagnosis and management in the survival and proliferation of BI-ALCL cells guidelines that will help diagnosis this disease (Lechner MG et al., 2012). quicker (Clemens MW, Horwitz SM, 2017). An Epidemiology exhaustive physical examination has to be performed in case of clinical suspicion (fluid collection or Non-Hodgkin lymphomas (NHLs) involving the masses) as well as imaging studies. In peri-prosthetic breast represent between 1-2% of all NHLs, mostly fluid collection cases, the ultrasound achieves the diffuse large B-cell lymphomas (DLBCLs) and best results (sensitivity and specificity of 84% and extranodal marginal zone lymphoma of mucosa- 75% respectively), whereas magnetic resonance associated lymphoid tissue (Laurent C et al., 2018). imaging (MRI), computed tomography (CT) and On the other hand, ALCLs represent 3% of NHLs mammography are worse in terms of (Talwalkar SS et al., 2008). BI-ALCL is an sensitivity/specificity in a retrospective study. uncommon neoplasm; although in recent years an Nevertheless, in tumor masses, PET CT achieved increase in recognition of this entity has been better results than MRI, but same as ultrasound reported. In a meta-analysis, an incidence of fewer (Adrada BE, 2014). Once diagnostic of effusion or than 5 cases per 500,000 women with breast tumor mass is reached, cytological/histological implants was described (Brody GS et al., 2015). The examination is necessary. Fine needle aspiration or median age of diagnosis is 50 years (De Leval L, tissue biopsy, depending on the clinical presentation, 2019) will provide the samples for immunohistochemical Clinics and histological studies guiding to BI-ALCL diagnosis. The median time interval from implant surgery to lymphoma diagnosis is 8-9 years. Two clinical Pathology presentations are seen. The vast majority of patients The histological features of BI-ALCL cells resemble (80%) present with an effusion adjoining to the systemic ALCLs ones. They are large cells with implant without extension to the breast parenchyma anaplastic and pleomorphic morphology, also an or distance. Necrotic and liquefied lymphoma cells abundant cytoplasm is founded. The nuclei are large are identified on the effusion (Miranda RN et al., or oval, with prominent nucleoli and mitoses 2014). This malignant seroma could be associated (Miranda RN et al., 2014). Hallmarks-cells with asymmetry, pain or breast swelling. It is encountered in all forms of ALCL are also founded important to differentiate it from benign fluid on this subtype (specifically in 70% of cases). It is collections, that could appear early after the surgery defined by an eccentric horseshoe- or kidney-shaped (De Leval L, 2019). Secondly, the other 20% of nuclei (Swerdlow SH et al., 2016). patients usually present a tumor mass infiltrating breast tissue with or without effusion, recognized by Cytogenetics the patient as a continuous growth of an indurated ALK translocations or those involving DUSP22 or area (Miranda RN et al., 2014). Also, a minority of TP63 that characterize ALK positive large B-cell patients (20%) may present with lymph node lymphomas and ALK- ALCLs respectively, have not involvement, more frequent axillary in location been identified in BI-ALCLs (Oishi N et al., 2018). (Ferrufino-Schmidt MC et al., 2018). BI-ALCLs do However, other molecular genetics findings have not usually present at diagnosis time with B been reported. Based on Quesada AE et al., review, symptoms or skin lesions (Mehta-Shah N et al., monoclonal TRG and TRB rearrangements are
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carried by BI-ALCL cells (Quesada AE et al., 2019). Quesada AE, Pina-Oviedo S, Hu Q, Garcia-Gomez FJ, Jose Furthermore, activating mutations in STAT3 and Borrero J, Horna P, Thakral B, Narbaitz M, Hughes RC 3rd, Yang LJ, Fromm JR, Wu D, Zhang D, Sohani AR, Hunt J, JAK1 have also been described in neoplastic cells, as Vadlamani IU, Morgan EA, Ferry JA, Szigeti R, C Tardio J, mentioned before being involved in the Granados R, Dertinger S, Offner FA, Pircher A, Hosry J, pathogenesis. (Oishi N et al., 2018) Young KH, Miranda RN. Clinicopathologic Features and Prognostic Impact of Lymph Node Involvement in Patients Treatment With Breast Implant-associated Anaplastic Large Cell The treatment of choice depends on the extension of Lymphoma. Am J Surg Pathol. 2018 Mar;42(3):293-305 the disease. Notwithstanding, complete surgical Adrada BE, Miranda RN, Rauch GM, Arribas E, Kanagal- excision, which includes: total capsulectomy and Shamanna R, Clemens MW, Fanale M, Haideri N, Mustafa E, Larrinaga J, Reisman NR, Jaso J, You MJ, Young KH, removal of the implant and any mass with negative Medeiros LJ, Yang W. Breast implant-associated anaplastic margins; represents the optimal approach to all BI- large cell lymphoma: sensitivity, specificity, and findings of ALCL (Clemens MW, Horwitz SM, 2017). In imaging studies in 44 patients. Breast Cancer Res Treat. localized disease (Ann Arbor IE; TNM IA, IIA), the 2014 Aug;147(1):1-14 NCCN guidelines recommendation is complete Bizjak M, Selmi C, Praprotnik S, Bruck O, Perricone C, surgical excision, with no strong role of sentinel Ehrenfeld M, Shoenfeld Y. Silicone implants and lymphoma: lymph node biopsy or radical mastectomy. In The role of inflammation. J Autoimmun. 2015 Dec;65:64-73 residual localized disease or incomplete excision Brody GS, Deapen D, Taylor CR, Pinter-Brown L, House- (also including disease with chest wall invasion), Lightner SR, Andersen JS, Carlson G, Lechner MG, Epstein AL. Anaplastic large cell lymphoma occurring in women with radiation therapy (24-36 Gy) following surgery is a breast implants: analysis of 173 cases. Plast Reconstr Surg. reasonable option (Horwitz SM et al., 2018). It has 2015 Mar;135(3):695-705 been reported that 4.6% of patients may have Clemens MW, Medeiros LJ, Butler CE1, Hunt KK, et al.. incidental lymphoma in the contralateral breast, thus Complete Surgical Excision Is Essential for the surgeons may consider the removal of the Management of Patients With Breast Implant-Associated contralateral implant (Clemens MW et al., 2016). In Anaplastic Large-Cell Lymphoma J Clin Oncol. 2016 Jan systemic disease (Ann Arbor II-IV, TNM IIB-IV) 10;34(2):160-8. systemic therapy is recommended by NCCN Horwitz SM, Ansell SM, Ai WZ, Barnes J, et al.. NCCN guidelines. Despite limited data, anthracycline-based Guidelines Insights: T-Cell Lymphomas, Version 2.2018 J chemotherapy, like cyclophosphamide, doxorubicin, Natl Compr Canc Netw. 2018 Feb;16(2):123-135 vincristine, prednisone (CHOP) or with the addition Hu H, Johani K, Almatroudi A, Vickery K, et al.. Bacterial of etoposide (EPOCH), are usually administrated. Biofilm Infection Detected in Breast Implant-Associated Anaplastic Large-Cell Lymphoma Plast Reconstr Surg. The use of brentuximab vedotin (anti-CD30 2016 Jun;137(6):1659-69 antibody) has provided responses in systemic Laurent C, Haioun C, Brousset P, Gaulard P. New insights ALCLs, however further studies are needed in BI- into breast implant-associated anaplastic large cell ALCLs (Vaklavas C, Forero-Torres A, 2012). There lymphoma Curr Opin Oncol. 2018 Sep;30(5):292-300 is no standard guideline for reconstructive surgery, Lechner MG, Megiel C, Church CH, Angell TE, et al.. and both immediate and delayed reconstruction has Survival signals and targets for therapy in breast implant- been done (Mehta-Shah N et al., 2018). associated ALK--anaplastic large cell lymphoma Clin Prognosis Cancer Res. 2012 Sep 1;18(17):4549-59 Mehta-Shah N, Clemens MW, Horwitz SM. How I treat BI-ALCLs have a better prognosis than systemic breast implant-associated anaplastic large cell lymphoma ALCL. Stage I patients have a 100% 3-year OS and Blood. 2018 Nov 1;132(18):1889-1898 63% EFS (Adrada BE, 2014). A 5-year OS of 98.8% Meza Britez ME, Caballero Llano C, Chaux A. Periprosthetic has been reported in patients treated with complete breast capsules and immunophenotypes of inflammatory capsulectomy compared with those cases where it cells Eur J Plast Surg. 2012 Sep;35(9):647-651 was not performed (57.2%) (Clemens MW et al., Miranda RN, Aladily TN, Prince HM, Kanagal-Shamanna R, 2016). Lymph node involvement confers worse et al.. Breast implant-associated anaplastic large-cell prognosis since a 5-year overall survival of 75% for lymphoma: long-term follow-up of 60 patients J Clin Oncol. those with lymph node involvement has been 2014 Jan 10;32(2):114-20 described, compared to a 97.9% in those without. Oishi N, Brody GS, Ketterling RP, Viswanatha DS, et al.. Equally, tumor masses affect prognosis since poor Genetic subtyping of breast implant-associated anaplastic OS and progression free survival were found compared with patients without masses (Adrada BE, large cell lymphoma Blood. 2018 Aug 2;132(5):544-547 2014). Quesada AE, Medeiros LJ, Clemens MW, Ferrufino- Schmidt MC, et al.. Breast implant-associated anaplastic References large cell lymphoma: a review Mod Pathol. 2019 Ferrufino-Schmidt MC, Medeiros LJ, Liu H, Clemens MW, Feb;32(2):166-188 Hunt KK, Laurent C, Lofts J, Amin MB, Ming Chai S, Morine Roden AC, Macon WR, Keeney GL, Myers JL, et al.. A, Di Napoli A, Dogan A, Parkash V, Bhagat G, Tritz D, Seroma-associated primary anaplastic large-cell lymphoma
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adjacent to breast implants: an indolent T-cell Vaklavas C, Forero-Torres A.. Safety and efficacy of lymphoproliferative disorder Mod Pathol. 2008 brentuximab vedotin in patients with Hodgkin lymphoma or Apr;21(4):455-63 systemic anaplastic large cell lymphoma Ther Adv Hematol. 2012 Aug;3(4):209-25 Swerdlow SH, Campo E, Pileri SA, Harris NL, et al.. The 2016 revision of the World Health Organization de Leval L. Breast implant-associated anaplastic large cell classification of lymphoid neoplasms Blood. 2016 May lymphoma and other rare T-cell lymphomas Hematol Oncol. 19;127(20):2375-90 2019 Jun;37 Suppl 1:24-29
Talwalkar SS, Miranda RN, Valbuena JR, Routbort MJ, et This article should be referenced as such: al.. Lymphomas involving the breast: a study of 106 cases Conde Royo D, Juárez-Salcedo LM, Dalia S. Breast comparing localized and disseminated neoplasms Am J implant-associated anaplastic large cell lymphoma. Atlas Surg Pathol. 2008 Sep;32(9):1299-309 Genet Cytogenet Oncol Haematol. 2020; 24(4):170-173.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4) 173 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Leukaemia Section Short Communication Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2: Overview 2019 Sheng Xiao Brigham and Women's Hospital, Boston, MA 02215; [email protected] Published in Atlas Database: July 2019
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/PDGFRAPDGFRBFGFR1PCM1-JAK2ID1855.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70698/07-2019-PDGFRAPDGFRBFGFR1PCM1-JAK2ID1855.pdf DOI: 10.4267/2042/70698 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Disease (1) Myeloid/lymphoid neoplasms with PDGFRA Review on the group of myeloid/lymphoid rearrangement neoplasms with eosinophilia and rearrangement of (2) Myeloid/lymphoid neoplasms with PDGFRB PDGFRA, PDGFRB, or FGFR1, or with PCM1- rearrangement JAK2 defined by the WHO 2016. (3) Myeloid/lymphoid neoplasms with FGFR1 Keywords rearrangement eosinophilia; PDGFRA; PDGFRB; FGFR1, (4) Provisional entity: Myeloid/lymphoid neoplasms PCM1/JAK2 with PCM1/JAK2 Treatment Clinics and pathology This group of patients can be treated with tyrosine Disease kinase inhibitors. While patients with PDGFRA or PDGFRB rearrangement are highly sensitive to Eosinophilia is defined as a peripheral blood Imatinib, PCM1-JAK2 patients had varying 9 9 eosinophil count > 0.5x10 /L, with > 1.5x10 /L of responses to JAK2 inhibitor Ruxolitinib, which can eosinophil count sometimes referred to as induce complete remission, although the duration is hypereosinophlia. Eosinophilia is a common clinical often limited. FGFR1 inhibitors have not been very phenotype associated with various conditions successful in treating tumors with FGFR1 including allergies, infections, medications, rearrangement. PKC412 was effective in a patient autoimmune disorders and malignancies. Although with progressive myeloproliferative disorder with malignancy-related eosinophilia is rare, it is an (8;13) (Chen et al., 2004); however, subsequent important clinical sign of these tumors, which studies with the FGFR1 inhibitor ponatinib were less require early diagnosis and clinical intervention. successful. Novel FGFR1 inhibitors are currently Figure 1 summaries the initial workup of patients being tested in clinical trials for solid tumors with with eosinophilia. FGFR1 activation. Recently a new FGFR family Phenotype/cell stem origin kinase inhibitor INCB054828 induced complete WHO 2016 defines a group of myeloid/lymphoid resolution of eosinophilia as well as complete neoplasms with eosinophilia and rearrangement of hematologic, cytogenetic and molecular remission in PDGFRA, PDGFRB, or FGFR1, or with PCM1 / a patient with FGFR1 rearranged MPN (Verstovsek JAK2 as: et al., 2018).
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4) 174 Myeloid/lymphoid neoplasms with eosinophilia and Xiao S rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2: Overview 2019
Genetics or FGFR1 have been steadily accumulating and are The fusion partner genes for PDGFRA, PDGFRB, updated below in Tables.
Figure 1. Testing algorithm for possible haematological neoplasms with clonal eosinophilia. Courtesy of the British Committee for Standards in Haematology
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Myeloid/lymphoid neoplasms with eosinophilia and Xiao S rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2: Overview 2019
Detection methods Gene name Rearrangements Ref (PMID) Karyotype FISH RT-PCR NGS
BCR t(4;22)(q12;q11.2) Yes Yes Yes Yes 15034867
CDK5RAP2 ins(9;4)(q33;q12q25) Yes Yes Yes Yes 16845659
ETV6 t(4;12)(q12;p13) Yes Yes Yes Yes 17555450
FIP1L1 del(4)(q12q12) No Yes Yes Yes 12660384
FOXP1 t(3;4)(p13;q12) Yes Yes Yes Yes 26319757
KIF5B t(4;10)(q12;p11) Yes Yes Yes Yes 16498388
STRN t(2;4)(p24;q12) Yes Yes Yes Yes 17555450
TNKS2 t(4;10)(q12;q23.3) Yes Yes Yes Yes 25658984
Table 1: PDGFRA fusion partners, chromosome locations, detection methods and references
Detection methods Gene name Rearrangements Ref (PMID) Karyotype FISH RT-PCR NGS 28552906;
AGGF1 add(5) Yes Yes Yes Yes 29284681
ATF7IP t(5;12)(q33;p13) Yes Yes Yes Yes 24628626
BIN2 t(5;12)(q32;q13) Yes Yes Yes Yes 20085582
CAPRIN1 t(5;11)(q33;p13) Yes Yes Yes Yes 17296564
CCDC6 t(5;10)(q33;q21) Yes Yes Yes Yes 10910073
CCDC88C t(5;14)(q33;q32) Yes Yes Yes Yes 15496975; 24772479
CEP85L t(5;6)(q33-34;q23) Yes Yes Yes Yes 21938754
CPSF6 t(5;12)(q33;q15) Yes Yes Yes Yes 26355392
DIAPH1 t(5;5)(q31.3;q32) No Yes Yes Yes 28751768
DOCK2 del(5) No Yes Yes Yes 28552906
DTD1 t(5;20)(q33;p11) Yes Yes Yes Yes 24772479
EBF1 del(5)(q32q33) No Yes Yes Yes 23835704
ERC1 t(5;12)(q33;p13) Yes Yes Yes Yes 17690697
ETV6 t(5;12)(q33;p13) Yes Yes Yes Yes 8168137
GCC2 t(2;5)(q37;q31) Yes Yes Yes Yes 30697976
GIT2 t(5;12)(q33;q24) Yes Yes Yes Yes 17296564
GOLGA4 t(3;5)(p22;q31) Yes Yes Yes Yes 20085582
GOLGB1 t(3;5)(q13;q32) Yes Yes Yes Yes 26355392
HIP1 t(5;7)(q33;q11) No Yes Yes Yes 9616134
KANK1 t(5;9)(q32;p24) Yes Yes Yes Yes 20164854
MPRIP t(5;17)(q32;p11) Yes Yes Yes Yes 26355392
MYO18A t(5;17)(q32;q11) Yes Yes Yes Yes 28261327
NDE1 t(5;16)(q32;p13) Yes Yes Yes Yes 17301821
NIN t(5;14)(q33;q24) Yes Yes Yes Yes 15087377
NUMA1 t(5;11) (q32;q13.4) Yes Yes Yes Yes 28449810
PCM1 ins(8;5)(p23;q33q35) Yes Yes Yes Yes 29169164
PRKG2 t(4;5)(q21;q33) Yes Yes Yes Yes 18262053
RABEP1 t(5;17)(q33;p13) Yes Yes Yes Yes 11588050
SART3 t(5;12)(q32;q23) Yes Yes Yes Yes 20107158
SATB1 t(3;5)(p24;q32) Yes Yes Yes Yes 28552906
SPECC1 t(5;17)(q33;p11.2) Yes Yes Yes Yes 15087372
SPTBN1 t(2;5)(p21;q33) Yes Yes Yes Yes 18262053
TBL1XR1 (3;5)(q26;q32) Yes Yes Yes Yes 28509585
TNIP1 t(5;5)(q32;q33) No Yes Yes Yes 28408464
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Myeloid/lymphoid neoplasms with eosinophilia and Xiao S rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2: Overview 2019
TP53BP1 t(5;15)(q33;q22) Yes Yes Yes Yes 15492236
TPM3 t(1;5)(q21;q32) Yes Yes Yes Yes 16838028
TRIP11 t(5;14)(q33;q32) Yes Yes Yes Yes 9373237
TSC1 t(5;9)(q32;q34) Yes Yes Yes Yes 29384404
WDR48 t(1;3;5)(p36;p21;q33) Yes Yes Yes Yes 20085582
ZMYND8 t(5;20)(q32;q13) Yes Yes Yes Yes 28408464 Table 2: PDGFRB fusion partners, chromosome locations, detection methods and references
Detection methods Gene name Rearrangements Ref (PMID) Karyotype FISH RT-PCR NGS 11746971;
BCR t(8;22)(p11;q11) Yes Yes Yes Yes 11739186
CNTRL t(8;9)(p12;q33) Yes Yes Yes Yes 10688839
CPSF6 t(8;12)(p11;q15) Yes Yes Yes Yes 18205209
CUX1 t(7;8)(q22;p11) Yes Yes Yes Yes 21330321
FGFR1OP t(6;8)(q27;p11) Yes Yes Yes Yes 9949182 t(8;12)(p12;p11);
FGFR1OP2 Yes Yes Yes Yes 15034873 ins(12;8)(p11;p12p22)
ERVK-6 t(8;19)(p12;q13) Yes Yes Yes Yes 12393597
Table 3: FGFR1 fusion partners, chromosome locations, detection methods and references Chmielecki J, Peifer M, Viale A, Hutchinson K, Giltnane J, References Socci ND, Hollis CJ, Dean RS, Yenamandra A, Jagasia M, Kim AS, Davé UP, Thomas RK, Pao W. Systematic screen Abe A, Emi N, Tanimoto M, Terasaki H, Marunouchi T, Saito for tyrosine kinase rearrangements identifies a novel H. Fusion of the platelet-derived growth factor receptor beta C6orf204-PDGFRB fusion in a patient with recurrent T-ALL to a novel gene CEV14 in acute myelogenous leukemia and an associated myeloproliferative neoplasm Genes after clonal evolution Blood 1997 Dec 1;90(11):4271-7 Chromosomes Cancer 2012 Jan;51(1):54-65 Belloni E, Trubia M, Gasparini P, Micucci C, Tapinassi C, Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Confalonieri S, Nuciforo P, Martino B, Lo-Coco F, Pelicci Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, PG, Di Fiore PP. 8p11 myeloproliferative syndrome with a Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose M, novel t(7;8) translocation leading to fusion of the FGFR1 Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska I, and TIF1 genes Genes Chromosomes Cancer 2005 Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland DG. Mar;42(3):320-5 A tyrosine kinase created by fusion of the PDGFRA and Benden C, Goldfarb SB, Stehlik J. An aging population of FIP1L1 genes as a therapeutic target of imatinib in patients with cystic fibrosis undergoes lung transplantation: idiopathic hypereosinophilic syndrome N Engl J Med 2003 An analysis of the ISHLT Thoracic Transplant Registry J Mar 27;348(13):1201-14 Heart Lung Transplant 2019 Jul 4 Curtis CE, Grand FH, Musto P, Clark A, Murphy J, Perla G, Campregher PV, Halley NDS, Vieira GA, Fernandes JF, Minervini MM, Stewart J, Reiter A, Cross NC. Two novel Velloso EDRP, Ali S, Mughal T, Miller V, Mangueira CLP, imatinib-responsive PDGFRA fusion genes in chronic Odone V, Hamerschlak N. Identification of a novel fusion eosinophilic leukaemia Br J Haematol 2007 Jul;138(1):77- TBL1XR1-PDGFRB in a patient with acute myeloid 81 leukemia harboring the DEK-NUP214 fusion and clinical Demiroglu A, Steer EJ, Heath C, Taylor K, Bentley M, Allen response to dasatinib Leuk Lymphoma 2017 SL, Koduru P, Brody JP, Hawson G, Rodwell R, Doody ML, Dec;58(12):2969-2972 Carnicero F, Reiter A, Goldman JM, Melo JV, Cross NC. Chalmers ZR, Ali SM, Ohgami RS, Campregher PV, The t(8;22) in chronic myeloid leukemia fuses BCR to Frampton GM, Yelensky R, Elvin JA, Palma NA, Erlich R, FGFR1: transforming activity and specific inhibition of Vergilio JA, Chmielecki J, Ross JS, Stephens PJ, Hermann FGFR1 fusion proteins Blood 2001 Dec 15;98(13):3778-83 R, Miller VA, Miles CR. Comprehensive genomic profiling Erben P, Gosenca D, Müller MC, Reinhard J, Score J, Del identifies a novel TNKS2-PDGFRA fusion that defines a Valle F, Walz C, Mix J, Metzgeroth G, Ernst T, Haferlach C, myeloid neoplasm with eosinophilia that responded Cross NC, Hochhaus A, Reiter A. Screening for diverse dramatically to imatinib therapy Blood Cancer J 2015 Feb PDGFRA or PDGFRB fusion genes is facilitated by generic 6;5:e278 quantitative reverse transcriptase polymerase chain Chen J, Deangelo DJ, Kutok JL, Williams IR, Lee BH, reaction analysis Haematologica 2010 May;95(5):738-44 Wadleigh M, Duclos N, Cohen S, Adelsperger J, Okabe R, Gallagher G, Horsman DE, Tsang P, Forrest DL. Fusion of Coburn A, Galinsky I, Huntly B, Cohen PS, Meyer T, Fabbro PRKG2 and SPTBN1 to the platelet-derived growth factor D, Roesel J, Banerji L, Griffin JD, Xiao S, Fletcher JA, Stone receptor beta gene (PDGFRB) in imatinib-responsive RM, Gilliland DG. PKC412 inhibits the zinc finger 198- atypical myeloproliferative disorders Cancer Genet fibroblast growth factor receptor 1 fusion tyrosine kinase Cytogenet 2008 Feb;181(1):46-51 and is active in treatment of stem cell myeloproliferative disorder Proc Natl Acad Sci U S A 2004 Oct Gervais C, Dano L, Perrusson N, Hélias C, Jeandidier E, 5;101(40):14479-84 Galoisy AC, Ittel A, Herbrecht R, Bilger K, Mauvieux L. A
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A PDGFRB-positive acute myeloid malignancy disorders with a t(5;10)(q33;q21) Cancer Res 2000 Jul with a new t(5;12)(q33;p13 3) involving the ERC1 gene 1;60(13):3592-8 Leukemia La Starza R, Rosati R, Roti G, Gorello P, Bardi A, Crescenzi Gosenca D, Kellert B, Metzgeroth G, Haferlach C, Fabarius B, Pierini V, Calabrese O, Baens M, Folens C, Cools J, A, Schwaab J, Kneba M, Scheid C, Töpelt K, Erben P, Marynen P, Martelli MF, Mecucci C, Cuneo A. A new Haferlach T, Cross NC, Hofmann WK, Seifarth W, Reiter A. NDE1/PDGFRB fusion transcript underlying chronic Identification and functional characterization of imatinib- myelomonocytic leukaemia in Noonan Syndrome Leukemia sensitive DTD1-PDGFRB and CCDC88C-PDGFRB fusion 2007 Apr;21(4):830-3 genes in eosinophilia-associated myeloid/lymphoid neoplasms Genes Chromosomes Cancer 2014 Levine RL, Wadleigh M, Sternberg DW, Wlodarska I, May;53(5):411-21 Galinsky I, Stone RM, DeAngelo DJ, Gilliland DG, Cools J. KIAA1509 is a novel PDGFRB fusion partner in imatinib- Grand EK, Grand FH, Chase AJ, Ross FM, Corcoran MM, responsive myeloproliferative disease associated with a Oscier DG, Cross NC. Identification of a novel gene, t(5;14)(q33;q32) Leukemia 2005 Jan;19(1):27-30 FGFR1OP2, fused to FGFR1 in 8p11 myeloproliferative syndrome Genes Chromosomes Cancer 2004 Li F, Zhai YP, Tang YM, Wang LP, Wan PJ. Identification of May;40(1):78-83 a novel partner gene, TPR, fused to FGFR1 in 8p11 myeloproliferative syndrome Genes Chromosomes Cancer Grand FH, Burgstaller S, Kühr T, Baxter EJ, Webersinke G, 2012 Sep;51(9):890-7 Thaler J, Chase AJ, Cross NC. p53-Binding protein 1 is fused to the platelet-derived growth factor receptor beta in Magnusson MK, Meade KE, Brown KE, Arthur DC, Krueger a patient with a t(5;15)(q33;q22) and an imatinib-responsive LA, Barrett AJ, Dunbar CE. Rabaptin-5 is a novel fusion eosinophilic myeloproliferative disorder Cancer Res 2004 partner to platelet-derived growth factor beta receptor in Oct 15;64(20):7216-9 chronic myelomonocytic leukemia Blood 2001 Oct 15;98(8):2518-25 Guasch G, Mack GJ, Popovici C, Dastugue N, Birnbaum D, Rattner JB, Pébusque MJ. FGFR1 is fused to the Medves S, Duhoux FP, Ferrant A, Toffalini F, Ameye G, centrosome-associated protein CEP110 in the 8p12 stem Libouton JM, Poirel HA, Demoulin JB. KANK1, a candidate cell myeloproliferative disorder with t(8;9)(p12;q33) Blood tumor suppressor gene, is fused to PDGFRB in an imatinib- 2000 Mar 1;95(5):1788-96 responsive myeloid neoplasm with severe thrombocythemia Leukemia 2010 May;24(5):1052-5 Guasch G, Popovici C, Mugneret F, Chaffanet M, Pontarotti P, Birnbaum D, Pébusque MJ. Endogenous retroviral Morerio C, Acquila M, Rosanda C, Rapella A, Dufour C, sequence is fused to FGFR1 kinase in the 8p12 stem-cell Locatelli F, Maserati E, Pasquali F, Panarello C. HCMOGT- myeloproliferative disorder with t(8;19)(p12;q13 3) Blood 1 is a novel fusion partner to PDGFRB in juvenile myelomonocytic leukemia with t(5;17)(q33;p11 2) Cancer Heilmann AM, Schrock AB, He J, Nahas M, Curran K, Res Shukla N, Cramer S, Draper L, Verma A, Erlich R, Ross J, Stephens P, Miller VA, Ali SM, Verglio JA, Tallman MS, Nakamura Y, Ito Y, Wakimoto N, Kakegawa E, Uchida Y, Mughal TI. Novel PDGFRB fusions in childhood B- and T- Bessho M. A novel fusion of SQSTM1 and FGFR1 in a acute lymphoblastic leukemia Leukemia 2017 patient with acute myelomonocytic leukemia with Sep;31(9):1989-1992 t(5;8)(q35;p11) translocation Blood Cancer J 2014 Dec 12;4:e265 Hidalgo-Curtis C, Chase A, Drachenberg M, Roberts MW, Finkelstein JZ, Mould S, Oscier D, Cross NC, Grand FH. Naumann N, Schwaab J, Metzgeroth G, Jawhar M, The t(1;9)(p34;q34) and t(8;12)(p11;q15) fuse pre-mRNA Haferlach C, Göhring G, Schlegelberger B, Dietz CT, processing proteins SFPQ (PSF) and CPSF6 to ABL and Schnittger S, Lotfi S, Gärtner M, Dang TA, Hofmann WK, FGFR1 Genes Chromosomes Cancer 2008 Cross NC, Reiter A, Fabarius A. Fusion of PDGFRB to May;47(5):379-85 MPRIP, CPSF6, and GOLGB1 in three patients with eosinophilia-associated myeloproliferative neoplasms Iriyama N, Takahashi H, Naruse H, Miura K, Uchino Y, Genes Chromosomes Cancer 2015 Dec;54(12):762-70 Nakagawa M, Iizuka K, Hamada T, Hatta Y, Nakayama T, Takei M. A novel fusion gene involving PDGFRB and GCC2 Popovici C, Zhang B, Grégoire MJ, Jonveaux P, Lafage- in a chronic eosinophilic leukemia patient harboring Pochitaloff M, Birnbaum D, Pébusque MJ. The t(2;5)(q37;q31) Mol Genet Genomic Med 2019 t(6;8)(q27;p11) translocation in a stem cell Apr;7(4):e00591 myeloproliferative disorder fuses a novel gene, FOP, to
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Myeloid/lymphoid neoplasms with eosinophilia and Xiao S rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2: Overview 2019
fibroblast growth factor receptor 1 Blood 1999 Feb 15;64(8):2673-6 15;93(4):1381-9 Walz C, Chase A, Schoch C, Weisser A, Schlegel F, Reshmi SC, Harvey RC, Roberts KG, Stonerock E, Smith Hochhaus A, Fuchs R, Schmitt-Gräff A, Hehlmann R, Cross A, Jenkins H, Chen IM, Valentine M, Liu Y, Li Y, Shao Y, NC, Reiter A. The t(8;17)(p11;q23) in the 8p11 Easton J, Payne-Turner D, Gu Z, Tran TH, Nguyen JV, myeloproliferative syndrome fuses MYO18A to FGFR1 Devidas M, Dai Y, Heerema NA, Carroll AJ 3rd, Raetz EA, Leukemia 2005 Jun;19(6):1005-9 Borowitz MJ, Wood BL, Angiolillo AL, Burke MJ, Salzer WL, Zweidler-McKay PA, Rabin KR, Carroll WL, Zhang J, Loh Walz C, Curtis C, Schnittger S, Schultheis B, Metzgeroth G, ML, Mullighan CG, Willman CL, Gastier-Foster JM, Hunger Schoch C, Lengfelder E, Erben P, Müller MC, Haferlach T, SP. Targetable kinase gene fusions in high-risk B-ALL: a Hochhaus A, Hehlmann R, Cross NC, Reiter A. Transient study from the Children's Oncology Group Blood 2017 Jun response to imatinib in a chronic eosinophilic leukemia 22;129(25):3352-3361 associated with ins(9;4)(q33;q12q25) and a CDK5RAP2- PDGFRA fusion gene Genes Chromosomes Cancer 2006 Rosati R, La Starza R, Luciano L, Gorello P, Matteucci C, Oct;45(10):950-6 Pierini V, Romoli S, Crescenzi B, Rotoli B, Martelli MF, Pane F, Mecucci C. TPM3/PDGFRB fusion transcript and its Walz C, Metzgeroth G, Haferlach C, Schmitt-Graeff A, reciprocal in chronic eosinophilic leukemia Leukemia 2006 Fabarius A, Hagen V, Prümmer O, Rauh S, Hehlmann R, Sep;20(9):1623-4 Hochhaus A, Cross NC, Reiter A. Characterization of three new imatinib-responsive fusion genes in chronic Ross TS, Bernard OA, Berger R, Gilliland DG. Fusion of myeloproliferative disorders generated by disruption of the Huntingtin interacting protein 1 to platelet-derived growth platelet-derived growth factor receptor beta gene factor beta receptor (PDGFbetaR) in chronic Haematologica 2007 Feb;92(2):163-9 myelomonocytic leukemia with t(5;7)(q33;q11 2) Blood Wasag B, Lierman E, Meeus P, Cools J, Vandenberghe P. Safley AM, Sebastian S, Collins TS, Tirado CA, Stenzel TT, The kinase inhibitor TKI258 is active against the novel Gong JZ, Goodman BK. Molecular and cytogenetic CUX1-FGFR1 fusion detected in a patient with T- characterization of a novel translocation t(4;22) involving lymphoblastic leukemia/lymphoma and t(7;8)(q22;p11) the breakpoint cluster region and platelet-derived growth Haematologica 2011 Jun;96(6):922-6 factor receptor-alpha genes in a patient with atypical chronic myeloid leukemia Genes Chromosomes Cancer 2004 Weston BW, Hayden MA, Roberts KG, Bowyer S, Hsu J, May;40(1):44-50 Fedoriw G, Rao KW, Mullighan CG. Tyrosine kinase inhibitor therapy induces remission in a patient with Score J, Curtis C, Waghorn K, Stalder M, Jotterand M, refractory EBF1-PDGFRB-positive acute lymphoblastic Grand FH, Cross NC. Identification of a novel imatinib leukemia J Clin Oncol 2013 Sep 1;31(25):e413-6 responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with Xiao S, Nalabolu SR, Aster JC, Ma J, Abruzzo L, Jaffe ES, hypereosinophilia Leukemia 2006 May;20(5):827-32 Stone R, Weissman SM, Hudson TJ, Fletcher JA. FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) Sheng G, Zeng Z, Pan J, Kou L, Wang Q, Yao H, Wen L, leukaemia/lymphoma syndrome Nat Genet 1998 Ma L, Wu D, Qiu H, Chen S. Multiple MYO18A-PDGFRB Jan;18(1):84-7 fusion transcripts in a myeloproliferative neoplasm patient with t(5;17)(q32;q11) Mol Cytogenet 2017 Feb 27;10:4 Zabriskie MS, Antelope O, Verma AR, Draper LR, Eide CA, Pomicter AD, Tran TH, Druker BJ, Tyner JW, Miles RR, Soler G, Nusbaum S, Varet B, Macintyre EA, Vekemans M, Graham JM, Hwang JY, Varley KE, Toydemir RM, Romana SP, Radford-Weiss I. LRRFIP1, a new FGFR1 Deininger MW, Raetz EA, O'Hare T. A novel AGGF1- partner gene associated with 8p11 myeloproliferative PDGFRb fusion in pediatric T-cell acute lymphoblastic syndrome Leukemia 2009 Jul;23(7):1359-61 leukemia Haematologica 2018 Feb;103(2):e87-e91 Sugimoto Y, Sada A, Shimokariya Y, Monma F, Ohishi K, Zhang Y, Qu S, Wang Q, Li J, Xu Z, Qin T, Huang G, Xiao Masuya M, Nobori T, Matsui T, Katayama N. A novel Z. A novel fusion of PDGFRB to TSC1, an intrinsic FOXP1-PDGFRA fusion gene in myeloproliferative suppressor of mTOR-signaling pathway, in a chronic neoplasm with eosinophilia Cancer Genet 2015 eosinophilic leukemia patient with t(5;9)(q32;q34) Leuk Oct;208(10):508-12 Lymphoma 2018 Oct;59(10):2506-2508 Verstovsek S, Subbiah V, Masarova L, Yin CC, Tang G, Zou YS, Hoppman NL, Singh ZN, Sawhney S, Kotiah SD, Manshouri T, Asatiani E, Daver NG. Treatment of the Baer MR. Novel t(5;11)(q32;q13 4) with NUMA1-PDGFRB myeloid/lymphoid neoplasm with FGFR1 rearrangement fusion in a myeloid neoplasm with eosinophilia with with FGFR1 inhibitor Ann Oncol 2018 Aug 1;29(8):1880- response to imatinib mesylate Cancer Genet 1882 This article should be referenced as such: Vizmanos JL, Novo FJ, Román JP, Baxter EJ, Lahortiga I, Larráyoz MJ, Odero MD, Giraldo P, Calasanz MJ, Cross Xiao S. Myeloid/lymphoid neoplasms with eosinophilia NC. NIN, a gene encoding a CEP110-like centrosomal and rearrangement of PDGFRA, PDGFRB, or FGFR1, protein, is fused to PDGFRB in a patient with a or with PCM1-JAK2: Overview 2019. Atlas Genet t(5;14)(q33;q24) and an imatinib-responsive Cytogenet Oncol Haematol. 2020; 24(4):174-179. myeloproliferative disorder Cancer Res 2004 Apr
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Juvenile myelomonocytic leukemia (JMML) Karen M. Chisholm Department of Laboratories, Seattle Children's Hospital, Seattle, WA, USA; [email protected] Published in Atlas Database: August 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/JCMLID1099.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70699/08-2019-JCMLID1099.pdf DOI: 10.4267/2042/70699 This article is an update of : Hess JL. Juvenile Chronic Myelogenous Leukemia (JCML). Atlas Genet Cytogenet Oncol Haematol 2001;5(1)
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
leukoproliferative disorder (RALD), which is a Abstract nonmalignant disorder with myelomonocytic hyperplasia and somatic mutations in KRAS or Review on juvenile myelomonocytic leukemia, with NRAS, often showing clinical overlap with JMML data on clinics, pathology, and involved genes. (Calvo et al., 2015) Keywords Juvenile myelomonocytic Leukemia, Clinics and pathology Myelodysplastic syndrome, Myeloproliferative disorder, Pediatric Disease JMML is a chronic myeloproliferative disorder that Identity typically affects young children: more than 95% of cases are diagnosed before age 4 Other names Juvenile chronic myelogenous leukemia (JCML); Phenotype/cell stem origin Juvenile chronic myelomonocytic leukemia JMML arises from pluripotent hematopoietic stem Note cells (Cooper et al., 2000). Clonal proliferations of This current topic of JMML does not include myeloid, monocyte-macrophages, erythroid, and discussion on Ras-associated autoimmune sometimes lymphoid progenitor cells are seen.
Figure 1. A 21 month old boy presented with peripheral monocytosis, increased fetal hemoglobin. His bone marrow aspirate showed <20% blasts. Cytogenetics identified monosomy 7, and genetic testing identified a PTPN11 mutation. This bone marrow core biopsy demonstrates a hypercellular marrow with decreased megakaryocytes.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4) 180 Juvenile myelomonocytic leukemia (JMML) Chisholm KM
Epidemiology increased risk of JMML (Stiller et al., 1994) The annual incidence of JMML is estimated to be Clinics roughly 0.67/million (Passmore et al, 2003). The Children with JMML commonly have median age is 1.1-1.8 years with a male to female splenomegaly, lymphadenopathy, and skin rashes ratio of 2-3:1. (Hasle et al., 1999; Niemeyer et al., (Hess et al., 1996). Involvement of the liver, lung, 1997; Passmore et al., 2003). Those with and GI tract can also occur. neurofibromatosis type 1 (NF-1) have a 200-fold The diagnostic criteria for JMML are:
Clinical and hematologic
features (all 4 required) Peripheral blood monocyte count ≥1 x
109/L Peripheral blood and bone marrow blast
percentages <20%
No Philadelphia (Ph) chromosome or
BCR-ABL1 fusion Genetic criteria (1 finding is
sufficient) Somatic mutation in PTPN11 , KRAS, or
NRAS Clinical diagnosis of neurofibromastosis
type 1 or NF1 mutation Germline CBL mutation and loss of
heterozygosity of CBL Other criteria* Monosomy 7 or any other chromosomal
abnormality or ≥ 2 of the following: Increased hemoglobin F (HbF) for age Myeloid or erythroid precursors on peripheral blood
smear Granulocyte-macrophages colony-stimulating factor
(GM-CSF) hypersensitivity in colony assay
* (those not meeting genetic criteria but having clinical and hematologic criteria must also have). (Locatelli and Neimeyer, 2015; Baumann, et al., 2017)
Cytology blood, and are usually enumerated at 5-10% (Hess et Typical peripheral blood findings include al., 1996; Niemeyer et al., 1997). leukocytosis (usually less than 100 x 109/L) with Treatment variable degree of left shift, monocytosis, and thrombocytopenia. Nucleated red blood cells are Curative therapy involves an allogeneic often identified in the peripheral blood. Myeloblasts hematopoietic stem cell transplant (HSCT). average about 1-5% of total nucleated cells, and by Locatelli and Neimeyer (2015) recommend swift definition, blasts account for <20% of cells. (Hess et HSCT for those with germline NF1 mutations, al., 1996; Niemeyer et al., 1997) somatic PTPN11 mutations, somatic KRAS mutations, and most children with somatic NRAS Pathology mutations. Most children with germline CBL Bone marrow findings are not specific. The marrow mutations demonstrate spontaneous regression, is usually hypercellular with a mildly increased M:E though if there is disease progression, a HSCT ratio (typically 3-5:1), dispersed erythroid elements, should be considered. In children with Noonan and decreased numbers of megakaryocytes. syndrome (germline mutations of PTPN11, KRAS, Dysplasia is usually not prominent. Blasts are and/or NRAS), the disease may be transient, and required to be less than 20%; monocytes are less hence one can consider a 'watch and wait' scenario, prominent in the marrow than in the peripheral with mild cytoreductive therapy for symptoms, usually 6-mercaptopruine.
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In the rare patients with tyrosine kinase fusions, A recent study reported receptor tyrosine kinase ALK/ROS1 inhibitors, such as crizotinib, may be fusions (DCTN1 /ALK, RANBP2 /ALK, and beneficial (Murakami et al., 2018). TBL1XR1 / ROS1) in patients without identified Evolution RAS pathway mutations (Murakami et al., 2018). As stated above, those with Noonan syndrome with Cytogenetics germline mutations in PTPN11, KRAS, and/or NRAS as well as those with germline CBL mutations Normal karyotypes are present in most cases of have disease that may spontaneously regress without JMML (~68%). Another 16-25% of cases have therapy (Locatelli and Neimeyer, 2015). However, monosomy 7 or deletion 7q (Aricò et al, 1997; in other cases, in those who did not receive an Niemeyer et al., 1997). allogeneic hematopoietic stem cell transplant (HSCT), the median survival after diagnosis is <12 Genes involved and months (Niemeyer et al., 1997). In those who proteins receive HSCT, the 5-year overall survival rate is 64%, with an event free survival of 52% (Locatelli CBL et a., 2005). The 5-year cumulative incidence of Location 11q23.3 relapse is 35%, while the 5-year cumulative incidence of transplantation-related mortality is 13% Note (Locatelli et al., 2005) There is a high rate of spontaneous resolution of disease without stem cell transplant in those with Prognosis homozygous mutations including a germline High risk features include older age (>1.4-4 years), mutation (Chang et al., 2014). PTPN11 mutation, monosomy 7, HbF >40%, low DNA/RNA 16 exons. platelets (20% bone marrow blasts (Dvorak and Loh, 2014; Locatelli et al., 2005; Niemeyer et al., 1997; Protein Novitzky et al., 2000; Passmore et al., 2003). In This oncogene encodes a RING finger E3 ubiquitin genetic studies, patients with <2 somatic alterations ligase which marks activated receptor and have improved outcomes compared to those with ≥2 nonreceptor tyrosine kinases and other proteins for alterations (Stiegliz et al., 2015). DNA methylation degradation by ubiquitination. studies have also been done, showing three clusters Homozygous mutations lead to continuous of methylation in JMML; those with the highest activation of RAS. (Chang et al., 2014). levels of methylation have been found to have poorer Germinal mutations clinical outcomes (Lipka et al., 2017; Stieglitz et al., Germline heterozygous mutations (autosomal 2017). dominant) lead to a Noonan syndrome-like disorder. The most common mutation is c.1111T>C (Y371H); Genetics other common mutations are missense mutations in exons 8 and 9 or in introns 7 or 8 (Loh et al., 2009). Note Approximately 85-90% of children with JMML have Somatic mutations identified mutations, either germline and/or somatic. Loss of wild-type allele with duplication of mutant Somatic, gain-of-function mutations occur in allele. PTPN11, KRAS, and NRAS, in 35-38%, 18%, and KRAS 14% of cases respectively. NF1 germline mutations Location 12p12.1 with acquired loss of the normal allele are seen in 5- 15% of patients, and CBL germline mutations with Note acquired loss of the normal allele and duplication of Somatic mutations also occur in RALD (Ras- the mutant allele (acquired uniparental disomy) are associated lymphoproliferative disease). seen in 9-18% of patients. (Chan et al., 2009; DNA/RNA 6 exons. Niemeyer and Flotho, 2019). Rare cases without any Protein of the above mutations have been found to harbor A Ras oncogene which encodes a member of the RRAS or RRAS2 somatic mutations (Stieglitz et al., small GTPase superfamily. Mutations lead to 2015). activation. Secondary mutations in SETBP1, JAK3, ASXL1, and SH2B3 are also identified and are often Germinal mutations subclonal. Additional mutations in the RAS Germline heterozygous mutations (autosomal pathway genes are also sometimes detected, coined dominant) lead to Noonan syndrome. 'Ras double mutants' (Caye et al., 2015; Stieglitz et Somatic mutations al., 2015).
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Somatic mutations are usually point mutations at (E76K), c.214G>A, c.227A>G, c.1508G>C. (Chan codons G12, G13, and Q61 (exons 2 and 3) leading et al., 2009; Chang et al., 2014). to amino acid substitutions (Chan et al., 2009; Chang et al., 2014). References NF1 (neurofibromin 1) Aricò M, Biondi A, Pui CH. Juvenile myelomonocytic Location 17q11.2 leukemia. Blood. 1997 Jul 15;90(2):479-88 DNA/RNA 57-58 exons (depending on transcript Baumann I, Bennett JM, Neimeyer CM, Thiele J.. Juvenile myelomonocytic leukaemia WHO Classification of Tumours variant). of Haematopoietic and Lymphoid tissues. Editors: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. International Agency for Research on Protein Cancer, Lyon, 2017. Pgs 89-92 GTPase activating protein for Ras. Normally acts as Brotherton J. Biological assay of fungicides against yeasts tumor suppressor by inhibiting Ras signaling in vitro using a coulter counter Mykosen 1976 Germinal mutations Oct;19(10):361-72 Germline mutations cause neurofibromatosis type 1 Calvo KR, Price S, Braylan RC, Oliveira JB, Lenardo M, (NF1) characterized by café-au-lait spots, Lisch Fleisher TA, Rao VK. JMML and RALD (Ras-associated nodules, neurofibromas, optic pathway gliomas. autoimmune leukoproliferative disorder): common genetic etiology yet clinically distinct entities Blood 2015 Apr Somatic mutations 30;125(18):2753-8 Somatic mutations are usually deletions leading to Caye A, Strullu M, Guidez F, Cassinat B, Gazal S, loss of heterozygosity with duplication of the Fenneteau O, Lainey E, Nouri K, Nakhaei-Rad S, Dvorsky mutated germline allele. R, Lachenaud J, Pereira S, Vivent J, Verger E, Vidaud D, Galambrun C, Picard C, Petit A, Contet A, Poirée M, Sirvent NRAS N, Méchinaud F, Adjaoud D, Paillard C, Nelken B, Reguerre Y, Bertrand Y, Häussinger D, Dalle JH, Ahmadian MR, Location 1p13.2 Baruchel A, Chomienne C, Cavé H. Juvenile myelomonocytic leukemia displays mutations in Note components of the RAS pathway and the PRC2 network Nat Somatic mutations also occur in RALD (Ras- Genet 2015 Nov;47(11):1334-40 associated lymphoproliferative disease). Chan RJ, Cooper T, Kratz CP, Weiss B, Loh ML. Juvenile DNA/RNA 7 exons. myelomonocytic leukemia: a report from the 2nd International JMML Symposium Leuk Res 2009 Protein Mar;33(3):355-62 A Ras oncogene which encodes a membrane protein Chang TY, Dvorak CC, Loh ML. Bedside to bench in with intrinsic GTPase activity that shuttles between juvenile myelomonocytic leukemia: insights into the Golgi apparatus and the plasma membrane. leukemogenesis from a rare pediatric leukemia Blood 2014 Germinal mutations Oct 16;124(16):2487-97 Germline heterozygous mutations (autosomal Cooper LJ, Shannon KM, Loken MR, Weaver M, Stephens dominant) lead to Noonan syndrome. K, Sievers EL. Evidence that juvenile myelomonocytic leukemia can arise from a pluripotential stem cell Blood Somatic mutations 2000 Sep 15;96(6):2310-3 Somatic mutations are usually point mutations at Dvorak CC, Loh ML. Juvenile myelomonocytic leukemia: codons G12, G13, and Q61 (exons 2 and 3) leading molecular pathogenesis informs current approaches to to amino acid substitutions (Chan et al., 2009; Chang therapy and hematopoietic cell transplantation Front Pediatr et al., 2014). 2014 Mar 28;2:25 Hanke J, Indulski JA. [Immunotoxicology] Med Pr PTPN11 1988;39(3):186-92 Location 12q24.13 Hasle H, Aricò M, Basso G, Biondi A, Cant Rajnoldi A, DNA/RNA 16 exons Creutzig U, Fenu S, Fonatsch C, Haas OA, Harbott J, Kardos G, Kerndrup G, Mann G, Niemeyer CM, Ptoszkova Protein H, Ritter J, Slater R, Starý J, Stollmann-Gibbels B, Testi AM, A member of the protein tyrosine phosphatase van Wering ER, Zimmermann M. Myelodysplastic family which relays signals from activated GM-CSF syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial receptor complexes, regulating proliferation, monosomy 7 European Working Group on MDS in differentiation, and migration. Childhood (EWOG-MDS) Leukemia Germinal mutations Hess JL, Zutter MM, Castleberry RP, Emanuel PD. Juvenile Germline mutations (autosomal dominant) lead to chronic myelogenous leukemia Am J Clin Pathol 1996 Noonan syndrome, usually within exons 3, 4, and 13. Feb;105(2):238-48 Somatic mutations Lipka DB, Witte T, Toth R, Yang J, Wiesenfarth M, Nöllke P, Fischer A, Brocks D, Gu Z, Park J, Strahm B, Wlodarski M, Somatic mutations usually involve exons 3, 4, and Yoshimi A, Claus R, Lübbert M, Busch H, Boerries M, 13, with most common mutations being: c.226G>A Hartmann M, Schönung M, Kilik U, Langstein J,
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Wierzbinska JA, Pabst C, Garg S, Catalá A, De Moerloose Niemeyer CM, Arico M, Basso G, Biondi A, Cantu Rajnoldi B, Dworzak M, Hasle H, Locatelli F, Masetti R, Schmugge A, Creutzig U, Haas O, Harbott J, Hasle H, Kerndrup G, M, Smith O, Stary J, Ussowicz M, van den Heuvel-Eibrink Locatelli F, Mann G, Stollmann-Gibbels B, van't Veer- MM, Assenov Y, Schlesner M, Niemeyer C, Flotho C, Plass Korthof ET, van Wering E, Zimmermann M. Chronic C. RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia Nat myelomonocytic leukemia in childhood: a retrospective Commun 2017 Dec 19;8(1):2126 analysis of 110 cases European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS) Locatelli F, Niemeyer CM. How I treat juvenile Blood myelomonocytic leukemia Blood 2015 Feb 12;125(7):1083- 90 Novitzky N. Myelodysplastic syndromes in children A critical review of the clinical manifestations and management Am Loh ML, Sakai DS, Flotho C, Kang M, Fliegauf M, J Hematol Archambeault S, Mullighan CG, Chen L, Bergstraesser E, Bueso-Ramos CE, Emanuel PD, Hasle H, Issa JP, van den Passmore SJ, Chessells JM, Kempski H, Hann IM, Heuvel-Eibrink MM, Locatelli F, Stary J, Trebo M, Wlodarski Brownbill PA, Stiller CA. Paediatric myelodysplastic M, Zecca M, Shannon KM, Niemeyer CM. Mutations in CBL syndromes and juvenile myelomonocytic leukaemia in the occur frequently in juvenile myelomonocytic leukemia Blood UK: a population-based study of incidence and survival Br J 2009 Aug 27;114(9):1859-63 Haematol 2003 Jun;121(5):758-67 Maioli MC, Fernandez Tde S, Campos MM, Diamond HR, Stieglitz E, Mazor T, Olshen AB, Geng H, Gelston LC, Veranio-Silva GA, de Souza AM, da Costa ES, Ornellas Akutagawa J, Lipka DB, Plass C, Flotho C, Chehab FF, MH, Thiago LS. Flow cytometry as a diagnostic support tool Braun BS, Costello JF, Loh ML. Genome-wide DNA in juvenile myelomonocytic leukemia Leuk Lymphoma methylation is predictive of outcome in juvenile 2016;57(1):233-6 myelomonocytic leukemia Nat Commun 2017 Dec 19;8(1):2127 Murakami N, Okuno Y, Yoshida K, Shiraishi Y, Nagae G, Suzuki K, Narita A, Sakaguchi H, Kawashima N, Wang X, This article should be referenced as such: Xu Y, Chiba K, Tanaka H, Hama A, Sanada M, Ito M, Hirayama M, Watanabe A, Ueno T, Kojima S, Aburatani H, Chisholm KM. Juvenile myelomonocytic leukemia Mano H, Miyano S, Ogawa S, Takahashi Y, Muramatsu H. (JMML). Atlas Genet Cytogenet Oncol Haematol. 2020; Integrated molecular profiling of juvenile myelomonocytic 24(4):180-184. leukemia Blood 2018 Apr 5;131(14):1576-1586
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Solid Tumour Section Short Communication
EEF1G/PPP6R3 (11q12-13) Luigi Cristiano Aesthetic and medical biotechnologies research unit, Prestige, Terranuova Bracciolini, Italy. [email protected] - [email protected]
Published in Atlas Database: May 2019 Online updated version : http://AtlasGeneticsOncology.org/Tumors/EEF1G_PPP6R3ID6948.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70700/05-2019-EEF1G_PPP6R3ID6948.pdf DOI: 10.4267/2042/70700 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
this cancer type are t(7;11)(q21;q13) Abstract CCDC132/PPP6R3, t(7;11)(q34;q13) Analysis of the EEF1G/PPP6R3 fusion involving PPP6R3/MGAM, t(7;11)(q34;q13)SSBP1/PPP6R3, EEF1G (alias, eukaryotic translation elongation and fusion genes PPP6R3/ARHGAP1, factor 1 gamma) gene and PPP6R3 (alias, protein PPP6R3/CNTN5, and PPP6R3/LRP5 (Yoshihara et phosphatase 6 regulatory subunit 3) gene. It was al., 2015; Hammerman et al., 2012; detected in lung squamous cell carcinoma. http://www.tumorfusions.org) Keywords Prognosis Chromosome 11; EEF1G; eukaryotic translation There is no evidence of the impact of the elongation factor 1 gamma; EF1G, GIG35, EEF1G/PPP6R3 fusion gene on the tumour PRO1608, EEF1 gamma, EEF-1B gamma, EF-1- behaviour and so its contribution in the prognosis of gamma, elongation factor 1-gamma, translation lung squamous cell carcinoma is still unknown. elongation factor EEF-1 gamma chain, pancreatic tumor-related protein; PPP6R3, protein phosphatase Genes involved and 6 regulatory subunit 3, PP6R3, chromosome 11 open reading frame 23, C11orf23, SAPS domain family proteins member 3, SAPS3, EEF1G/PPP6R3, lung squamous cell carcinoma EEF1G Location 11q12.3 Clinics and pathology Note Disease Eukaryotic translation elongation factor 1 gamma, alias eEF1G, is a protein that play a main function in Lung squamous cell carcinoma the elongation step of translation process but also Note cover numerous moonlighting roles. Lung squamous cell carcinoma (lung SqCC) shows It is expressed ubiquitously in human tissues and very complex genomic alterations with abundant often it is found over-expressed in human cancer exonic mutations, genomic rearrangements and gene samples and cancer cell lines. copy number alterations. DNA / RNA Some authors detected the presence of the EEF1G (Eukaryotic Translation Elongation Factor 1 EEF1G/PPP6R3 fusion deriving by the genomic Gamma) is a protein coding gene with 10 exons and translocation of a part of EEF1G gene with a portion a length of 14388 bp (RefSeq NC_000011.10). Its of PPP6R3 gene, both located on chromosome 11 transcript is 1446 bp long (RefSeq NM_001404.5) (Hammerman et al., 2012). Other fusion genes or but was observed five splice variants and nine abnormal chromosomal translocations detected for pseudogenes probably originated by PPP6R3 in retrotransposition.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4) 185 EEF1G/PPP6R3 (11q12-13) Christiano L
Protein (RefSeq NC_000011.10) and with an abundant eEF1G is formed by 437 amino acids (RefSeq number of alternative splicing variants, i.e. 38 NP_001395.1), it has a molecular weight of 50.12 coding mRNA and 24 non-coding mRNA. kDa and it is a multi-domain protein which consist Protein of three main domains: from the amino to carboxyl PPP6R3 counts 24 protein isoforms and is one of the half terminal there are a glutathione S-transferase three regulatory subunits of protein phosphatase 6 (GST)-like N-terminus domain (NT-eEF1G), a (PP6) complex (York et al., 2014; Guergnon et al., glutathione S-transferase (GST)-like C-terminus 2009) and has a sit4-associated protein domain, alias domain (CT-eEF1G) and a conserved C-terminal SAPS domain (Stefansson and Brautigan, 2006). It domain (CD-eEF1G)(Achilonu et al.,2014). plays a role, as member of PP6 holoenzyme, in the eEF1G is a subunit of the eukaryotic elongation turnover of serine and threonine phosphorylation factor-1 complex named eEF1H that result by the events during mitosis acting as a regulatory element aggregation of different proteins that play a central of the complex. role in peptide elongation during eukaryotic protein biosynthesis. The physiological role of eEF1G is still Result of the chromosomal not well defined, however eEF1G seems to be necessary for guarantee the stability to entire eEF1H anomaly complex and to stimulate the activity of the eEF1B2 subunit during the elongation step of translation Hybrid Gene (Mansilla et al., 2002). However, are known that it The result of chromosomal anomaly is the has multiple non-canonical roles (moonlighting EEF1G/PPP6R3 fusion with the formation of a novel roles) inside the cell such as the interaction with but not still characterized fusion gene 5' EEF1G - 3' cytoskeleton and binding with various mRNA and PPP6R3. Hammerman and colleagues several proteins, comprise membrane-bound (Hammerman et al., 2012) found it in patients with receptors (Coumans et al., 2014; Corbi et al., 2010; lung squamous cell carcinoma (lung SqCC), but Cho et al., 2003). there are no data or evidence about its mRNA and/or PPP6R3 its protein. So, in this review, with the use of Ensembl (http://www.ensembl.org), will be Location 11q13.2 predicted the result of this rearrangement. However, DNA / RNA the data collected and showed are hypothesis and PPP6R3 is a protein coding gene of 154617 nt long have to be experimentally verified.
Figure 1. Schematic representation of the EEF1G gene, PPP6R3 gene and the EEF1G-PPP6R3 fusion. [A] In the upper side of the picture there are the genomic sequences of EEF1G and PPP6R3 genes with the indication of DNA breakpoints individuated by Hammerman and colleagues (Hammerman et al., 2012); [B] in the bottom side of the picture are reported the genomic rearrangement on chromosome 11 and the predicted structure of the novel EEF1G/PPP6R3 fusion after the analysis with Ensembl (http://www.ensembl.org). In addition, there are also indicated the promoter/enhancer elements (reworked from https://www.genecards.org).
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4) 186
EEF1G/PPP6R3 (11q12-13) Christiano L
Description kind of tumors as EEF1G that is involved in A EEF1G/PPP6R3 fusion was found in lung numerous genomic alterations such as translocations squamous cell carcinoma (lung SqCC) and in novel fusion genes. Both genes are important (Hammerman et al., 2012). Hammerman and for cell biology and it is normal that they are colleagues (Hammerman et al., 2012) identified two subjected to rearrangements in cancer cells. In DNA breakpoints that cause the EEF1G/PPP6R3 addition, this could happens also for the fusion: the first is located at the position 62,323,148 characteristics of their promoters because at least for of the EEF1G gene, while the second is located at the PPP6R3 it is known that it possess a potent promoter position 68,368,269 of PPP6R3 (alias, SAPS3) gene, activity (Guo et al., 2016). However, the truly both upstream of the respective genes involved. In oncogenic potential of EEF1G/PPP6R3 in addition, Hammerman and colleagues (Hammerman proliferation and cancer aggressiveness needs to be et al., 2012) identified a novel fusion gene 5'EEF1G better elucidated. - 3'PPP6R3 derived by this abnormal translocation thus formed: at 5' fusion end there is a sequence References starting from 4 kb before EEF1G gene while at 3' Achilonu I, Siganunu TP, Dirr HW. Purification and fusion end there is a sequence starting from 303 bp characterisation of recombinant human eukaryotic after exon 19 of PPP6R3 gene. However, the elongation factor 1 gamma. Protein Expr Purif. 2014 nucleotide sequence of this novel chimeric gene is Jul;99:70-7 not reported or registered anywhere and so it remains Cho DI, Oak MH, Yang HJ, Choi HK, Janssen GM, Kim KM. uncharacterized. Direct and biochemical interaction between dopamine D3 receptor and elongation factor-1Bbetagamma. Life Sci. From the direct analysis of the gene sequences and 2003 Oct 24;73(23):2991-3004 the respective DNA breakpoints using Ensembl (http://www.ensembl.org), could be advanced the Corbi N, Batassa EM, Pisani C, et al. The eEF1γ subunit contacts RNA polymerase II and binds vimentin promoter hypothesis that the chromosomal rearrangement region. PLoS One. 2010 Dec 31;5(12):e14481 where EEF1G and PPP6R3 are involved, although it was described as an intra-chromosomal Coumans JVF, Gau D, Poljak A, Wasinger V, Roy P, Moens P. Green fluorescent protein expression triggers proteome translocation, it seems more similar to an inversion. changes in breast cancer cells Exp Cell Res 2014; 320(1): Moreover the first breakpoint is located 236,453 nt 33-45 before EEF1G gene while the second breakpoint is Guergnon J, Derewenda U, Edelson JR, Brautigan DL. located just before PPP6R3 gene, i.e. 92,441 nt Mapping of protein phosphatase-6 association with its before PPP6R3 gene (Figure.1). This chromosomal SAPS domain regulatory subunit using a model of helical rearrangement permits to bring near EEF1G to repeats BMC Biochem 2009; 10:24 PPP6R3, reducing the long distance between them, Guo R, Wang X, Chou MM, et al. PPP6R3-USP6 i.e. from 5,886,730 nt (about 5,886 kb) to only Amplification: Novel Oncogenic Mechanism in Malignant 328,894 nt (about 328 kb). The reason of this Nodular Fasciitis Genes Chromosomes Cancer 2016; 55:640-649 rearrangement is unknown. Hammerman PS, Lawrence MS, Voet D, et al. Transcript Comprehensive genomic characterization of squamous cell There is no evidence about the mRNA of the lung cancers Nature 2012; 489(7417):519-25 EEF1G/PPP6R3 fusion gene or other transcript Mansilla F, Friis I, Jadidi M, et al. Mapping the human resulting from the EEF1G/PPP6R3. translation elongation factor eEF1H complex using the yeast two-hybrid system. Biochem J 2002; 365(Pt 3):669- Fusion Protein 76 Description Stefansson B, Brautigan DL. Protein phosphatase 6 subunit There is no evidence of protein from the with conserved Sit4-associated protein domain targets IkappaBepsilon J Biol Chem 2006; 281(32):22624-34 EEF1G/PPP6R3 fusion gene. York A, Hutchinson EC, Fodor E. Interactome analysis of Oncogenesis the influenza A virus transcription/replication machinery The role in oncogenesis of the EEF1G/PPP6R3 identifies protein phosphatase 6 as a cellular factor required fusion is unclear, and there is no evidence about its for efficient virus replication J Virol. 2014 Nov;88(22):13284- effective transcription and/or translation. 99 Hammerman and colleagues (Hammerman et al., Yoshihara K, Wang Q, Torres-Garcia W, et al. The 2012) have supposed the presence of a fusion gene landscape and therapeutic relevance of cancer-associated 5'EEF1G - 3'PPP6R3 but actually there are poor data transcript fusions Oncogene 2015; 34(37):4845-54 about it and thus it is unclearly the role of this fusion This article should be referenced as such: gene, i.e. if is effectively translated into a functional Cristiano L. EEF1G/PPP6R3 (11q12-13). Atlas Genet protein or instead it plays a regulatory role. What it Cytogenet Oncol Haematol. 2020; 24(4):185-187. is clear is that PPP6R3 is involved in many and heterogeneous genomic translocations in different
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4) 187 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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