Volume 1 - Number 1 May - September 1997
Volume 24 - Number 9 September 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It 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).
Publisher Contact: INIST-CNRS Mailing Address: Catherine Morel, 2,Allée du Parc de Brabois, CS 10130, 54519 Vandoeuvre-lès-Nancy France. Email Address:[email protected] Articles of the ATLAS are free in PDF format, and metadata are available on the web in Dublin Core XML format and freely harvestable.A Digital object identifier (DOI®), recorded at the International Agency CrossRefhttp://www.crossref.org/ is assigned to each article.
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS. Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
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(9) Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Volume 24, Number 9, September 2020 Table of contents
Gene Section
EGFR (Epidermal Growth Factor Receptor) 325 Ayca Circir Hatil, Esra Cicek, Merve Oyken, A.Elif Erson-Bensan SNX3 (Sorting Nexin 3) 333 Esra Cicek, Ayca Circir Hatil, Merve Oyken, Harun Cingoz, A.Elif Erson-Bensan EEF1B2 (eukaryotic translation elongation factor 1 beta 2) 337 Luigi Cristiano
Leukaemia Section t(12;15)(p13;q25) ETV6/NTRK3 in Hematological malignancies 346 Jean Loup Huret
Solid Tumour Section t(12;15)(p13;q25) ETV6/NTRK3 in solid tumors 350 Jean Loup Huret Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS Gene Section Review
EGFR (Epidermal Growth Factor Receptor) Ayca Circir Hatil, Esra Cicek, Merve Oyken, A.Elif Erson-Bensan Department of Biological Sciences, Middle East Technical University, Ankara/TURKEY, [email protected]; [email protected]; [email protected]; [email protected]
Published in Atlas Database: December 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/EGFRID147ch7p11.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70782/12-2019-EGFRID147ch7p11.pdf DOI: 10.4267/2042/70782
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
mENA; ERBB1 (erb-b2 receptor tyrosin kinase 1); Abstract PIG61; NISBD2 (neonatal inflammatory skin and ERBB family member epidermal receptor tyrosine bowel disease-2),; Erythroblastic leukemia viral (v- kinase (EGFR) is composed of 28 exons and 27 erb-b) oncogene homolog (avian) introns. EGFR codes for 11 transcripts and 8 of them HGNC (Hugo) EGFR are protein coding. EGFR is a transmembrane Location 7p11.2 glycoprotein that can be activated by several different ligands such as epidermal growth factor Local order (EGF), transforming growth factor-alpha (TGFA), Arrangement of genes on chromosome 7 from heparin-binding EGF-like growth factor (HBEGF), centromere to telomere: LOC100996654, betacellulin (BTC), amphiregulin (AREG), LOC643168, LOC105375284, EGFR, EGFR-AS1, epiregulin (EREG), and epigen (EPGN) (Singh, LOC100130121, ELDR, CALM1P2 2016). Ligand binding induces the dimerization of EGFR and autophosphorylation followed by a DNA/RNA cascade of downstream phosphorylation events (Capuani et al., 2015). EGFR activation plays a key Description role in cell survival, proliferation, migration and EGFR gene is 244589 bp long and resides on the differentiation (Purba, 2017). positive strand of DNA Keywords Transcription Epidermal Growth Factor Receptor (EGFR), EGFR gene codes for 11 transcripts which are splice transmembrane receptor tyrosine kinase variants; 8 of them are protein coding (9905 bp, 3844 bp, 5464 bp, 2239 bp, 2864 bp, 1570 bp, 4735 bp and Identity 691 bp) and 3 of them are non-protein coding (561 Other names bp, 452 bp and 665 bp) ERBB (erb-b2 receptor tyrosin kinase); HER1 Pseudogene (human epidermal growth factor receptor 1) Not-reported
Figure 1. Local order of EGFR is shown together with proximal and distal genes on chromosome 7. The direction of arrows indicates transcriptional direction on the chromosome and arrow sizes approximate gene sizes
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 325 EGFR (Epidermal Growth Factor Receptor) Circir Hatil A et al.
Figure 2. EGFR structural variants. EGFR has 11 structural variants with different exon and intron numbers as stated: 1 EGFR- 201: 9905 bp, 1210 aa, 28 exons, transcript type: protein coding; 2 EGFR-207: 3844bp, 1091 aa, 26 exons, transcript type: protein coding; 3 EGFR-206: 5464bp, 1165 aa, 27 exons, transcript type: protein coding; 4 EGFR-202: 2239 bp, 628 aa, 16 exons, transcript type: protein coding; 5 EGFR-203: 2864 bp, 705 aa, 16 exons, transcript type: protein coding; 6 EGFR-204: 1570 bp, 405 aa, 10 exons, transcript type: protein coding; 7 EGFR-208: 452 bp, 2 exons, transcript type: lncRNA; 8 EGFR- 209: 561 bp, 2 exons, transcript type: lncRNA; 9 EGFR-205: 691 bp, 128 aa, 4 exons, transcript type: protein coding; 10 EGFR-211: 4735 bp, 464 aa, 24 exons, transcript type: protein coding; 11 EGFR-210: 665 bp, 3 exons, transcript type: retained intron
with ligand binding is a well characterized function Protein of EGFR. With ligand binding, trans- autophosphorylation takes place between on tyrosine Description residues, which triggers the downstream signaling EGFR protein has four isoforms which are results of cascades (Maruyama, 2014). Conformational alternative splicing. Isoform 1 is the canonical one changes of C-terminal tail also trigger the depicted above. Other isoforms are isoform 2 (p60, components of endocytosis pathway and leads to 405 aa, 44,664 Da), isoform 3 (p110, 705 aa, 77,312 EGFR internalization. EGFR, without ligand, can Da) and isoform 4 (628 aa, 69,228 Da). also be endocytosed with a rate 10-fold lower than the ligand induced ones (Sigismund, 2018). Localisation When EGFR is induced with ligand binding on Plasma membrane, Endosome, Endoplasmic plasma membrane, it is not only phosphorylated, but Reticulum, Golgi apparatus, Nucleus also ubiquitinated at lysine residues on the cytoplasmic kinase domain by E3 ubiquitin ligase Function Cbl complex including GRB2 adaptor protein. EGFR is transmembrane receptor tyrosine kinase Concentration of EGF is the regulator of EGFR belonging to a cell surface receptor family. Other ubiquitination. family members are HER2 (ERBB2), HER3 ( At the beginning of internalization of EGFR, ERBB3) and HER4 ( ERBB4). Orthologs of EGFR ubiquitination drives the non-clathrin endocytosis in Drosophila melanogaster and Caenorhabditis pathway, at later stages it steers EGFR to lysosomal elegans are DER (Lusk, 2017) and Let-23 (Bae, degradation (Sigismund, 2013 and Sigismund, 2012), respectively. These monomeric proteins have 2005). intracellular C-terminal tyrosine kinase domain, After internalization, some of its ligands, like TGFA membrane spanning domain and extracellular, and EREG (epiregulin), dissociates from EGFR in cysteine rich N-terminal ligand binding domain from the milder acidic environment of endosome and bottom to top of its structure. Without ligand drives recycling of EGFR to plasma membrane. In binding, EGFR is in its monomeric form, once the contrast, ligands (like EGF) which are not affected ligand is bound, they form either homodimer or from the acidity of endosome, favors the passage of heterodimer resulting in autophosphorylation of majority of EGFR from early to late endosomes to their C-terminal domain (Ferguson, 2008). be degraded by the lysosome (Ebner, 1991). In canonical EGFR signaling pathway, activation
Figure 3. Isoform 1 (p170) is the canonical sequence of EGFR. The EGFR protein is 1,210 aa long and 134,277 Da.
Fate of EGFR depends also on the type of ligand. Additionally, HBEGF (heparin-binding EGF-like
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 326
EGFR (Epidermal Growth Factor Receptor) Circir Hatil A et al.
growth factor) and BTC (betacellulin) drives all EGF anagen phase and prevent beginning of catagen receptors to lysosomal degradation (Sigismund, phase (Mak and Chan, 2003). The importance of 2018; Roepstorff et al., 2009; Ebner and Derync, EGFR signaling in fur development and 1991). maintenance of hair follicle integrity and Ligand induced EGFR activation in turn activates differentiation were shown in EGFR null mice downstream signaling pathways, named as, models. Deregulation of keratin synthesis, RAS/MAPK pathway, PI3K/AKT pathway and dysregulated differentiation of follicle bulb, cuticle PLC/Protein kinase C cascade. Activation of these disorder and improper integration of hair fibers were pathways with canonical EGFR signaling controls observed in EGFR null mice (Hansen et al., 1997) the crucial functions of cells such as survival, EGFR signaling and its downstream pathways are proliferation, differentiation and migration (Scaltriti also important in skin homeostasis. Activation of and Baselga, 2006). In addition, activation of EGFR EGFR-ERK pathway has a critical role in healing of regulates other important metabolic functions such skin damages, while EGFR-PI3K/AKT pathway is as autophagy in response to cellular or critical to inhibits initiation of apoptosis under UV environmental stress via non-canonical signaling. stress (Peus et al., 2000). Additionally, for Dealing with stress conditions with the action of keratinocyte migration during healing of skin non-canonical EGFR signal is preferred in cancer wounds, necessary amount of collagenase-1 cells to provide advantage for survival and drug production is provided by the activation of EGFR by resistance (Tan et al., 2015; Henson, Chen and autocrine manner (Pilcher et al., 1999). In case of Gibson, 2017). skin lesion, released cytokines from leukocytes EGFR is expressed in many organs is involved in activates keratinocytes, which in turn release several diverse roles including proliferation (Buchon et al., chemokines like CXCLs, and ILs. EGFR is 2010), survival (Crossman, Streichan and Vincent, responsible from the regulation of chemokine release 2018), embryogenesis (Lusk, Lam and Tolwinski, from keratinocytes, which sets a crosstalk between 2017) differentiation during development and skin inflammation and EGFR signaling (Pastore et maintenance of cellular physiology (Dumstrei et al., al., 2008). 1998). Even though the mechanism of transport of EGFR to During lung development, EGFR is critical in type II nucleus is still not clear, EGFR also functions in pneumocyte maturity. Inhibition of EGFR gives rise nucleus as transcriptional co-activator of cell cycle to immature type II pneumocytes and alveolar related genes like CCND1 (cyclin D1) and MYC. deficiency (Inamura, 2018; Kothe et al., 2018) Additionally; EGFR nuclear signaling is stimulated In heart development, EGFR takes role in by EGF and stress factors like H2O2, UV, ionizing differentiation of cardiac valves (Barrick et al., 2009; radiation and drugs (Wee and Wang, 2017). Qi, 2015) Surviving mice among the EGFR deficient group Homology showed valvular deficiency and further survived Human EGFR has homologs in chimpanzee (Pan mice experienced aortic valve thickening, aortic troglodytes), Rhesus monkey (Macaca mulatta), dog stenosis and heart deficit (Makki et al., 2013) (Canis lupus familiaris), cattle (Bos taurus), mouse Expression of EGFR also correlates with the level of (Mus musculus), rat (Rattus norvegicus), chicken neurogenesis in rodents and EGFR activity controls (Gallus gallus), zebrafish (Danio rerio) and frog the proliferation and survival of neuronal cells and (Xenopus tropicalis). Human EGFR has orthologs their proper migration (Puehringer et al., 2014). with 259 organisms. Moreover, EGFR mutant mice showed substantial neurodegenerative damage in the frontal cortex, Mutations olfactory bulb, thalamus and irregular migration in Somatic mutant mice brains (Sibilia et al., 1998) EGFR null mice have abnormal primary According to current information in cbioportal endochondral ossification and malformation of database, somatic mutation frequency is 3.8% in osteoclasts (Wang et al., 2009). 10967 samples obtained from 10953 patients. EGFR-/- mice models show massive abnormality in Distribution of totally 512 mutations: 412 missense epithelial development in which newborns had open mutations, 42 truncating mutations (including eyes, whiskers were curly, and they died within 8 nonsense, nonstop, frameshift deletion, frameshift days after birth due to the epithelial disorder in skin, insertion, splice site mutations), 33 in-frame lung and gastrointestinal tract (Miettinen et al., mutations (in-frame deletions and in-frame 1995). insertions) and 30 other mutations. EGFR is expressed normally in the outer sheath of Non-small cell lung cancer (NSCLC): Very the root and its expression decreases when follicular common (85-90%) and classical mutations growth is completed. Impaired downregulation of frequently seen in NSCLC are L858R point mutation EGFR in hair growth arrest the hair growing cycle at in exon 21 and residual deletions of exon 19. Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 327
EGFR (Epidermal Growth Factor Receptor) Circir Hatil A et al.
Additionally, insertions in exon 20 is related with the Gastric cancer: Exon 19 and exon 21 EGFR resistance against therapeutic EGFR inhibitors like mutations were identified in gastric cancer in Afatinib, Erlotinib and Gefitinib. H773-V774insX, addition to single nucleotide polymorphisms Q787Q D770-N771insX and V769-D770insX are the (37.9%). In addition, Y801C, L858R and G863D insertions of exon 20 with higher incidence (Vyse point mutations were revealed for the first time in and Huang, 2019). T790M point mutation on gastric cancer samples (Liu et al., 2011). tyrosine kinase domain of EGFR is accepted as a Endometrial cancer: Samples taken from 28 drug resistance marker of NSCLC and this mutation woman with endometrial cancer showed three typically coexist with L858R mutation (Denis et al., different mutations in separate patients. L688F and 2015; Li et al., 2018). In general, substitution in E690K were in exon 18 and K754E in exon 19, leucine to arginine at position 858 in tyrosine kinase which is in contrast to others responsive to lapatinib domain of EGFR is well known activating mutation. treatment (Leslie et al., 2013; Reyes et al., 2014) With this mutation, autoinhibitory conformation of Colorectal cancer: EGFR mutation status of 13 EGFR is suppressed and the receptor becomes active patients among 35 male and 23 female patients at even without ligand binding (Wee and Wang, 2017). different stages of colorectal cancer showed exon 20 Glioblastoma (GBM): Point mutations of EGFR are mutation but not exons 18,19 and 21 mutations (Oh common in GBM. Deletions observed in GBM are et al., 2011). S492R EGFR ectodomain mutation N-terminal deletion of EGFR (EGFRvI), exon 14-15 also increases the mutation rate and mABCH12 was deletion (EGFRvII that is oncogenic), exon 2-4 suggested to prevent the effect of mutated EGFR deletion (EGFRvII, which is oncogenic), exon 25-27 (Dong et al., 2019). deletion (EGFRvIV), exon 25-28 deletion Prostate cancer: Studies revealed the (EGFRvV). R108K, A289V, A289D, A289T and overexpression, amplification and mutation of G598D are point mutations in EGFR seen in 24% of EGFR in prostate cancer (Guerin et al., 2010). GBM cases (Larysz, 2011; An et al., 2018). Testicular cancer: From 110 testicular germ cell Breast cancer: 11.4% of 70 paraffin tumor samples tumors 209 distinct components were obtained and randomly selected from among 653 triple negative analyzed for EGFR expression. Among those breast cancer (TNBC) patients showed EGFR components, 28% of 83 seminomas, 11% of 27 mutations. These mutations were deletions in exon embryonal carcinomas, 88% of 8 choriocarcinomas 19, missense substitutions of exon 21 and inversions and 44% of 18 yolk sac tumors showed EGFR in EGFR sequence (Teng et al., 2011). Another overexpression. Additionally, among them, some of study showed 28.3% of 180 patients had EGFR the samples showed amplification and high copy mutations. Thirty patients had exon 19 deletions, 21 number of EGFR, which is also in correlation with of them showed exon 21 mutations (Ma et al., 2017). overexpression of EGFR according to IHC studies Additionally, 50% of TNBC cases were (Miyai et al., 2010). characterized by EGFR overexpression, which is correlated with poor prognosis, less differentiation Implicated in and increased tumor size. Percentage of EGFR overexpression in TNBC is quite high when Non-Small Cell Lung Cancer compared to other subtypes of breast cancer Approximately 70% of lung cancers is non-small (Masuda et al., 2012). cell lung cancer (NSCLC) and 43-89% of NSCLC is Esophageal cancer: Although it is rare, G to A caused by EGFR overexpression. Other mutations substitution was observed in esophageal cancer. 40- are short in frame deletions in exon 19 which 70% of esophageal squamous cell carcinoma shows includes leucine-747 to glutamic acid-749 (ΔLRE) overexpression and increased gene copy number of deletion or point mutations in exon 21 (L858R). EGFR (Anvari, Anvari and Toosi, 2014) These two mutations constitute around 90% of Head and Neck squamous cell carcinoma EGFR activating mutations and lead to cell (HNSCC): Among 47 HNSCC cases, 21% of proliferation, anti-apoptotic signaling by EGFR mutations is L861Q point mutation in exon constitutively activating the downstream signaling 21, 19% of them is insertion in exon 20 and 17% of pathways (Bethune et al., 2010). Bases insertions to them included exon 19 deletions (Vatte et al., 2017). exon 20 of EGFR is related with de novo resistance Additionally, with 41.5, exon 19 had the highest against EGFR inhibitors and poor patient prognosis percentage of tyrosine kinase domain (TKD) (Vyse and Huang, 2019). Additionally, point mutations. 32.1 %, 17 % and 9.4 % are distribution mutation at exon 20; threonine to methionine of TKD mutations in exon 20, exon 21 and exon 18, transition (T790M) is strongly linked to acquired respectively. Among all EGFR mutations, 73% of resistance especially against very commonly used them was exon 18-21 missense mutations, 22% was EGFR inhibitors, namely, erlotinib and gefitinib exon 19 deletions and 5% was exon 20 insertion (Gazdar, 2009). Higher methylation pattern at mutations (Perisanidis, 2017) promoter region of EGFR is related with insensitivity against EGFR targeted treatments in
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 328 EGFR (Epidermal Growth Factor Receptor) Circir Hatil A et al.
NSCLC with low expression of EGFR (Pan, 2015). recurrence free survival times, 18 and 13 months Moreover, higher DNA methylation level of EGFR respectively. Including anti-EGFR agents in indicates the stage of malignancy in these patients combination with chemotherapy in esophago-gastric (Li, 2015) adenocarcinoma provided no advantage in terms of Breast Cancer overall and relapse-free survival of patients (from meta-analysis of 1817 patients of six studies) (Kim In triple negative breast cancer (TNBC), EGFR is et al., 2017; Wang et al., 2017). frequently overexpressed and EGFR inhibition in Hypermethylation of EGFR promoter region in these patients is mostly ineffective. EGFR analyzed tumor samples indicates the possible use of methylation by PRMT1 at arginine 198/200 of this methylation status as a maker for gastric cancer extracellular domain is related to resistance to EGFR (Weng et al., 2015). monoclonal antibody therapies (Nakai et al., 2018). CAMA1, MDA-MB-453 and MDA-MB-435 were Alzheimer's Disease also shown to be methylated at EGFR CpG island in Analysis of Genome wide linkage (GWL), genome- exon 1 as a reason for transcriptional downregulation wide associations (GWA) and genome-wide of EGFR (Montero et al., 2006). expression (GWE) datasets for Alzheimer's disease Head and Neck Cancer (AD) revealed EGFR to be a significant AD specific biomarker. Dataset analysis revealed 108 AD related Mono methylation of lysine 721 in the tyrosine genes including EGFR and ACTB. Since, these two kinase domain of EGFR by NSD3 (WHSC1L1) biochemical markers were found overlapping with results in enhanced downstream signaling (ERK) in proteins of cerebrospinal fluid and plasma proteins, the squamous cell carcinoma of head and neck cells they were characterized as the most significant risk even in the absence of EGF (Saloura et al., 2017) genes in AD (Talwar et al., 2014). Cutaneous Melanoma Mutations in Presenilin (PS) proteins PSEN1 and PSEN2 cause dramatic severity in early-onset of AD. EGFR promoter and regulatory elements PSEN1 controls the cell-specific transcription of hypomethylation increases EGFR expression and EGFR in neural cells. PSEN1 null (PS1(-/-)) cortical enhances PI3K/AKT pathway in cutaneous neurons showed decreased level of EGFR related melanoma. Activation of PI3K/AKT pathway leads survival signaling, until exogenous EGFR rescues to BRAF inhibitor resistance (Wang et al., 2015). the signaling phenotype. Interestingly, while Glioma overexpression of PSEN1 upregulates the In gliomas and development of neurons, H3K27ac transcriptional level of EGFR, downregulation of it and H3K4me3 were found at promoter region of reduces the EGFR mRNA level (Bruban et al., EGFR. Additionally, during development of 2015). germinal matrix, both EGFR-positive and EGFR- EGFR has critical role in APBA2 (amyloid β42) negative germinal matrix cells show DNA induced memory loss in AD. Studies on APP hypomethylation at promoter region but H3K27ac /PSEN1 double transgenic mice had high levels of and H2K4me3 marks the EGFR-expressing, active EGFR level. Inhibition of EGFR activity activated germinal matrix cells (Erfani et al., 2015). reversed the action of APP/PSEN1 related impairment of memory in mice. Similarly, in fruit Prostate Cancer flies, upregulation of EGFR elevated the memory 18% of tissue samples obtained from 2497 prostate loss while pharmaceutical inhibition of EGFR tumors showed DNA level amplification or rescued memory loss in Aβ42 expressing fruit flies overexpression at protein level. high EGFR levels (Wang et al., 2012). correlate with grade and stages of prostate cancer Immuneperoxidase staining showed higher level of (Guerin et al., 2010). Interestingly, in prostate cancer EGFR immune reactivity in both pathologically patients, EGFR was detected in secreted exosomes, confirmed AD brain samples and in normal aging also in serum of mouse models, and these secreted brain samples with neuritic plaques (Birecree et al., exosomes could be related with the resistance 1988). against EGFR targeted therapies (Kharmate et al., Rapidly Progressive 2016). Glomerulonephritis (RPGN) Gastric Cancer EGFR pathway is implicated in RPGN and other Analysis of 683 T3 stage gastric adenocarcinoma glomerular diseases. RPGN is mainly characterized samples revealed that low EGFR expressing 406 by proliferation of epithelial cells and inflammatory patients showed longer overall (39 months) and cell infiltration (Harskamp et al., 2016). HBEGF recurrence free (37 months) survival time while (Heparin Binding EGF) is increased in RPGN and patients having high EGFR expression experienced other glomerular diseases such as puromycin- distant metastasis with decreased overall and aminonucleoside-induced focal segmental
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 329 EGFR (Epidermal Growth Factor Receptor) Circir Hatil A et al.
glomerulosclerosis and membranous nephropathy in the development of obstructive nephropathy (passive Heymann nephritis) (Paizis et al., 1999). (Yang et al.., 2006). there is de novo expression of heparin- binding epidermal growth factor- References like growth factor (HBEGF) in glomerular epithelial An Z, Aksoy O, Zheng T, Fan QW, Weiss WA. Epidermal cells specifically in human glomerulonephritis growth factor receptor and EGFRvIII in glioblastoma: (Flamant et al., 2012). signaling pathways and targeted therapies. Oncogene. Diabetic Nephropathy 2018 Mar;37(12):1561-1575 Anvari K, Anvari A, Silanian Toosi M.. Esophageal Cancer Phosphorylated EGFR and EGF upregulation were and the Importance of Epidermal Growth Factor (EGFR) shown in high glucose treated renal cells (Saad et al., Reviews in Clinical Medicine 2014; 1(2): 44-50 2005). Activation of EGFR causes upregulation of Bae YK, Sung JY, Kim YN, Kim S, Hong KM, Kim HT, Choi SGK1 (serum glucocorticoid-regulated kinase1), MS, Kwon JY, Shim J. An in vivo C elegans model system which is important in regulating ion transport protein for screening EGFR-inhibiting anti-cancer drugs PLoS One ENaC, important in sodium reabsorption (Saad et al., Barrick CJ, Roberts RB, Rojas M, Rajamannan NM, Suitt 2005). Also, Ang II mediated EGFR transactivation CB, O'Brien KD, Smyth SS, Threadgill DW. Reduced EGFR regulates gene expression of glucose transporter 1 causes abnormal valvular differentiation leading to calcific (Nose et al., 2003). Finally, EGFR activation in aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice Am J Physiol Heart Circ Physiol diabetic animals, mediates deviated activation of 2009 Jul;297(1):H65-75 TGFB1 (Uttarwar et al., 2011). Bethune G, Bethune D, Ridgway N, Xu Z. Epidermal growth Chronic Allograft Nephropathy factor receptor (EGFR) in lung cancer: an overview and Increased levels of renal EGF and EGFR was shown update J Thorac Dis 2010 Mar;2(1):48-51 in rats and EGFR expression was demonstrated in Birecree E, Whetsell WO Jr, Stoscheck C, King LE Jr, human renal allograft biopsy samples (Sis et al., Nanney LB. Immunoreactive epidermal growth factor receptors in neuritic plaques from patients with Alzheimer's 2004). Erlotinib (a tyrosine kinase inhibitor) prevent disease J Neuropathol Exp Neurol 1988 Sep;47(5):549-60 chronic allograft rejection (Rintala et al., 2014). Bogdan S, Klambt C. Epidermal growth factor receptor Polycystic Kidney Disease signaling Curr Biol 2001; 11(8): 292-295 EGFR expression is increased in PKD and EGFR Bollée G, Flamant M, Schordan S, Fligny C, Rumpel E, activation via its ligands (EGF, TGFA, HBEGF and Milon M, Schordan E, Sabaa N, Vandermeersch S, Galaup A, Rodenas A, Casal I, Sunnarborg SW, Salant DJ, Kopp AREG26) leads to cyst formation (Harskamp et al., JB, Threadgill DW, Quaggin SE, Dussaule JC, Germain S, 2016). Cellular localization alteration of EGFR is Mesnard L, Endlich K, Boucheix C, Belenfant X, Callard P, also found in PKD. Normally, EGFR is localized on Endlich N, Tharaux PL. Epidermal growth factor receptor the basolateral membrane of tubular cells, but in promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis Nat Med 2011 PKD, receptor is found on the apical surface of the Sep 25;17(10):1242-50 cyst epithelium (Du and Wilson, 1995). Brodsky SV, Nadasdy T, Rovin BH, Satoskar AA, Nadasdy Kidney Fibrosis GM, Wu HM, Bhatt UY, Hebert LA. Warfarin-related nephropathy occurs in patients with and without chronic Ang II-induced renal fibrosis is associated with kidney disease and is associated with an increased EGFR pathway. EGFR inhibition attenuates renal mortality rate Kidney Int 2011 Jul;80(2):181-9 fibrosis and kidney dysfunction in Ang II infused Bruban J, Voloudakis G, Huang Q, Kajiwara Y, Al Rahim M, mouse models, indicating that EGFR may be a Yoon Y, Shioi J, Gama Sosa MA, Shao Z, Georgakopoulos therapeutic target in chronic renal diseases (Qian et A, Robakis NK. Presenilin 1 is necessary for neuronal, but al., 2016). not glial, EGFR expression and neuroprotection via γ- secretase-independent transcriptional mechanisms FASEB Hypertension J 2015 Sep;29(9):3702-12 Kidney is known to express four members of ErbB Buchon N, Broderick NA, Kuraishi T, Lemaitre B. receptor family (Staruschenko et al.,2013). EGFR Drosophila EGFR pathway coordinates stem cell pathway may regulate sodium transport and proliferation and gut remodeling following infection BMC development of hypertension because EGFR Biol 2010 Dec 22;8:152 pathway determines renal lesions and regulates Capuani F, Conte A, Argenzio E, Marchetti L, Priami C, Polo sodium reabsorption in collecting ducts S, Di Fiore PP, Sigismund S, Ciliberto A. Quantitative (Staruschenko et al., 2013). analysis reveals how EGFR activation and downregulation are coupled in normal but not in cancer cells Nat Commun Congenital Hydronephrosis 2015 Aug 12;6:7999 Children with pelviureteral junction obstruction Chen DQ, Cao G, Chen H, Argyopoulos CP, Yu H, Su W, (PUJO) had a significant increase in TGF-β1 and Chen L, Samuels DC, Zhuang S, Bayliss GP, Zhao S, Yu decrease in EGF expression which may play a role XY, Vaziri ND, Wang M, Liu D, Mao JR, Ma SX, Zhao J, Zhang Y, Shang YQ, Kang H, Ye F, Cheng XH, Li XR, Zhang L, Meng MX, Guo Y, Zhao YY. Identification of serum
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 330 EGFR (Epidermal Growth Factor Receptor) Circir Hatil A et al.
metabolites associating with chronic kidney disease Adenocarcinoma: Tumor Initiation and Progression Int J Mol progression and anti-fibrotic effect of 5-methoxytryptophan Sci 2018 Apr 23;19(4) Nat Commun 2019 Apr 1;10(1):1476 Javed S, Petropoulos IN, Alam U, Malik RA. Treatent of Cox JJ, Sheynin J, Shorer Z, Reimann F, Nicholas AK, painful diabetic neuropathy Ther Adv Chronic Dis 2015 Zubovic L, Baralle M, Wraige E, Manor E, Levy J, Woods Jan;6(1):15-28 CG, Parvari R. Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations Hum Khan AH, Falck JR, Manthati VL, Campbell WB, Imig JD. Mutat 2010 Sep;31(9):E1670-86 Epoxyeicosatrienoic acid analog attenuates angiotensin II hypertension and kidney injury Front Pharmacol 2014 Sep Crossman SH, Streichan SJ, Vincent JP. EGFR signaling 23;5:216 coordinates patterning with cell survival during Drosophila epidermal development PLoS Biol 2018 Oct Kharmate G, Hosseini-Beheshti E, Caradec J, Chin MY, 31;16(10):e3000027 Tomlinson Guns ES. Epidermal Growth Factor Receptor in Prostate Cancer Derived Exosomes PLoS One 2016 May Denis MG, Vallée A, Théoleyre S. EGFR T790M resistance 6;11(5):e0154967 mutation in non small-cell lung carcinoma Clin Chim Acta 2015 Apr 15;444:81-5 Kim BJ, Kim JH, Jang HJ, Kim HS. The role of anti-EGFR agents in the first-line treatment of advanced esophago- Dong Q, Shi B, Zhou M, Gao H, Luo X, Li Z, Jiang H. Growth gastric adenocarcinoma: a meta-analysis Oncotarget 2017 suppression of colorectal cancer expressing S492R EGFR Sep 16;8(58):99033-99040 by monoclonal antibody CH12 Front Med 2019 Feb;13(1):83-93 Kothe TB, Royse E, Kemp MW, Usuda H, Saito M, Musk GC, Jobe AH, Hillman NH. Epidermal growth factor receptor Du J, Wilson PD. Abnormal polarization of EGF receptors inhibition with Gefitinib does not alter lung responses to and autocrine stimulation of cyst epithelial growth in human mechanical ventilation in fetal, preterm lambs PLoS One ADPKD Am J Physiol 1995 Aug;269(2 Pt 1):C487-95 2018 Jul 13;13(7):e0200713 Dumstrei K, Nassif C, Abboud G, Aryai A, Aryai A, Larysz D, Kula D, Kowal M, Rudnik A, Jarzb M, Blamek S, Hartenstein V. EGFR signaling is required for the Bierzyńska-Macyszyn G, Kowalska M, Baowski P, differentiation and maintenance of neural progenitors along Jarzb B. Epidermal growth factor receptor gene expression the dorsal midline of the Drosophila embryonic head in high grade gliomas Folia Neuropathol 2011;49(1):28-38 Development 1998 Sep;125(17):3417-26 Leslie KK, Sill MW, Lankes HA, Fischer EG, Godwin AK, Ebner R, Derynck R. Epidermal growth factor and Gray H, Schilder RJ, Walker JL, Tewari K, Hanjani P, transforming growth factor-alpha: differential intracellular Abulafia O, Rose PG. Lapatinib and potential prognostic routing and processing of ligand-receptor complexes Cell value of EGFR mutations in a Gynecologic Oncology Group Regul 1991 Aug;2(8):599-612 phase II trial of persistent or recurrent endometrial cancer Gynecol Oncol 2012 Nov;127(2):345-50 Erfani P, Tome-Garcia J, Canoll P, Doetsch F, Tsankova NM. EGFR promoter exhibits dynamic histone modifications Li J, Jia XF, Liu J, Liu JJ, Zhao HB. Relationship of EGFR and binding of ASH2L and P300 in human germinal matrix DNA methylation with the severity of non-small cell lung and gliomas Epigenetics 2015;10(6):496-507 cancer Genet Mol Res 2015 Oct 5;14(4):11915-23 Flamant M, Bollée G, Hénique C, Tharaux PL. Epidermal Li W, Qiu T, Guo L, Ling Y, Gao Y, Ying J, He J. Primary growth factor: a new therapeutic target in glomerular and acquired EGFR T790M-mutant NSCLC patients disease Nephrol Dial Transplant 2012 Apr;27(4):1297-304 identified by routine mutation testing show different characteristics but may both respond to osimertinib Fletcher JT, Nankivell BJ, Alexander SI. Chronic allograft treatment Cancer Lett 2018 Jun 1;423:9-15 nephropathy Pediatr Nephrol 2009 Aug;24(8):1465-71 Liu Z, Liu L, Li M, Wang Z, Feng L, Zhang Q, Cheng S, Lu Gazdar AF. Activating and resistance mutations of EGFR in S. Epidermal growth factor receptor mutation in gastric non-small-cell lung cancer: role in clinical response to cancer Pathology 2011 Apr;43(3):234-8 EGFR tyrosine kinase inhibitors Oncogene 2009 Aug;28 Suppl 1:S24-31 Lusk JB, Lam VY, Tolwinski NS. Epidermal Growth Factor Pathway Signaling in Drosophila Embryogenesis: Tools for Guérin O, Fischel JL, Ferrero JM, Bozec A, Milano G. EGFR Understanding Cancer Cancers (Basel) 2017 Feb 7;9(2) Targeting in Hormone-Refractory Prostate Cancer: Current Appraisal and Prospects for Treatment Pharmaceuticals Mak KK, Chan SY. Epidermal growth factor as a biologic (Basel) 2010 Jul 19;3(7):2238-2247 switch in hair growth cycle J Biol Chem 2003 Jul Hansen LA, Alexander N, Hogan ME, Sundberg JP, 11;278(28):26120-6 Dlugosz A, Threadgill DW, Magnuson T, Yuspa SH. Genetically null mice reveal a central role for epidermal Maruyama IN. Mechanisms of activation of receptor tyrosine growth factor receptor in the differentiation of the hair follicle kinases: monomers or dimers Cells 2014 Apr 22;3(2):304- and normal hair development Am J Pathol 1997 30 Jun;150(6):1959-75 Masuda H, Zhang D, Bartholomeusz C, Doihara H, Harskamp LR, Gansevoort RT, van Goor H, Meijer E. The Hortobagyi GN, Ueno NT. Role of epidermal growth factor epidermal growth factor receptor pathway in chronic kidney receptor in breast cancer Breast Cancer Res Treat 2012 diseases Nat Rev Nephrol 2016 Aug;12(8):496-506 Nov;136(2):331-45 Henson E, Chen Y, Gibson S. EGFR Family Members' Miettinen PJ, Berger JE, Meneses J, Phung Y, Pedersen Regulation of Autophagy Is at a Crossroads of Cell Survival RA, Werb Z, Derynck R. Epithelial immaturity and and Death in Cancer Cancers (Basel) 2017 Mar 24;9(4) multiorgan failure in mice lacking epidermal growth factor receptor Nature 1995 Jul 27;376(6538):337-41 Inamura K. Clinicopathological Characteristics and Mutations Driving Development of Early Lung Miyai K, Yamamoto S, Asano T, Tamai S, Matsubara O, Tsuda H. Protein overexpression and gene amplification of
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 331 EGFR (Epidermal Growth Factor Receptor) Circir Hatil A et al.
epidermal growth factor receptor in adult testicular germ cell endocytosis of ubiquitinated cargos Proc Natl Acad Sci U S tumors: potential role in tumor progression Cancer Sci 2010 A 2005 Feb 22;102(8):2760-5 Sep;101(9):1970-6 Singh B, Carpenter G, Coffey RJ. EGF receptor ligands: Montero AJ, Díaz-Montero CM, Mao L, Youssef EM, Estecio recent advances F1000Res 2016 Sep 8;5 M, Shen L, Issa JP. Epigenetic inactivation of EGFR by CpG island hypermethylation in cancer Cancer Biol Ther 2006 Tajti G, Gesztelyi R, Pak K, Papp C, Keki S, Szilasi ME, Nov;5(11):1494-501 Mikaczo A, Fodor A, Szilasi M, Zsuga J. Positive correlation of airway resistance and serum asymmetric Nakai K, Xia W, Liao HW, Saito M, Hung MC, Yamaguchi dimethylarginine level in COPD patients with systemic H. The role of PRMT1 in EGFR methylation and signaling in markers of low-grade inflammation Int J Chron Obstruct MDA-MB-468 triple-negative breast cancer cells Breast Pulmon Dis 2017 Mar 14;12:873-884 Cancer 2018 Jan;25(1):74-80 Talwar P, Silla Y, Grover S, Gupta M, Agarwal R, Kushwaha Oh BY, Lee RA, Chung SS, Kim KH. Epidermal growth S, Kukreti R. Genomic convergence and network analysis factor receptor mutations in colorectal cancer patients J approach to identify candidate genes in Alzheimer's Korean Soc Coloproctol 2011 Jun;27(3):127-32 disease BMC Genomics 2014 Mar 15;15:199 Pan ZY, Jiang ZS, Ouyang HQ. Study of the methylation Tan X, Thapa N, Sun Y, Anderson RA. A kinase- patterns of the EGFR gene promoter in non-small cell lung independent role for EGF receptor in autophagy initiation cancer Genet Mol Res 2015 Aug 19;14(3):9813-20 Cell 2015 Jan 15;160(1-2):145-60 Pastore S, Mascia F, Mariani V, Girolomoni G. The Teng YH, Tan WJ, Thike AA, Cheok PY, Tse GM, Wong epidermal growth factor receptor system in skin repair and NS, Yip GW, Bay BH, Tan PH. Mutations in the epidermal inflammation J Invest Dermatol 2008 Jun;128(6):1365-74 growth factor receptor (EGFR) gene in triple negative breast cancer: possible implications for targeted therapy Perisanidis C. Prevalence of EGFR Tyrosine Kinase Breast Cancer Res 2011 Apr 1;13(2):R35 Domain Mutations in Head and Neck Squamous Cell Carcinoma: Cohort Study and Systematic Review In Vivo Vyse S, Huang PH. Targeting EGFR exon 20 insertion 2017 Jan 2;31(1):23-34 mutations in non-small cell lung cancer Signal Transduct Target Ther 2019 Mar 8;4:5 Peus D, Vasa RA, Meves A, Beyerle A, Pittelkow MR. UVB- induced epidermal growth factor receptor phosphorylation Wang D, Wang B, Wang R, Zhang Z, Lin Y, Huang G, Lin is critical for downstream signaling and keratinocyte survival S, Jiang Y, Wang W, Wang L, Huang Q. High expression Photochem Photobiol 2000 Jul;72(1):135-40 of EGFR predicts poor survival in patients with resected T3 stage gastric adenocarcinoma and promotes cancer cell Puehringer D, Orel N, Lüningschrör P, Subramanian N, survival Oncol Lett 2017 May;13(5):3003-3013 Herrmann T, Chao MV, Sendtner M. EGF transactivation of Trk receptors regulates the migration of newborn cortical Wang J, Huang SK, Marzese DM, Hsu SC, Kawas NP, neurons Nat Neurosci 2013 Apr;16(4):407-15 Chong KK, Long GV, Menzies AM, Scolyer RA, Izraely S, Sagi-Assif O, Witz IP, Hoon DSB. Epigenetic changes of Purba ER, Saita EI, Maruyama IN. Activation of the EGF EGFR have an important role in BRAF inhibitor-resistant Receptor by Ligand Binding and Oncogenic Mutations: The cutaneous melanomas J Invest Dermatol 2015 "Rotation Model" Cells 2017 Jun 2;6(2) Feb;135(2):532-541 Qi YF. Aortic regurgitation and heart valve disease in mice Wang K, Yamamoto H, Chin JR, Werb Z, Vu TH. Epidermal J Thorac Dis 2015 Oct;7(10):1676-7 growth factor receptor-deficient mice have delayed primary Reyes HD, Thiel KW, Carlson MJ, Meng X, Yang S, endochondral ossification because of defective osteoclast Stephan JM, Leslie KK. Comprehensive profiling of recruitment J Biol Chem 2004 Dec 17;279(51):53848-56 EGFR/HER receptors for personalized treatment of Wang L, Chiang HC, Wu W, Liang B, Xie Z, Yao X, Ma W, gynecologic cancers Mol Diagn Ther 2014 Apr;18(2):137- Du S, Zhong Y. Epidermal growth factor receptor is a 51 preferred target for treating amyloid-β-induced memory loss Roepstorff K, Grandal MV, Henriksen L, Knudsen SL, Proc Natl Acad Sci U S A 2012 Oct 9;109(41):16743-8 Lerdrup M, Grøvdal L, Willumsen BM, van Deurs B. Differential effects of EGFR ligands on endocytic sorting of Wee P, Wang Z. Epidermal Growth Factor Receptor Cell the receptor Traffic 2009 Aug;10(8):1115-27 Proliferation Signaling Pathways Cancers (Basel) 2017 Saloura V, Vougiouklakis T, Zewde M, Deng X, Kiyotani K, May 17;9(5) Park JH, Matsuo Y, Lingen M, Suzuki T, Dohmae N, Hamamoto R, Nakamura Y. WHSC1L1-mediated EGFR Weng X, Zhang H, Ye J, Kan M, Liu F, Wang T, Deng J, Tan mono-methylation enhances the cytoplasmic and nuclear Y, He L, Liu Y. Hypermethylated Epidermal growth factor oncogenic activity of EGFR in head and neck cancer Sci receptor (EGFR) promoter is associated with gastric cancer Rep 2017 Jan 19;7:40664 Sci Rep 2015 May 11;5:10154 Scaltriti M, Baselga J. The epidermal growth factor receptor Yang Y, Hou Y, Wang CL, Ji SJ. Renal expression of pathway: a model for targeted therapy Clin Cancer Res epidermal growth factor and transforming growth factor- 2006 Sep 15;12(18):5268-72 beta1 in children with congenital hydronephrosis Urology 2006 Apr;67(4):817-21; discussion 821-2 Sibilia M, Steinbach JP, Stingl L, Aguzzi A, Wagner EF. A strain-independent postnatal neurodegeneration in mice This article should be referenced as such: lacking the EGF receptor EMBO J 1998 Feb 2;17(3):719-31 Circir Hatil A, Cicek E, Oyken M, Erson-Bensan AE. Sigismund S, Woelk T, Puri C, Maspero E, Tacchetti C, EGFR (Epidermal Growth Factor Receptor). Atlas Genet Transidico P, Di Fiore PP, Polo S. Clathrin-independent Cytogenet Oncol Haematol. 2020; 24(9):325-332.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 332 Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Gene Section Review
SNX3 (Sorting Nexin 3) Esra Cicek, Ayca Circir Hatil, Merve Oyken, Harun Cingoz, A.Elif Erson-Bensan Department of Biological Sciences, Middle East Technical University, Ankara/TURKEY, [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
Published in Atlas Database: December 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/SNX3ID43757ch6q21.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70783/12-2019-SNX3ID43757ch6q21.pdf DOI: 10.4267/2042/70783
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 Sorting Nexin 3 (SNX3) gene maps to chromosome Other names: SDP3; Grd19; MCOPS8 6, minus strand and has 4 exons and 3 introns. There HGNC (Hugo): SNX3 are 3 alternatively spliced isoforms (transcripts). Location: 6q21 SNX3 is a member of the sorting nexin family. Members of this family generally have BAR Local order domains and phosphoinositide binding regions From centromere to telomere: OSTM1-AS1, called the phox (PX) domain, and are involved in NR2E1, SNX3, RNA5SP212, RNU6-1144P, intracellular trafficking. Unlike other sorting nexins, AFG1L, RPL36AP24. SNX3 does not contain a BAR domain. SNX3 protein interacts with phosphatidylinositol-3- DNA/RNA phosphates, and is involved in protein trafficking SNX3 gene consists of 4 exons and 3 introns. The through its role in the retromer complex. gene maps to 6q21 and is 49,819 kb long (NCBI Keywords Reference Sequence: NC_000006.12 : 108211217- Sorting Nexin 3, protein trafficking 108261260). Highlighted in red is protein coding sequence from exons 1-4.
Figure 1. Local order of SNX3 is shown together with leading and subsequent genes on chromosome 6. The direction of arrows indicates transcriptional direction on the chromosome and arrow sizes approximate gene sizes.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 333 PARP1 (poly(ADP-ribose) polymerase 1) Tunçer S, Kavak K
Figure 2. SNX3 gene has 4 exons and 3 introns. Numbers indicate the exons. Red boxes represents exons/ protein- coding regions and blue boxes represent untranslated regions.
Description Description SNX3 gene is 49,819 kb long and is on the minus SNX3 is a small protein of 162 amino acids. strand. SNX3 gene has 4 exons. Molecular weight of the protein is 18,762 Da. Transcription Expression SNX3 produces 4 coding transcripts (1755 bp, 1072 SNX3 is expressed in brain, eye, endocrine tissues, bp, 890 bp and 1537 bp) and there is non-sense lung, proximal digestive tract, gastrointestinal tract, mediated decay for a transcript (1537 bp). liver and gallbladder, pancreas, kidney and urinary Alternative polyadenylation (APA) also creates 2 bladder, male tissues, female tissues, muscle tissues, different isoforms which has short (636 bp) or long adipose and soft tissue, skin, bone marrow and (934 bp) untranslated regions (UTRs) (Akman et.al., lymphoid tissues and blood. (The Human Protein 2015). Atlas, http://www.proteinatlas.org/). Pseudogene Localisation There are 2 pseudogenes of SNX3 which are: SNX3 protein is mostly localized to the endosomes SNX3P1Y (sorting nexin 3 pseudogene 1 Y-linked) with the retromer complex (M. Harterink, 2011). on chromosome Y and SNX3P1X (sorting nexin 3 Function pseudogene 1 X-linked) on X chromosome (NCBI, 2018). SNX3 functions within the retromer complex. There is no data available for SNX3P1Y expression. Among other members of the nexins, only SNX3 is There are RNAseq data results showing SNX3P1X indispensable for recognition and recycling of WLS is expressed in blood, brain, cortex, tibial nerve, (Wntless) in Drosophila (P. Zhang, 2011). SNX3 is artery, thyroid, breast, ovary and testis required for the binding of VPS26 and VPS35 (genecards.org). association complex to endosomal membranes (M. Lucas, 2016). For efficient recruitment of retromer Protein proteins to the endosomes, SNX3 binding to PI3Ps of endosomes through its PX domain. RAB7A SNX3 belongs to Sorting Nexins family consisting GTPase is also recruited to the endosome. of more than 30 members (P.J. Cullen, 2008). SNX Consequently, VPS35, VPS26 and VPS29 trimer family members are classified according to their interacts with the endosome. SNX3 almost functions domain structures. Members of sorting nexins have as a bridge by interacting with the PI3Ps and the VPS a combination of the following domains: trimer. Binding of retromer to SNX3 causes a Bin/Rvs/Amphiphysin domain (BAR), Phox conformational change on retromer complex, which homology domain (PX), 4.1/Ezrin/Radixin/Moesin- creates a binding surface for cargo proteins (M. like domain (FERM), PXA (PX-associated domain Gallon, 2015). A), RGS (Regulator of G-protein signaling), PXC (PX- associated domain C) and MIT (microtubule- Homology interacting and trafficking molecule domain) (R.D. The SNX3 gene is conserved among species such as Teasdale, 2012). SNX3 has only the PX domain. chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, frog, zebrafish and yeast.(NCBI).
Figure 3. SNX3 consists of only the PX domain.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(8) 334 SNX3 (Sorting Nexin 3) Cicek E et al.
accumulation in early endosomes (Chiow et al., Mutations 2012). A de novo reciprocal t(6;13)(q21;q12) translocation Acute Lymphoblastic Leukemia was detected in a patient with microcephaly, Dexamethasone (DEXA) is a frequently preferred microphthalmia, ectrodactyly, and prognathism chemotherapeutic drug for childhood acute (MMEP) and mental retardation. Gene mapping at lymphoblastic leukemia (ALL) patients, however, the site of the breakpoints showed that the drug resistance is a problem. Proteomic studies translocation breakpoint does not appear to disrupt revealed that SNX3 is expressed differentially any gene on chromosome 13, but does disrupt SNX3 between DEXA treated DEXA- resistant cell line gene on chromosome 6q21 (Ververoot et al., 2002). (REH) and non-DEXA treated REH. In REH cells, There are a mutations reported for SNX3 in bladder SNX3 expression is down-regulated. Additionally, urothelial carcinoma, breast invasive ductal both in high risk and standard risk group ALL carcinoma, breast invasive lobular carcinoma, colon patients, SNX3 downregulation is observed when adenocarcinoma, cutaneous melanoma, esophageal compared to normal control group. Downregulation squamous cell carcinoma, head and neck squamous of SNX3 may be associated with both cell carcinoma, lung squamous cell carcinoma, chemoresistance and tumorigenesis (Dehghan- papillary renal cell carcinoma, serous ovarian Nayeri et al., 2017). cancer, tubular stomach adenocarcinoma, uterine endometrioid carcinoma (cBioPortal database) Alzheimier Disease (Cerami et al., 2012; Gao et al., 2013). Neurotoxic amyloid β peptide (Aβ) with the processing of amyloid precursor protein ( APP) by Implicated in proteolytic cleavage has the leading role in SNX3 has been implicated in diverse diseases. Alzheimier disease (AD) pathogenesis (Vardarajan, 2012). Retromer complex including SNX3 provides Split Hand/Foot Malformation (SHFM) proper trafficking of APP, which is necessary to SNX3 locus has been implicated to be a possibly prevent abnormal production of Aβ peptide. It was important region for SHFM (Duijf et.al., 2003; reported that SNX3 has AD related SNPs. Braverman et.al., 1993; Gurrieri et.al., 1995; Correa- Overexpression of SNX3 in HEK293T showed Cerro et.al., 1996). 6q21 region is also associated reduction in the secreted Aβ level. Regulation of Aβ with some other malformations like microcephaly, peptide with controlling APP may make SNX3 a microphthalmia, ectrodactyly and prognathism candidate for AD treatment (Xu, 2018). (Duijf et. al., 2003 and Vervoort et.al., 2002). Parkinson's Disease MMEP (Microcephaly, Alpha-synuclein (SNCA) protein has a role in the microphthalmia, ectrodactyly and iron metabolism and expression. High expression prognathism) level of alpha-synuclein in dopaminergic neurons SNX3 disruption on 6q21 was reported in a patient causes Parkinson's disease. with MMEP and t(6;13)(q21;q12) but SNX3 In yeast, Fet3/Ftr1 complex has role in external iron mutations were not identified in other MMEP intake. When the external iron concentration is low, patients, which may suggest involvement of other interaction of Ftr1 C-terminus with Snx3-retromer genes (Vervoort et.al., 2002). complex provides retrograde transport of the complex. Under the condition of high external iron Autosomal Dominant Polycyctic concentration, internalized complex is degraded. Kidney Disease (ADPKD). Interestingly, action of the α-syn mimics the high Polycystin-1 (PKD1) and Polycystin-2 (PKD2) are iron concentration response and leads to degradation plasma membrane receptor-ion channel proteins of Fet3/Ftr1 via hindering the Snx3 interaction with implicated in ADPKD. SNX3 has a role in early endosome and hence, cellular iron homeostasis endocytosis of PKD2. It was reported that is disrupted (Patel, 2018). compounds that downregulate SNX3 expression or Anemia which inhibit its function could have therapeutic benefits for ADPKD patients. (Feng et al.,2017). SNX3 functions in the recycling of TFRC (transferrin receptor). Knockdown of snx3 in Epidermoid Carcinoma zebrafish embryos results in intensive anemia. SNX3 has a role in endosomal trafficking of TFRC Consistently, silencing of Snx3 in mouse primary (transferrin receptor) (Chen et al., 2013). Aspirin is fatal liver cells causes reduced total hemoglobin suggested to regulate the recycling of TFRC and content (Chen et al., 2013). possibly EGFR in epidermoid carcinoma cell lines (A-431) by delaying their recycling and causing their
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 335
SNX3 (Sorting Nexin 3) Cicek E et al.
Infection Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N. Integrative analysis of complex SNX3 has a role in Salmonella typhimirium cancer genomics and clinical profiles using the cBioPortal infection in human cells. S.typhimirium is an Sci Signal 2013 Apr 2;6(269):pl1 intracellular pathogen and resides in Salmonella Gurrieri F, Cammarata M, Avarello RM, Genuardi M, containing vesicles (SCVs) in cell. During infection, Pomponi MG, Neri G, Giuffrè L. Ulnar ray defect in an infant SNX3 functions in the tubule formation from the with a 6q21;7q31 2 translocation: further evidence for the existence of a limb defect gene in 6q21 Am J Med Genet SCVs during Salmonella invasion (Braun et al., 2010). Harterink M, Port F, Lorenowicz MJ, McGough IJ, Silhankova M, Betist MC, van Weering JRT, van Heesbeen RGHP, Middelkoop TC, Basler K, Cullen PJ, Korswagen References HC. A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and Braun V, Wong A, Landekic M, Hong WJ, Grinstein S, is required for Wnt secretion Nat Cell Biol 2011 Jul Brumell JH. Sorting nexin 3 (SNX3) is a component of a 3;13(8):914-923 tubular endosomal network induced by Salmonella and involved in maturation of the Salmonella-containing Lucas M, Gershlick DC, Vidaurrazaga A, Rojas AL, vacuole. Cell Microbiol. 2010 Sep 1;12(9):1352-67 Bonifacino JS, Hierro A. Structural Mechanism for Cargo Recognition by the Retromer Complex Cell 2016 Dec Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy 1;167(6):1623-1635 BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N. The cBio Patel D, Xu C, Nagarajan S, Liu Z, Hemphill WO, Shi R, cancer genomics portal: an open platform for exploring Uversky VN, Caldwell GA, Caldwell KA, Witt SN. Alpha- multidimensional cancer genomics data. Cancer Discov. synuclein inhibits Snx3-retromer-mediated retrograde 2012 May;2(5):401-4 recycling of iron transporters in S cerevisiae and C elegans models of Parkinson's disease Chen C, Garcia-Santos D, Ishikawa Y, Seguin A, Li L, Fegan KH, Hildick-Smith GJ, Shah DI, Cooney JD, Chen W, Roti E, Minelli R, Gardini E, Braverman LE. The use and King MJ, Yien YY, Schultz IJ, Anderson H, Dalton AJ, misuse of thyroid hormone Endocr Rev 1993 Freedman ML, Kingsley PD, Palis J, Hattangadi SM, Lodish Aug;14(4):401-2 HF, Ward DM, Kaplan J, Maeda T, Ponka P, Paw BH. Snx3 regulates recycling of the transferrin receptor and iron Teasdale RD, Collins BM. Insights into the PX (phox- assimilation. Cell Metab. 2013 Mar 5;17(3):343-52 homology) domain and SNX (sorting nexin) protein families: structures, functions and roles in disease Biochem J 2012 Chiow KH, Tan Y, Chua RY, Huang D, Ng ML, Torta F, Jan 1;441(1):39-59 Wenk MR, Wong SH. SNX3-dependent regulation of epidermal growth factor receptor (EGFR) trafficking and Vardarajan BN, Bruesegem SY, Harbour ME, Inzelberg R, degradation by aspirin in epidermoid carcinoma (A-431) Friedland R, St George-Hyslop P, Seaman MN, Farrer LA. cells. Cell Mol Life Sci. 2012 May;69(9):1505-21 Identification of Alzheimer disease-associated variants in genes that regulate retromer function Neurobiol Aging 2012 Correa-Cerro L, Garcíaz-Cruz D, Díaz-Castaños L, Figuera Sep;33(9):2231 LE, Sanchez-Corona J. Interstitial deletion 6q16 2q22 2 in a child with ectrodactyly Vervoort R, Wright AF. Mutations of RPGR in X-linked retinitis pigmentosa (RP3) Hum Mutat 2002 May;19(5):486- Cullen PJ. Endosomal sorting and signalling: an emerging 50 role for sorting nexins Nat Rev Mol Cell Biol 2008 Jul;9(7):574-82 Vervoort VS, Viljoen D, Smart R, Suthers G, DuPont BR, Abbott A, Schwartz CE. Sorting nexin 3 (SNX3) is disrupted Dehghan-Nayeri N, Rezaei-Tavirani M, Omrani MD, in a patient with a translocation t(6;13)(q21;q12) and Gharehbaghian A, Goudarzi Pour K, Eshghi P. Identification microcephaly, microphthalmia, ectrodactyly, prognathism of potential predictive markers of dexamethasone (MMEP) phenotype J Med Genet 2002 Dec;39(12):893-9 resistance in childhood acute lymphoblastic leukemia J Cell Commun Signal 2017 Jun;11(2):137-145 Xu S, Nigam SM, Brodin L. Overexpression of SNX3 Decreases Amyloid-β Peptide Production by Reducing Duijf PH, van Bokhoven H, Brunner HG. Pathogenesis of Internalization of Amyloid Precursor Protein Neurodegener split-hand/split-foot malformation Hum Mol Genet 2003 Apr Dis 2018;18(1):26-37 1;12 Spec No 1:R51-60 Zhang P, Wu Y, Belenkaya TY, Lin X. SNX3 controls Feng S, Streets AJ, Nesin V, Tran U, Nie H, Onopiuk M, Wingless/Wnt secretion through regulating retromer- Wessely O, Tsiokas L, Ong ACM. The Sorting Nexin 3 dependent recycling of Wntless Cell Res 2011 Retromer Pathway Regulates the Cell Surface Localization Dec;21(12):1677-90 and Activity of a Wnt-Activated Polycystin Channel Complex J Am Soc Nephrol 2017 Oct;28(10):2973-2984 This article should be referenced as such: Gallon M, Cullen PJ. Retromer and sorting nexins in Cicek E, Circir Hatil A, Oyken M, Cingoz H, Erson- endosomal sorting Biochem Soc Trans 2015 Feb;43(1):33- Bensan AE. SNX3 (Sorting Nexin 3). Atlas Genet 47 Cytogenet Oncol Haematol. 2020; 24(9): 334-336. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B,
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 336 Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Gene Section Review
EEF1B2 (eukaryotic translation elongation factor 1 beta 2) Luigi Cristiano Aesthetic and medical biotechnologies research unit, Prestige, Terranuova Bracciolini, Italy; [email protected] - [email protected]
Published in Atlas Database: January 2020 Online updated version : http://AtlasGeneticsOncology.org/Genes/EEF1B2ID43239ch2q33.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70784/01-2020-EEF1B2ID43239ch2q33.pdf DOI: 10.4267/2042/70784
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 Keywords EEF1B2; Eukaryotic translation elongation factor 1 Eukaryotic translation elongation factor 1 beta 2, beta 2; Translation; Translation elongation factor; alias EEF1B2, is a protein-coding gene that plays a protein synthesis; cancer; oncogene; cancer marker role in the elongation step of translation: In fact, it mediates GDP/GTP exchange on eEF1A. Identity Considering its importance it is found frequently overexpressed in human cancer cells. Other names: EEF1B1; EEF1B; EF1B; eEF1β; This review collects the data on DNA/RNA, on the eEF1Bα; EF-1-beta protein encoded and on the diseases where EEF1B2 HGNC (Hugo): EEF1B2 is involved. Location: 2q33.3
Figure. 1. EEF1B2 gene and splicing variants/isoforms. The figure shows the locus on chromosome 2 of the EEF1B2 gene (reworked from https://www.ncbi.nlm.nih.gov/gene; http://grch37.ensembl.org; www.genecards.org)
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 337 EEF1B2 (eukaryotic translation elongation factor 1 beta 2) Cristiano L
DNA/RNA 0.2 kb. Description Transcription EEF1B2 (eukaryotic translation elongation factor 1 Three main alternative splicing transcript variants beta 2) was identified for the first time by Sanders for EEF1B2 were detected although several others and colleagues in 1991 (Sanders et al, 1991) and were reported. The three main transcript variants afterwards, its gene location was described by differ from each other only in the 5' UTR. In Pizzuti and colleagues in 1993 (Pizzuti et al, 1993). addition, it was speculated the presence of four EEF1B2 is a protein-coding gene that starts at protein isoforms, one main isoform of 225 amino 206,159,594 nt and ends at 206,162,929 nt from pter. acids and other three minor isoforms of 123 residues, It has a length of 3,336 bp and the current reference 68 residues and 29 residues respectively. However, sequence is NC_000002.12. It is proximal to only the protein with the highest number of amino SNORA41 (small nucleolar RNA, H/ACA box 41) acids was detected. The main characteristics of the gene, SNORD51 (small nucleolar RNA, C/D box alternative splicing transcript variants are reported in 51) gene and NDUFS1 (NADH: ubiquinone Table.1. The main mRNA reference sequence is oxidoreductase core subunit S1) gene. Near to the NM_001959.4 and it is 808 bp long. The 5'UTR genomic sequence of EEF1B2 there is a strong counts 85 nt, the CDS is extended from 86 to 763 nt, promoter transcriptional element that is located at – while the 3'UTR covers the last 45 nt. Leng Leng MW Varia Exon Isofor Name RefSeq (1) Transcript ID Type ht Alias RefSeq (2) ht (kDa pI nt s m (bp) (aa) ) EEF1B2- ENST0000023695 protein 844 P2453 24.7 4.5 201 (EEF1B Var.2 NM_021121.3 7 - NP_066944.1 225 7.9 coding (854) 4 6 0 2-001) EEF1B2- NM_00103766 ENST0000039222 protein 880 P2453 NP_00103275 24.7 4.5 202 (EEF1B Var.3 7 - 225 3.1 1.5 coding (900) 4 2.1 6 0 2-201) EEF1B2- ENST0000039222 protein P2453 24.7 4.5 203 (EEF1B Var.1 NM_001959.4 6 808 - NP_001950.1 225 2.7 coding 4 6 0 2-003) EEF1B2- ENST0000041590 nonsen 204 (EEF1B - - 4 649 - - - 68 - - 4.1 se md 2-005) EEF1B2- ENST0000042976 nonsen 205 (EEF1B - - 8 912 - - - 68 - - 9.5 se md 2-007) EEF1B2-206 ENST0000043512 nonsen (EEF1B2- - - 3 389 - - - 29 - - 3.1 se md 009) EEF1B2-207 ENST0000044550 protein (EEF1B2- - - 5 515 - - - 123 - - 5.5 coding 004) EEF1B2-208 ENST0000045515 nonsen (EEF1B2- - - 6 670 - - - 68 - - 0.1 se md 010) EEF1B2- ENST0000046076 retaine 209 (EEF1B - - 2 1025 ------0.1 d intron 2-008) EEF1B2- ENST0000047958 retaine 210 (EEF1B - - 3 701 ------7.1 d intron 2-006) EEF1B2-211 ENST0000048210 retaine (EEF1B2- - - 2 587 ------3.1 d intron 002)
Table.1 Alterative splicing variants and isoforms of EEF1B2. (reworked from http://grch37.ensembl.org; https://www.ncbi.nlm.nih.gov; https://web.expasy.org/protparam/; https://www.uniprot.org). ncRNA = non-coding RNA; nonsense md = nonsense mediated decay;(?) = undetermined; MW = molecular weight; pI = theoretical pI.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 338 EEF1B2 (eukaryotic translation elongation factor 1 beta 2) Cristiano L
Lenght Main Gene Gene name Gene ID RefSeq Locus Location Start End Reference (nt) diseases EEF1B2 Chromosome EEF1B2P1 1932 NC_000015.10 15q21.2 52505029 52505908 880 - - pseudogene 1 15 EEF1B2 Chromosome EEF1B2P2 1934 NC_000005.10 5q13.1 68159175 68159977 803 - - pseudogene 2 5 EEF1B2 Chromosome EEF1B2P3 644820 NC_000023.11 Xp22.11 24788347 24789110 764 - - pseudogene 3 X EEF1B2 Chromosome EEF1B2P4 100130631 NC_000012.12 12q23.3 106901238 106902398 1161 - - pseudogene 4 12 EEF1B2 Chromosome EEF1B2P5 442227 NC_000006.12 6q12 63480050 63481926 1877 - - pseudogene 5 6 EEF1B2 Chromosome EEF1B2P6 647030 NC_000007.14 7q32.3 131661900 131662665 766 - - pseudogene 6 7 EEF1B2 Chromosome EEF1B2P7 100421756 NC_000002.12 2q37.1 232729478 232730276 799 - - pseudogene 7 2 EEF1B2 Chromosome EEF1B2P8 100421774 NC_000003.12 3q26.31 175059315 175060110 796 - - pseudogene 8 3
Table.2 EEF1B2 pseudogenes (reworked from https://www.ncbi.nlm.nih.gov/gene/1933; https://www.targetvalidation.org; https://www.ncbi.nlm.nih.gov/geoprofiles/) [ (?) ] uncertain; [ - ] no reference
Pseudogene Protein According to Entrez Gene, the analysis of the human genome revealed the presence of several Description pseudogenes for EEF1B2 (Table.2), which are The eukaryotic translation elongation factor 1 beta 2 perhaps related to recent retrotransposition events (alias eEF1B2, eEF1β, eEF1Bα) is the smallest (Chambers et al, 2001). subunit of the macromolecular eukaryotic translation The alternative forms EEF1B3 and EEF1B4 elongation factor-1 complex (alias eEF1, also called previously designated for EEF1B2 (Pizzuti et al, eEF1H)(Cao et al, 2014), a high-molecular-weight 1993) have instead proved to form made up of an aggregation of different protein be pseudogenes: i.e. EEF1B2P2 and EEF1B2P3 subunits: EEF1A1 (alias eEF1α), EEF1B2, EEF1G respectively. (alias eEF1γ, heEF1γ, eEF1Bγ), EEF1D (alias If these elements have any regulatory role in the eEF1δ, eEF1Bδ) and VARS2 (valyl t-RNA expression of the respective gene as described for synthetase val-RS). eEF1H protein complex plays a others (Hirotsune et al., 2003), is only speculation in central role in peptide elongation during eukaryotic the absence of experimental evidence. protein biosynthesis, in particular for the delivery of Currently, there is no evidence about the aminoacyl-tRNAs to the ribosome mediated by the involvement of these pseudogenes in human cancers hydrolysis of GTP. or in other diseases.
Figure.2 eEF1B2 protein. Graphical representation of eEF1B2 protein with the evidence of the main verified post-translational modifications (reworked from Le Sourd et al., 2006; http://grch37.ensembl.org; https://www.ncbi.nlm.nih.gov; http://bioinf.umbc.edu/dmdm/gene_prot_page.php; http://www.hprd.org/ptms?hprd_id=02804isoform_id=02804_1isoform_name=Isoform_1).
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 339 EEF1B2 (eukaryotic translation elongation factor 1 beta 2) Cristiano L
In fact, during the translation elongation step, the GEF) while in the amino half terminal there is a inactive GDP-bound form of eEF1A (eEF1A-GDP) region called GST-C-eEF1b-like domain is converted to its active GTP-bound form (eEF1A- (Glutathione S-transferase C-terminal-like GTP) by eEF1BGD-complex through GTP domain)(see figure.2). hydrolysis. The fold of the C-terminal domain of eEF1B2 is Thus eEF1BGD-complex acts as a guanine found very similar to that many ribosomal proteins, nucleotide exchange factor (GEF) for the i.e. it shows two so-called split b-a-b motifs regeneration of eEF1A-GTP for the next elongation (Andersen et al, 2003). cycle. The physiological role of eEF1B2 in the This region possesses nucleotide exchange activity translation is fundamental to permit the conversion and interacts with eEF1A (Le Sourd et al., 2006). of the inactive form eEF1A-GDP into its The non-catalytic N-terminal domain of eEF1B2, corresponding active form eEF1A-GTP. In that interacts with the N-terminal domain of eEF1G particular, eEF1B2 strictly collaborate with eEF1D (Le Sourd et al., 2006; van Damme et al, 1991), has and eEF1G in the conversion of eEF1A from its a regulatory role on the eEF1B2 itself because it can inactive GDP-bound form to its active GTP-bound interfere with the guanine nucleotide exchange form and so it covers a role as a guanine nucleotide activity located on the C-terminal domain. In fact, exchange factor (GEF) for eEF1A (Le Sourd et al., the non-catalytic N-terminal domain of eEF1B2 2006; Browne and Proud, 2002). brings to the reduction in the overall rate of the It was shown that the nucleotide exchange reaction guanine nucleotide exchange reaction mediated by by eEF1B2 is inhibited by Mg2+ that binds on K205 eEF1B2. It is only thanks to the bond of eEF1B2 residue. Only after the displacing of Mg2+ from its with eEF1G that this inhibitory effect is abolished binding site eEF1B2 can function correctly (Trosiuk et al, 2016). EEF1B2 interacts primarily (Pittmann et al, 2006). with eEF1A1/ EEF1A2 and eEF1G but also with In prokaryotes, the homolog of eEF1B2 is known as valyl -tRNA synthetase (Val-RS)(Le Sourd et al., EF-Ts, while in eukaryotes it is known only one 2006; Bec et al., 1994). Seems that there are no direct functional protein form with the reference sequence interactions between eEF1B2 and eEF1D (Cao et al, NP_001950.1 by 225 residues. It is found in the 2014; Sheu and Traugh, 1997), although different eEF1H protein complex and it shows many domains: interactional models were proposed (Le Sourd et al., in the carboxyl half terminal there is an EF-1 guanine 2006; Jiang et al.,2005; Sheu and Traugh, 1999; nucleotide exchange domain (EF1-GNE domain / Minella et al., 1998).
Figure 3. The translation elongation mechanism. The active form of eukaryotic translation elongation factor 1 alpha (eEF1A) in complex with GTP delivers an aminoacylated tRNA to the A site of the ribosome. Following the proper codon-anticodon recognition the GTP is hydrolyzed and the inactive eEF1A-GDP is released from the ribosome and then it is bound by eEF1B2GD complex forming the macromolecular protein aggregate eEF1H. eEF1H is formed previously by the binding of three subunits: eEF1B2, eEF1G and eEF1D. This complex promotes the exchange between GDP and GTP to regenerate active form of eEF1A (reworked from Li et al., 2013; Ejiri, 2002; Riis et al, 1990; https://reactome.org)
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 340 EEF1B2 (eukaryotic translation elongation factor 1 beta 2) Cristiano L
In addition, eEF1B2 interact with translationally and contributes to catalyze the exchange of controlled tumor protein (TCTP) but the nature of GDP/GTP for eEF1A during the translation this interaction is still poorly understood (Wu et al, elongation cycle. It was shown that eEF1B2 has the 2015). ability to disrupt eEF1A-induced actin organization Post-translational modifications. Some post- and so engage eEF1A for protein synthesis (Pittman translational modifications are observed, such as et al, 2009). phosphorylation and acetylation Non-canonical roles: eEF1B2 seems to have other (https://www.ncbi.nlm.nih.gov). Phosphorylations functions inside the cell besides its involvement in of eEF1B2 are made by some protein kinases, translation. Together with eEF1D and eEF1G, it including casein kinase 2 (CK2) (Browne and Proud, controls the translation fidelity (Le Sourd et al, 2006) 2002). and in response to stressors such as heat shock, Expression oxidative stress, and toxins, it mediates the inhibition of protein synthesis. In addition, it seems to have eEF1B2 is expressed widely in human tissues interaction with the cytoskeleton (Khudhair et al., (https://www.genecards.org) although its expression 2014), but the effect of eEF1B2 on actin filaments is is not uniform in either tissues or cell lines (Cao et still poorly understood (Sasikumar et al, 2012). al, 2014). Homology Localisation eEF1B2 is highly conserved and its homology eEF1B2 is located mostly in the cytoplasm but it was between the species is reported in Table.3 also found in the nucleus (https://www.genecards.org/cgi- Mutations bin/carddisp.pl?gene=EEF1B2). It shows a perinuclear distribution (Sanders et al, 1996) and it A great number of mutations in the genomic is found on the endoplasmic reticulum (Cho et al, sequence and in the amino acid sequence for 2003; Sanders et al, 1996). EEF1B2 were discovered in cancer cells that are obviously genetically more unstable respect normal Function ones. eEF1B2 plays a fundamental role in the cell, in The genomic alterations observed include the particular in the translation elongation step. In fact, formation of novel fusion genes. eEF1B2 shows canonical functions and multiple However, there are no sufficient experimental data non-canonical roles (moonlighting roles) inside the yet to understand the repercussions on cellular cell. behaviour and so the implications in cancer of these Canonical function: eEF1B2 binds to eEF1D and alterations. eEF1G in the eEF1B2DG macromolecular complex
Organism Species Symbol DNA Identity (%) PROT Identity (%) Human H.sapiens EEF1B2 100 100 Chimpanzee P.troglodytes EEF1B2 99.9 100 Macaco M.mulatta EEF1B2 97.6 99.6 Wolf C.lupus EEF1B2 93.0 98.2 Cattle B.taurus EEF1B2 91.1 97.8 Mouse M.musculus Eef1b2 89.2 95.6 Rat R.norvegicus Eef1b2 89.2 94.7 Chicken G.gallus EEF1B2 82.0 93.3 Xenopus tropicalis X.tropicalis eef1b2 78.1 85.3 Zebrafish D.rerio eef1b2 73.8 82.6 Fruit fly D.melanogaster Ef1beta 58.7 58.8 Mosquito (Anopheles) A.gambiae AgaP_AGAP010612 60.2 62.0 Caenorhabditis C.elegans eef-1B.1 55.1 53.1
Table.3 EEF1B2 homology (reworked from htpps://www.ncbi.nlm.nih.gov/homologene)
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 341 EEF1B2 (eukaryotic translation elongation factor 1 beta 2) Cristiano L
Figure 4. Circos plot for fusion events involving eEF1B2. The picture summarizes all fusion events concerning eEF1B2 and its fusion partners (from https://fusionhub.persistent.co.in/search_genewise.html).
Implicated in Breast cancer It was reported that eEF1B2 is overexpressed in A different expression level of EEF1B2 was breast carcinoma (Al-Maghrebi et al, 2005). On the observed in many cancer types, i.e. some cancer contrary, Hassan et colleagues reported that eEF1B2 types show an increase of its expression levels, expression levels are reduced both in invasive ductal whereas others show a significant reduction of its breast carcinoma and invasive lobular breast expression level, compared to noncancerous control carcinoma (Hassan et al, 2018). tissue. Therefore, eEF1B2 seems to be involved in In addition, it is downregulated in IR-induced tumorigenesis like the other members of eEF1H senescence in MCF7 breast cancer cell line (Byun et complex (Hassan et al., 2018; Le Sourd et al., 2006) al, 2009). but not only: it was revealed that all subunits of Prognosis eEF1B2GD complex, included eEF1B2, can According to Hassan et colleagues, elevated levels function separately from the eEF1B2GD complex or of eEF1B2 expression predict a better overall the eEF1H complex in cancer tissues (Veremieva et survival (OS) in luminal B subtype breast cancer, a al, 2011). better overall survival (OS) and distant metastasis In addition, eEF1B2 is involved in some genomic free survival (DMFS) in luminal A subtype breast translocations with the creation of numerous fusion cancer, but a worse DMFS in basal type (Hassan et genes (Table.4). al, 2018). Brain and central nervous system Colorectal cancer (CNS) cancers In colorectal cancer the involvement of eEF1B2 is Significative high expression levels for eEF1B2 controversial. were observed in atypical teratoid/rhabdoid tumor Although there are no significant difference in and oligodendroglioma (Hassan et al, 2018). expression levels of eEF1B2 in tumor samples Prognosis respect normal ones, it is believed that a reduction of Lower protein levels of eEF1B2 were correlated its expression level in colorectal cancer can be with poor survival in glioma patients (Biterge-Sut, related to poor patients survival (Hassan et al, 2018) 2019; Hassan et al, 2018)
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 342
EEF1B2 (eukaryotic translation elongation factor 1 beta 2) Cristiano L
Name 5' end 3' end Loc1 Loc2 Description Type Disease Organ Code Ref. t(2;17)(q33;q1 Translocatio ACACA/EEF1B2 ACACA EEF1B2 17q12 2q33.3 (?) - - - 2) n 20q11.2 t(2;20)(q33;q1 Translocatio BLCAP/EEF1B2 BLCAP EEF1B2 2q33.3 (?) - - - 3 1) n Yoshihar Translocatio Adenocarcinom CRIM1/EEF1B2 CRIM1 EEF1B2 2p22.3 2q33.3 t(2;2)(p22;q33) Kidney KIRC a et al n a 2015 t(X;2)(q27;q33 Translocatio EEF1B2/CDR1 EEF1B2 CDR1 2q33.3 Xq27.1 (?) - - - ) n EEF1B2/EEF1B2P EEF1B2P t(2;15)(q33;q2 Translocatio EEF1B2 2q33.3 15q21.2 (?) - - - 1 1 1) n EEF1B2/EEF1B2P EEF1B2P Xp22.1 t(X;2)(p22;q33 Translocatio EEF1B2 2q33.3 (?) - - - 3 3 1 ) n t(2;17)(q33;q2 Translocatio EEF1B2/H3F3B EEF1B2 H3F3B 2q33.3 17q25.1 (?) - - - 5) n t(2;18)(q33;q2 Translocatio EEF1B2/MBP EEF1B2 MBP 2q33.3 18q23 (?) - - - 3) n MICAL t(2;11)(q33;p1 Translocatio MICAL2/EEF1B2 EEF1B2 11p15.3 2q33.3 (?) - - - 2 5) n Cell line NDUFS Readthrough (urinar BFTC Klijn et NDUFS1/EEF1B2 EEF1B2 2q33.3 2q33.3 Fusion gene - 1 transcription y -905 al., 2015 bladder ) 10p11.2 t(2;10)(q33;p1 Translocatio ZEB1/EEF1B2 ZEB1 EEF1B2 2q33.3 (?) - - - 2 1) n Translocatio Klijn et ZNF620/EEF1B2 ZNF620 EEF1B2 3p22.1 2q33.3 t(2;3)(q33;p22) (?) - - n al., 2015
Table.4 EEF1B2 rearrangements: translocations and fusion genes (reworked from: http://www.tumorfusions.org; https://mitelmandatabase.isb-cgc.org/; http://quiver.archerdx.com; http://atlasgeneticsoncology.org//Bands/2q33.html#REFERENCES; https://fusionhub.persistent.co.in/home.html; https://ccsm.uth.edu/FusionGDB/index.html) [ (?) ] unknown; [ - ] no reference
Gastric cancer Head and neck squamous cell It is found that eEF1B2 is expressed at levels about carcinoma (HNSC) three times higher in gastric cancer tissues compared with respective normal ones and that the high eEF1B2 expression levels are significantly lower in expression of eEF1B2 seems to be significantly tongue squamous cell carcinoma, salivary gland associated with histological type, TNM stage, tumor adenoid cystic carcinoma, and hypopharyngeal size, and distant metastases (Jia et al, 2019). This squamous cell carcinoma respect normal ones could suggest that eEF1B2 participate in gastric (Hassan et al, 2018). tumorigenesis and progression and so it may a Kidney cancer possible prognostic biomarker for gastric cancer. On EEF1B2 mRNA levels were found to be upregulated the contrary, a previous study reported that eEF1B2 in cancer samples, in particular in kidney clear cell levels in gastric cancer were significantly carcinoma (Hassan et al., 2018). In addition, the yet downregulated (Hassan et al, 2018). poorly understood translocation t(2;2)(p22;q33) Prognosis CRIM1/EEF1B2 was reported in kidney clear cell High expression levels for eEF1B2 in gastric cancer carcinoma (Yoshihara et al, 2015). patients predict poor overall survival (Jia et al, Liver cancer 2019). On the contrary, Hassan and colleagues, reported that its elevated transcript levels may There is not much data on the expression levels of predict better overall survival (OS) and better first eEF1B2 in liver tumors however lower protein levels progression (FP) (Hassan et al, 2018). for eEF1B2 seems to be correlated with better survival in hepatocellular carcinoma patients (Biterge-Sut, 2019; Hassan et al, 2018).
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 343 EEF1B2 (eukaryotic translation elongation factor 1 beta 2) Cristiano L
Lung cancer translation elongation factor 1 as promising markers of cellular senescence Cancer Res 2009 Jun 1;69(11):4638- eEF1B2 expression levels seem to not show any 47 significant difference between tumor and normal Cao Y, Portela M, Janikiewicz J, Doig J, Abbott CM. tissue (Hassan et al, 2018) although other research Characterisation of translation elongation factor eEF1B revealed that it is overexpressed in 8% of cancer subunit expression in mammalian cells and tissues and co- samples examined (Veremieva et al, 2014). localisation with eEF1A2 PLoS One 2014 Dec 1;9(12):e114117 Prognosis Chambers DM, Rouleau GA, Abbott CM. Comparative An overexpression of EEF1B2 predicts poor genomic analysis of genes encoding translation elongation prognosis in lung cancer, in particular in factor 1B(alpha) in human and mouse shows EEF1B1 to be adenocarcinoma (Hassan et al, 2018). a recent retrotransposition event Genomics 2001 Oct;77(3):145-8 Lymphoma and other blood cancers Cho DI, Oak MH, Yang HJ, Choi HK, Janssen GM, Kim KM. High expression levels of eEF1B2 were detected in Direct and biochemical interaction between dopamine D3 follicular lymphoma, diffuse large B-Cell lymphoma receptor and elongation factor-1Bbetagamma Life Sci and Burkitt's lymphoma (Hassan et al, 2018). 2003 Oct 24;73(23):2991-3004 Ejiri S. Moonlighting functions of polypeptide elongation Neurological and factor 1: from actin bundling to zinc finger protein R1- neurodevelopmental disorders associated nuclear localization Biosci Biotechnol Biochem 2002 Jan;66(1):1-21 Loss of function of EEF1B2 brings to defects in the elongation process and it is involved in autosomal Hassan MK, Kumar D, Naik M, Dixit M. The expression recessive intellectual disability (ID) (Larcher et al., profile and prognostic significance of eukaryotic translation elongation factors in different cancers PLoS One 2018 Jan 2019). 17;13(1):e0191377 Oesophageal carcinoma Hirotsune S, Yoshida N, Chen A, Garrett L, Sugiyama F, It was detected that eEF1B2 is overexpressed in Takahashi S, Yagami K, Wynshaw-Boris A, Yoshiki A. An expressed pseudogene regulates the messenger-RNA about 20% of cardioesophageal carcinoma samples stability of its homologous coding gene Nature 2003 May examined respect noncancerous ones (Veremieva et 1;423(6935):91-6 al., 2014). Jia L, Yang T, Gu X, Zhao W, Tang Q, Wang X, Zhu J, Feng Pancreatic cancer Z. Translation elongation factor eEF1Bα is identified as a novel prognostic marker of gastric cancer Int J Biol EEF1B2 mRNA is found to be down-regulated in Macromol 2019 Apr 1;126:345-351 pancreatic cancer tissue samples and this can be Jiang S, Wolfe CL, Warrington JA, Norcum MT. Three- correlated to a better survival (Hassan et al., 2018). dimensional reconstruction of the valyl-tRNA synthetase/elongation factor-1H complex and localization of Prostate cancer the delta subunit FEBS Lett 2005 Nov 7;579(27):6049-54 There are no significant differences in expression Larcher L, Buratti J, Héron-Longe B, Benzacken B, Pipiras levels of eEF1B2 in prostate cancer respect normal E, Keren B, Delahaye-Duriez A. New evidence that biallelic one (Hassan et al, 2018). loss of function in EEF1B2 gene leads to intellectual disability Clin Genet 2019 Dec 16 References Le Sourd F, Boulben S, Le Bouffant R, Cormier P, Morales J, Belle R, Mulner-Lorillon O. eEF1B: At the dawn of the Al-Maghrebi M, Anim JT, Olalu AA. Up-regulation of 21st century Biochim Biophys Acta 2006 Jan-Feb;1759(1- eukaryotic elongation factor-1 subunits in breast carcinoma. 2):13-31 Anticancer Res. 2005 May-Jun;25(3c):2573-7 Li D, Wei T, Abbott CM, Harrich D. The unexpected roles of Andersen GR, Nissen P, Nyborg J. Elongation factors in eukaryotic translation elongation factors in RNA virus protein biosynthesis. Trends Biochem Sci. 2003 replication and pathogenesis Microbiol Mol Biol Rev 2013 Aug;28(8):434-41 Jun;77(2):253-66 Bec G, Kerjan P, Waller JP. Reconstitution in vitro of the Minella O, Mulner-Lorillon O, Bec G, Cormier P, Bellé R. valyl-tRNA synthetase-elongation factor (EF) 1 beta gamma Multiple phosphorylation sites and quaternary organization delta complex. Essential roles of the NH2-terminal of guanine-nucleotide exchange complex of elongation extension of valyl-tRNA synthetase and of the EF-1 delta factor-1 (EF-1betagammadelta/ValRS) control the various subunit in complex formation. J Biol Chem. 1994 Jan functions of EF-1alpha Biosci Rep 1998 Jun;18(3):119-27 21;269(3):2086-92 N Khudhair, Y Cuiping, A Khalid, X Gao. Role of eEF1B Biterge-Sut B. Alterations in Eukaryotic Elongation Factor subunits in regulation phosphorylation and some functions complex proteins (EEF1s) in cancer and their implications Journal of Genetic and Environmental Resources in epigenetic regulation Life Sci 2019 Dec 1;238:116977 Conservation 2014; 2(3): 270-282 Browne GJ, Proud CG. Regulation of peptide-chain Pittman YR, Valente L, Jeppesen MG, Andersen GR, Patel elongation in mammalian cells Eur J Biochem 2002 S, Kinzy TG. Mg2+ and a key lysine modulate exchange Nov;269(22):5360-8 activity of eukaryotic translation elongation factor 1B alpha J Biol Chem 2006 Jul 14;281(28):19457-68 Byun HO, Han NK, Lee HJ, Kim KB, Ko YG, Yoon G, Lee YS, Hong SI, Lee JS. Cathepsin D and eukaryotic
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 344
EEF1B2 (eukaryotic translation elongation factor 1 beta 2) Cristiano L
Pizzuti A, Gennarelli M, Novelli G, Colosimo A, Lo Cicero S, Caskey CT, Dallapiccola B. Human elongation factor EF-1 beta: cloning and characterization of the EF1 beta 5a gene elongation factor 1Bα FEBS J 2016 Feb;283(3):484-97 and assignment of EF-1 beta isoforms to chromosomes Veremieva M, Khoruzhenko A, Zaicev S, Negrutskii B, 2,5,15 and X Biochem Biophys Res Commun 1993 Nov El'skaya A. Unbalanced expression of the translation 30;197(1):154-62 complex eEF1 subunits in human cardioesophageal Riis B, Rattan SI, Clark BF, Merrick WC. Eukaryotic protein carcinoma Eur J Clin Invest 2011 Mar;41(3):269-76 elongation factors Trends Biochem Sci 1990 Wu H, Gong W, Yao X, Wang J, Perrett S, Feng Y. Nov;15(11):420-4 Evolutionarily conserved binding of translationally controlled Sanders J, Brandsma M, Janssen GM, Dijk J, Möller W. tumor protein to eukaryotic elongation factor 1B J Biol Chem Immunofluorescence studies of human fibroblasts 2015 Apr 3;290(14):8694-710 demonstrate the presence of the complex of elongation Yoshihara K, Wang Q, Torres-Garcia W, Zheng S, Vegesna factor-1 beta gamma delta in the endoplasmic reticulum J R, Kim H, Verhaak RG. The landscape and therapeutic Cell Sci 1996 May;109 ( Pt 5):1113-7 relevance of cancer-associated transcript fusions Sanders J, Maassen JA, Amons R, Möller W. Nucleotide Oncogene 2015 Sep 10;34(37):4845-54 sequence of human elongation factor-1 beta cDNA Nucleic van Damme H, Amons R, Janssen G, Möller W. Mapping Acids Res 1991 Aug 25;19(16):4551 the functional domains of the eukaryotic elongation factor 1 Sasikumar AN, Perez WB, Kinzy TG. The many roles of the beta gamma Eur J Biochem 1991 Apr 23;197(2):505-11 eukaryotic elongation factor 1 complex Wiley Interdiscip Rev RNA 2012 Jul-Aug;3(4):543-55 This article should be referenced as such: Sheu GT, Traugh JA. Recombinant subunits of mammalian Cristiano L. EEF1B2 (eukaryotic translation elongation elongation factor 1 expressed in Escherichia coli Subunit factor 1 beta 2). Atlas Genet Cytogenet Oncol Haematol. interactions, elongation activity, and phosphorylation by 2020; 24(9): 338-345. protein kinase CKII J Biol Chem Trosiuk TV, Shalak VF, Szczepanowski RH, Negrutskii BS, El'skaya AV. A non-catalytic N-terminal domain negatively influences the nucleotide exchange activity of translation
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 345 Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Leukaemia Section Short Communication t(12;15)(p13;q25) ETV6/NTRK3 in Hematological malignancies Jean-Loup Huret [email protected]
Published in Atlas Database: November 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1215p13q25ID1347.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70785/11-2019-t1215p13q25ID1347.pdf DOI: 10.4267/2042/70785
This article is an update of : Huret JL. t(12;15)(p13;q25). Atlas Genet Cytogenet Oncol Haematol 2009;13(2)
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 leukemia (ALL). Phenotype/cell stem origin Review on t(12;15)(p13;q25), with data on clinics, and the genes involved. Chronic eosinophilic leukemia (one case), acute myeloblastic leukemia with maturation (FAB type Keywords M2) (one case), acute myeloblastic leukemia with Chromosome 12; Chromosome 15; ETV6; NTRK3; minimal differentiation (FAB type M0) (one case), Chronic eosinophilic leukemia; Acute myeloid and B-lineage acute lymphoblastic leukemia (three leukemia; B-Lineage Acute lymphoblastic leukemia; cases). Secretory ductal breast carcinoma; Congenital mesoblastic nephroma; Congenital/infantile Epidemiology fibrosarcoma; Papillary thyroid carcinoma; A chronic eosinophilic leukemia was diagnosed in a Inflammatory myofibroblastic sarcoma; Secretory 82-year old female patient with a previous history of carcinoma of salivary glands (mammary analogue); breast and pancreatic carcinomas (Forghieri et al., atypical Spitz tumors. 2011). A M2-AML was diagnosed in a 52-yr old female patient. Identity The patient died 5 months after the onset of the leukaemia (Eguchi et al., 1999). The t(12;15)(p13;q25) ETV6/NTRK3 is also found A M0-AML was found in a 55-yr old male patient in: Secretory ductal breast carcinoma; Congenital who died after a short period of supportive care mesoblastic nephroma; Congenital/infantile (Kralik et al., 2011). fibrosarcoma; Papillary thyroid carcinoma (PTC), Three cases of B-cell ALL were diagnosed. especially so in radiation-associated PTCs; ALK- There was an adolescent boy and a 26-yr old male negative inflammatory myofibroblastic sarcoma; patient (Roberts et al., 2014; Gu et al., 2016; Reshmi Secretory carcinoma of salivary glands (mammary et al., 2017). analogue); atypical Spitz tumors, and rare other conditions. Cytogenetics There was a monosomy 7 in two of the three Clinics and pathology documented cases (Forghieri et al., 2011; Kralik et al., 2011), and a trisomy 8 in 2 cases as well (Eguchi Disease et al., 1999; Forghieri et al., 2011). The lymphoid Myeloid leukemias and acute lymphoblastic cases were not documented.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 346 t(12;15)(p13;q25) ETV6/NTRK3 in Hematological Huret JL malignancies
Genes involved and Result of the chromosomal proteins anomaly ETV6 (ets variant 6) Hybrid gene Location 12p13.2 Description Protein In most cases, ETV6 exon 5 was fused to NTRK3 ETV6 is a strong transcriptional repressor. ETV6 is exon 15 (Forghieri et al., 2011; Roberts et al., 2014). a 452 amino acid member of the ETS family (signal- In one case ETV6 exon 4 was fused to NTRK3 exon dependent transcriptional regulators, mediating cell 15 (Eguchi: et al., 1999), and in another case, fusion proliferation, differentiation and tumorigenesis. The transcripts contain ETV6 exons 1 through 5 fused to ETV6 protein contains two major domains, the HLH NTRK3 exons 13b and 14b or NTRK3 exons 13 (helix-loop-helix) and ETS domains. The N-term through 18 (Kralik et al., 2011). HLH domain, also referred to as the pointed or sterile In solid tumors, ETV6 exon 5 - NTRK3 exon 15 alpha motif domain, is responsible for hetero- and fusion is the most frequent: homodimerization. The C-term ETS domain is The fusion was exon 4 - exon 14 in most papillary responsible for sequence specific DNA-binding and thyroid carcinoma ceases, but one exon 5 - exon 14 protein-protein interaction. A central domain, called fusion case (Leeman-Neill et al., 2014), and exon 5 - internal domain, is involved in the recruitment of a exon 15 in: secretory ductal breast carcinoma repression complex includingNCOR1, NCOR2, and (Tognon et al., 2002), congenital mesoblastic SIN3A (Braekeleer et al., 2014 nephroma (Knezevich et al., 1998; Rubin et al., http://atlasgeneticsoncology.org//Genes/ETV6ID38. 1998; Argani et al., 2000; Ramachandran et al., html). 2001; Watanabe et al., 2002; Henno et al., 2003; Anderson et al., 2006; Bayindir et al., 2009), NTRK3 (neurotrophic tyrosine secretory carcinoma of salivary glands (mammary kinase, receptor, type 3) analogue) (Skálová et al., 2010; Skálová et al., Location 15q25.3 2014), atypical Spitz tumors (Yeh et al., 2016), and also in a case of colon adenocarcinoma (Seshagiri et Protein al., 2012). The classical exon 5 - exon 15 fusion is NTRK3 is a transmembrane receptor tyrosine kinase also found in congenital/infantile fibrosarcoma which triggers PI3K/AKT, RAS/RAF/MAPK, and (Knezevich et al., 1998; Rubin et al., 1998; PLCG pathways. NTRK3 is a 839 amino acid Bourgeois et al., 2000; Punnett et al., 2000; Argani protein with a N-term extra-cellular ligand binding et al., 2001; Dubus et al., 2001; Sheng et al., 2001; domain, a transmembrane domain, and a C-term Miura et al., 2002; McCahon et al., 2003; Ramphal intracellular tyrosine kinase domain. Ligand for et al., 2003; Nonaka and Sun, 2004; Himori et al., NTRK3 is NTF3 (neurotrophin 3) (Knezevich 2004 2005), but, also, a fusion NTRK3 exon 14 - ETV6 http://atlasgeneticsoncology.org/Genes/NTRK3ID4 exon 6 was found in one case (Dubus et al., 2001).
33.html).
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 347
t(12;15)(p13;q25) ETV6/NTRK3 in Hematological Huret JL malignancies
Fusion protein Mullighan CG. Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia Nat Commun Description 2016 Nov 8;7:13331 The SAM-PNT (sterile alpha motif- pointed) domain Henno S, Loeuillet L, Henry C, D'Hervé D, Azzis O, Ferrer of ETV6 is fused to the PTK (Protein Tyrosine J, Poulain P, Babut JM, Merlio JP, Jouan H, Dubus P. Kinase domain) of NTRK3. Cellular mesoblastic nephroma: morphologic, cytogenetic and molecular links with congenital fibrosarcoma Pathol Oncogenesis Res Pract 2003;199(1):35-40 It leads to dimerization, and induction of CCND1 Himori K, Hatori M, Watanabe M, Moriya T, Ogose A, (cyclin D1) and increased cell cycle progression. Hashimoto H, Kokubun S. Infantile fibrosarcoma of thigh--a ETV6/NTRK3 also leads to constitutive activation case report Ups J Med Sci 2005;110(1):85-93 of the PI3K/AKT, RAS/RAF/MAPK, and PLCG Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen pathways (Lannon and Sorensen, 2005). PH. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma Nat Genet 1998 Feb;18(2):184-7 References Kralik JM, Kranewitter W, Boesmueller H, Marschon R, Tschurtschenthaler G, Rumpold H, Wiesinger K, Erdel M, Anderson J, Gibson S, Sebire NJ. Expression of ETV6- Petzer AL, Webersinke G. Characterization of a newly NTRK in classical, cellular and mixed subtypes of congenital identified ETV6-NTRK3 fusion transcript in acute myeloid mesoblastic nephroma Histopathology 2006 leukemia Diagn Pathol 2011 Mar 15;6:19 May;48(6):748-53 Leeman-Neill RJ, Kelly LM, Liu P, Brenner AV, Little MP, Argani P, Fritsch MK, Shuster AE, Perlman EJ, Coffin CM. Bogdanova TI, Evdokimova VN, Hatch M, Zurnadzy LY, Reduced sensitivity of paraffin-based RT-PCR assays for Nikiforova MN, Yue NJ, Zhang M, Mabuchi K, Tronko MD, ETV6-NTRK3 fusion transcripts in morphologically defined Nikiforov YE. ETV6-NTRK3 is a common chromosomal infantile fibrosarcoma Am J Surg Pathol 2001 rearrangement in radiation-associated thyroid cancer Nov;25(11):1461-4 Cancer 2014 Mar 15;120(6):799-807 Bayindir P, Guillerman RP, Hicks MJ, Chintagumpala MM. McCahon E, Sorensen PH, Davis JH, Rogers PC, Schultz Cellular mesoblastic nephroma (infantile renal KR. Non-resectable congenital tumors with the ETV6- fibrosarcoma): institutional review of the clinical, diagnostic NTRK3 gene fusion are highly responsive to chemotherapy imaging, and pathologic features of a distinctive neoplasm Med Pediatr Oncol 2003 May;40(5):288-92 of infancy Pediatr Radiol 2009 Oct;39(10):1066-74 Miura K, Han G, Sano M, Tsutsui Y. Regression of Bourgeois JM, Knezevich SR, Mathers JA, Sorensen PH. congenital fibrosarcoma to hemangiomatous remnant with Molecular detection of the ETV6-NTRK3 gene fusion histological and genetic findings Pathol Int 2002 differentiates congenital fibrosarcoma from other childhood Sep;52(9):612-8 spindle cell tumors Am J Surg Pathol 2000 Jul;24(7):937- 46 Nonaka D, Sun CC. Congenital fibrosarcoma with metastasis in a fetus Pediatr Dev Pathol 2004 Mar- Diallo R, Tognon C, Knezevich SR, Sorensen P, Poremba Apr;7(2):187-91 C. Secretory carcinoma of the breast: a genetically defined carcinoma entity Verh Dtsch Ges Pathol 2003;87:193-203 Ramphal R, Manson D, Viero S, Zielenska M, Gerstle T, Pappo A. Retroperitoneal infantile fibrosarcoma: clinical, Dubus P, Coindre JM, Groppi A, Jouan H, Ferrer J, Cohen molecular, and therapeutic aspects of an unusual tumor C, Rivel J, Copin MC, Leroy JP, de Muret A, Merlio JP. The Pediatr Hematol Oncol 2003 Dec;20(8):635-42 detection of Tel-TrkC chimeric transcripts is more specific than TrkC immunoreactivity for the diagnosis of congenital Reshmi SC, Harvey RC, Roberts KG, Stonerock E, Smith fibrosarcoma J Pathol 2001 Jan;193(1):88-94 A, Jenkins H, Chen IM, Valentine M, Liu Y, Li Y, Shao Y, Easton J, Payne-Turner D, Gu Z, Tran TH, Nguyen JV, Eguchi M, Eguchi-Ishimae M, Tojo A, Morishita K, Suzuki K, Devidas M, Dai Y, Heerema NA, Carroll AJ 3rd, Raetz EA, Sato Y, Kudoh S, Tanaka K, Setoyama M, Nagamura F, Borowitz MJ, Wood BL, Angiolillo AL, Burke MJ, Salzer WL, Asano S, Kamada N. Fusion of ETV6 to neurotrophin-3 Zweidler-McKay PA, Rabin KR, Carroll WL, Zhang J, Loh receptor TRKC in acute myeloid leukemia with ML, Mullighan CG, Willman CL, Gastier-Foster JM, Hunger t(12;15)(p13;q25) Blood 1999 Feb 15;93(4):1355-63 SP. Targetable kinase gene fusions in high-risk B-ALL: a Forghieri F, Morselli M, Potenza L, Maccaferri M, Pedrazzi study from the Children's Oncology Group Blood 2017 Jun L, Paolini A, Bonacorsi G, Artusi T, Giacobbi F, Corradini G, 22;129(25):3352-3361 Barozzi P, Zucchini P, Marasca R, Narni F, Crescenzi B, Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, Mecucci C, Falini B, Torelli G, Luppi M. Chronic eosinophilic Pei D, McCastlain K, Ding L, Lu C, Song G, Ma J, Becksfort leukaemia with ETV6-NTRK3 fusion transcript in an elderly J, Rusch M, Chen SC, Easton J, Cheng J, Boggs K, patient affected with pancreatic carcinoma Eur J Haematol Santiago-Morales N, Iacobucci I, Fulton RS, Wen J, 2011 Apr;86(4):352-5 Valentine M, Cheng C, Paugh SW, Devidas M, Chen IM, Gu Z, Churchman M, Roberts K, Li Y, Liu Y, Harvey RC, Reshmi S, Smith A, Hedlund E, Gupta P, Nagahawatte P, McCastlain K, Reshmi SC, Payne-Turner D, Iacobucci I, Wu G, Chen X, Yergeau D, Vadodaria B, Mulder H, Winick Shao Y, Chen IM, Valentine M, Pei D, Mungall KL, Mungall NJ, Larsen EC, Carroll WL, Heerema NA, Carroll AJ, AJ, Ma Y, Moore R, Marra M, Stonerock E, Gastier-Foster Grayson G, Tasian SK, Moore AS, Keller F, Frei-Jones M, JM, Devidas M, Dai Y, Wood B, Borowitz M, Larsen EE, Whitlock JA, Raetz EA, White DL, Hughes TP, Guidry Auvil Maloney K, Mattano LA Jr, Angiolillo A, Salzer WL, Burke JM, Smith MA, Marcucci G, Bloomfield CD, Mrózek K, MJ, Gianni F, Spinelli O, Radich JP, Minden MD, Moorman Kohlschmidt J, Stock W, Kornblau SM, Konopleva M, AV, Patel B, Fielding AK, Rowe JM, Luger SM, Bhatia R, Paietta E, Pui CH, Jeha S, Relling MV, Evans WE, Gerhard Aldoss I, Forman SJ, Kohlschmidt J, Mrózek K, Marcucci G, DS, Gastier-Foster JM, Mardis E, Wilson RK, Loh ML, Bloomfield CD, Stock W, Kornblau S, Kantarjian HM, Downing JR, Hunger SP, Willman CL, Zhang J, Mullighan Konopleva M, Paietta E, Willman CL, Loh ML, Hunger SP, CG. Targetable kinase-activating lesions in Ph-like acute
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 348
t(12;15)(p13;q25) ETV6/NTRK3 in Hematological Huret JL malignancies
lymphoblastic leukemia N Engl J Med 2014 Sep transformation: report of 3 cases with the ETV6-NTRK3 11;371(11):1005-15 gene fusion and analysis of TP53, β-catenin, EGFR, and CCND1 genes Am J Surg Pathol 2014 Jan;38(1):23-33 Rubin BP, Chen CJ, Morgan TW, Xiao S, Grier HE, Kozakewich HP, Perez-Atayde AR, Fletcher JA. Congenital Tognon C, Knezevich SR, Huntsman D, Roskelley CD, mesoblastic nephroma t(12;15) is associated with ETV6- Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson NTRK3 gene fusion: cytogenetic and molecular relationship N, Horsman D, Poremba C, Sorensen PH. Expression of the to congenital (infantile) fibrosarcoma Am J Pathol 1998 ETV6-NTRK3 gene fusion as a primary event in human Nov;153(5):1451-8 secretory breast carcinoma Cancer Cell 2002 Nov;2(5):367-76 Seshagiri S, Stawiski EW, Durinck S, Modrusan Z, Storm EE, Conboy CB, Chaudhuri S, Guan Y, Janakiraman V, Watanabe N, Kobayashi H, Hirama T, Kikuta A, Koizumi S, Jaiswal BS, Guillory J, Ha C, Dijkgraaf GJ, Stinson J, Gnad Tsuru T, Kaneko Y. Cryptic t(12;15)(p13;q26) producing the F, Huntley MA, Degenhardt JD, Haverty PM, Bourgon R, ETV6-NTRK3 fusion gene and no loss of IGF2 imprinting in Wang W, Koeppen H, Gentleman R, Starr TK, Zhang Z, congenital mesoblastic nephroma with trisomy 11: Largaespada DA, Wu TD, de Sauvage FJ. Recurrent R- fluorescence in situ hybridization and IGF2 allelic spondin fusions in colon cancer Nature 2012 Aug expression analysis Cancer Genet Cytogenet 2002 Jul 30;488(7413):660-4 1;136(1):10-6 Sheng WQ, Hisaoka M, Okamoto S, Tanaka A, Meis- Yeh I, Tee MK, Botton T, Shain AH, Sparatta AJ, Gagnon Kindblom JM, Kindblom LG, Ishida T, Nojima T, Hashimoto A, Vemula SS, Garrido MC, Nakamaru K, Isoyama T, H. Congenital-infantile fibrosarcoma A clinicopathologic McCalmont TH, LeBoit PE, Bastian BC. NTRK3 kinase study of 10 cases and molecular detection of the ETV6- fusions in Spitz tumours J Pathol 2016 Nov;240(3):282-290 NTRK3 fusion transcripts using paraffin-embedded tissues Am J Clin Pathol This article should be referenced as such: Skálová A, Vanecek T, Majewska H, Laco J, Grossmann P, Huret JL. t(12;15)(p13;q25) ETV6/NTRK3 in Simpson RH, Hauer L, Andrle P, Hosticka L, Branžovský J, Hematological malignancies. Atlas Genet Cytogenet Michal M. Mammary analogue secretory carcinoma of Oncol Haematol. 2020; 24(9):347-349. salivary glands with high-grade
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 349 Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Leukaemia Section Short Communication t(12;15)(p13;q25) ETV6/NTRK3 in solid tumors Jean Loup Huret [email protected] Published in Atlas Database: November 2019 Online updated version : http://AtlasGeneticsOncology.org/Tumors/t1215p13q25ID5267.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70786/11-2019-t1215p13q25ID5267.pdf DOI: 10.4267/2042/70786
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
malignant spindle cell tumor of the soft tissues that Abstract usually presents before the age of 2 years (diagnosed at birth in 40%, before 6 months in 60% of cases, Review on t(12;15)(p13;q25) in solid tumors, with more common in boys than in girls), occurring 1) data on clinics, and the genes involved. most often in the extremities and with a good Keywords prognosis, at times 2) in the axial skeleton with a Chromosome 12; Chromosome 15; ETV6; NTRK3; somewhat worse prognosis. Chronic eosinophilic leukemia; Acute myeloid Local recurrence is common (10 to 30 % of cases) leukemia; B-Lineage Acute lymphoblastic leukemia; but metastases are rare. Overall 5-year survival is at Secretory ductal breast carcinoma; Congenital least 90% (Farmakis et al., 2014). CIF accounts for mesoblastic nephroma; Congenital/infantile 10% of soft tissue tumors in infants. fibrosarcoma; Papillary thyroid carcinoma; Cytogenetics Inflammatory myofibroblastic sarcoma; Secretory carcinoma of salivary glands (mammary analogue); A t(12;15)(p13;q25) ETV6/NTRK3 was found in atypical Spitz tumors. most cases, but is not found in either infantile fibromatosis, a close but benign entity, or in Clinics and pathology fibrosarcoma of the adulthood. The t(12;15) ETV6/NTRK3 is most often A t(12;15)(p13;q25) ETV6/NTRK3 has been found: accompanied with trisomy or tetrasomy 11 1) in congenital/infantile fibrosarcoma and cellular (Knezevich et al., 1998; Rubin et al., 1998; mesoblastic nephroma (which may be a renal form Bourgeois et al., 2000; Punnett et al., 2000; Argani of infantile fibrosarcoma), 2) in secretory breast et al., 2001; Dubus et al., 2001; Sheng et al., 2001; (ductal) carcinoma and in it's analogue in the salivary Miura et al., 2002; McCahon et al., 2003; Ramphal glands, 3) in acute leukemias (both myeloid and et al., 2003; Morerio et al., 2004; Nonaka and Sun, lymphoid), 4) in papillary thyroid carcinoma, often 2004; Himori et al., 2005; Rizkalla et al., 2011). radiation-associated, 5) in inflammatory The reciprocal NTRK3/ETV6 fusion product may myofibroblastic tumor, and, in few cases, in other also be found, with NTRK3 exon 14 fused to ETV6 tumors. exon 6 (Dubus et al., 2001). Equivalents of the ETV6/NTRK3 fusion was also A t(2;15)(p21;q24) EML4/NTRK3 has also been found in rare instances in the above mentioned found in two cases of CIF. tumors: EML4 /NTRK3, MYH9 /NTRK3, MYO5A One was a 9-mo-old male patient with recurrent /NTRK3, LMNA / NTRK1, and ETV6/? congenital fibrosarcoma and a history of left upper Disease extremity hemimelia without other congenital anomalies. Congenital/infantile fibrosarcoma Exon 2 of EML4 was fused to exon 14 of NTRK3 (WHO/OMS 8814/3) (CIF) (Tannenbaum-Dvir et al., 2015; Church et al., 2018). Congenital/infantile fibrosarcoma is a low-grade
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 350 t(12;15)(p13;q25) ETV6/NTRK3 in solid tumors Huret JL
A congenital infantile fibrosarcoma was found to patients. Breast secretory carcinoma is a slow- harbor a LMNA/NTRK1 gene fusion (Wong et al., growing, low-grade subtype of infiltrating ductal 2015). carcinoma. Disease The disease seems slightly more aggressive in adults (Vasudev and Onuma 2011; Ghilli et al., 2018). Congenital Mesoblastic Nephroma (WHO/OMS 8960/1) (CMN) Cytogenetics Congenital mesoblastic nephroma is the most A t(12;15)(p13;q25) ETV6/NTRK3 was found in common kidney tumor found in infants younger than most cases (Tognon et al., 2002; Diallo et al., 2003; 6 months and and accounts for 3-5% of all paediatric Stransky et al 2014). renal neoplasm. The 5-year event-free survival rate Genes is 95%. Histopathologically, it consist of spindled cells. ETV6/NTRK3 chimeric product can transform There are three histologic subtypes: classic, mixed, normal mouse mammary epithelial cells. and cellular. The cellular subtype is identical to Fusion was between ETV6 nucleotide 1033 and infantile fibrosarcoma and is the form with a t(12;15) NTRK3 nucleotide 1601 as previously shown for ETV6/NTRK3 and trisomy 11 (PDQ Pediatric sarcoma-associated fusions (Knezevich et al., 1998). Treatment Editorial Board, 2019). Cellular This differs from the ETV6/NTRK3 gene fusion mesoblastic nephroma tends to present later in infanc reported in a case of acute myeloid leukemia, in than the classic formy, and can exhibit aggressive which ETV6 exon 5 was not present in the fusion behavior including metastases (Bayindir et al., (Eguchi et al., 1999). 2009). It has been suggested that the cellular subtype The rare secretory breast carcinomas with represents in fact congenital infantile fibrosarcoma metastases, more aggressive tumors, showed occurring in the kidney (Bayindir et al., 2009; El amplification of the 16p13.3 locus, a TERT Demellawy et al., 2016). promotor mutation and loss of 9p21.3 locus (Hoda et A t(12;15) ETV6/NTRK3, most often accompanied al., 2019). with trisomy or tetrasomy 11, or a fusion Disease ETV6/NTRK3 has been found in more than 40 cases; some cases were mixed forms; none was Mammary analogue secretory carcinoma of classical form (Rubin et al., 1998; Knezevich et al., salivary glands (MASC) 1998; Argani et al., 2000; Ramachandran et al., A t(12;15)(p13;q25) ETV6/NTRK3 was found in 2001; Watanabe et al., 2002; Henno et al., 2003; salivary gland tumors (mostly from the parotid Anderson et al., 2006; Bayindir et al., 2009). gland) with histo-morphologic and immune- histochemical features reminiscent of secretory Cytogenetics carcinoma of the breast, with eosinophilic secretion, Although the t(12;15)(p13;q25) ETV6/NTRK3 was positivity for PAS, S-100 protein and mammaglobin found in most cases , a t(2;15)(p21;q24) (Skálová et al., 2010; Chiosea et al., 2012; Connor et EML4/NTRK3 has also been found in one case of al., 2012; Skálová et al., 2014; Pinto et al., 2014). CMN (Church et al., 2018). More than 250 cases have been described (review in Disease Skálová et al., 2017). Mean age was 47 years (14-78 years), there is a slight male predominance. MASC Breast Ductal carcinoma - Secretory breast mimick other salivary tumors, most often carcinoma subtype (WHO/OMS 8502/3) adenocarcinoma, not otherwise specified and acinic (SBC) cell carcinomas. Secretory breast carcinoma is a rare (less than 0.15% MASC usually behaves indolently, but like other of all breast cancers) subtype of breast ductal low-grade salivary gland carcinomas, there is some carcinoma (but the most common breast cancer in loco-regional recurrence and distant metastases the pediatric population), with a distinct (Skálová et al., 2017). morphology: eosinophilic secretion and positive periodic acid-Schiff (PAS) secretions are seen, Cytogenetics immune-positivity for S100 and mammaglobin, A t(12;15)(p13;q25) ETV6/NTRK3 was found in most often triple negativity (ESR1/2-, PGR-, most cases. ERBB2-)) and an excellent prognosis in children and A few cases where ETV6 was fused with an adolescents. It occurs in both children and adults unknown partner different from NTRK3 were with a wide age range from 3 to 83 years. Most described; these may behave more aggressively (Ito reported cases are in young women, with a median et al., 2015; Skálová et al., 2016). age of 25 years. There are only 120 cases published in literature, including 32 in male
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 351 t(12;15)(p13;q25) ETV6/NTRK3 in solid tumors Huret JL
Disease sequencing studies from the TCGA (Stransky et al 2014). Thyroid: Papillary thyroid carcinoma A secretory carcinoma of the skin mimicking (WHO/OMS 8260/3) (PTC) secretory carcinoma of the breast and the and In an analysis of 62 radiation-associated papillary secretory carcinoma salivary gland was found to thyroid carcinomas post-Chernobyl (iodine-131 harbor an ETV6/NTRK3 fusion gene (Huang et al., exposure), 9 (14.5%) of PTCs harbored 2016) ETV6/NTRK3 rearrangement; ETV6/NTRK3 fusion was the second most common rearrangement Cytogenetics type after "RET/PTC". Further screening of 151 Other cases presented with the following sporadic PTCs revealed three positive cases, translocations/genes fusions: MYH9/NTRK3 and resulting in a prevalence of 2%. The majority of MYO5A/NTRK3. In all those cases, NTRK3 fusions post-radiation-associated PTCs with ETV6/NTRK3 constitutively activated the RAS/RAF/MAPK, rearrangement were classified as the follicular PI3K/AKT/MTOR and PLCG pathways in variant of PTC (Leeman-Neill et al 2014). In a study melanocytes (Yeh et al., 2016). of 496 papillary thyroid carcinoma without radiation Disease exposure, and classified as low risk, 5 cases (three "classical", one "follicular") presented with an Brain tumors (WHO/OMS 9425/3 9401/3) ETV6/NTRK3 rearrangement. Ages and sex: were: Note 41/F, 36/F, 23/F, 17/F) (The Cancer Genome 2014). In a series of 149 pediatric low-grade gliomas, an Another genome sequencing study from "The ETV6/NTRK3 fusion was found in a 13-year-old Cancer Genome Atlas" (TCGA) found 6 such cases girl with a pilomyxoid astrocytoma (Zhang et al (Stransky et al 2014). 2013). Disease An ETV6/NTRK3 fusion was also found in a high grade astrocytoma (massive data from genome Inflammatory myofibroblastic sequencing) (Wu et al 2014). tumor/myofibroblastic sarcoma (WHO/OMS 8825/1) (IMT) Cytogenetics Inflammatory myofibroblastic tumor is a rare The reciprocal NTRK3/ETV6 fusion product was visceral and soft tissue tumor (commonly seen in the also found (Zhang et al 2013). lung), consisting of myofibroblastic spindle cells Disease with inflammatory cells. Local recurrences are seen in about 25% of patient, but metastases are rare. It Colon adenocarcinoma (WHO/OMS 8140/3) affects primarily children and young adults, with a At least 4 cases of colorectal carcinoma were found slight male predominance. Favorable outcome is to have an ETV6/NTRK3 fusion, in massive data documented in most cases. from genome sequencing studies from the TCGA An ETV6/NTRK3 fusion was found in at least 6 (Seshagiri et al 2012; Stransky et al 2014; Hu et al cases of .inflammatory myofibroblastic tumor: in a 2018). 17-year-old girl and in 2 other cases in a subset of Disease ALK-negative inflammatory myofibroblastic tumors, in a 7-year old child and in a 23-year-old Sinonasal adenocarcinoma adult patient, and in a 44-year-old female patient Two cases of low grade sinonasal adenocarcinoma (Alassiri et al 2016; Yamamoto et al 2016; were found to have the t(12;15)(p13;q25) Takahashi et al 2018). ETV6/NTRK3 (Andreasen et al 2017). Disease Cytogenetics Skin melanocytic tumors (WHO/OMS Another case presented with ETV6 fused to an unknown partner (Andreasen et al 2017). 8770/1 and 8720/3) and other skin carcinomas Genes involved and Note A t(12;15)(p13;q25) ETV6/NTRK3 was found in 4 proteins cases of atypical Spitz tumors (Yeh et al., 2016), a ETV6 (ets variant 6) group of cutaneous melanocytic tumors (Murali et al., 2012 Location 12p13.2 http://atlasgeneticsoncology.org/Tumors/SpitzTum Protein orID6241.html). Ages and sex were: 2/F, 6/F, 7/M, ETV6 is a strong transcriptional repressor. ETV6 is and 10/F (Yeh et al., 2016). a 452 amino acid member of the ETS family (signal- An ETV6/NTRK3 fusion was also detected in a skin dependent transcriptional regulators, mediating cell melanoma in massive data sets from genome proliferation, differentiation and tumorigenesis). The
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 352
t(12;15)(p13;q25) ETV6/NTRK3 in solid tumors Huret JL
ETV6 protein contains two major domains, the HLH The fusion was exon 5 - exon 15 in: secretory ductal (helix-loop-helix) and ETS domains. The N-term breast carcinoma (Tognon et al., 2002), congenital HLH domain, also referred to as the pointed or sterile mesoblastic nephroma (Knezevich et al., 1998; alpha motif domain, is responsible for hetero- and Rubin et al., 1998; Argani et al., 2000; homo-dimerization. The C-term ETS domain is Ramachandran et al., 2001; Watanabe et al., 2002; responsible for sequence specific DNA-binding and Henno et al., 2003; Anderson et al., 2006; Bayindir protein-protein interaction. A central domain, called et al., 2009), secretory carcinoma of salivary glands internal domain, is involved in the recruitment of a (mammary analogue) (Skálová et al., 2010; Skálová repression complex including NCOR1, NCOR2, and et al., 2014), atypical Spitz tumors (Yeh et al., 2016), SIN3A (Braekeleer et al., 2014 and also in a case of colon adenocarcinoma http://atlasgeneticsoncology.org//Genes/ETV6ID38. (Seshagiri et al., 2012). The classical exon 5 - exon html). 15 fusion is also found in congenital/infantile NTRK3 (neurotrophic tyrosine fibrosarcoma (Knezevich et al., 1998; Rubin et al., 1998; Bourgeois et al., 2000; Punnett et al., 2000; kinase, receptor, type 3) Argani et al., 2001; Dubus et al., 2001; Sheng et al., Location 15q25.3 2001; Miura et al., 2002; McCahon et al., 2003; Protein Ramphal et al., 2003; Nonaka and Sun, 2004; NTRK3 is a transmembrane receptor tyrosine kinase Himori et al., 2005), but, also, a fusion NTRK3 exon which triggers PI3K/AKT, RAS/RAF/MAPK, and 14 - ETV6 exon 6 was found in one case (Dubus et PLCG pathways. NTRK3 is a 839 amino acid al., 2001). protein with a N-term extra-cellular ligand binding In most leukemia cases, ETV6 exon 5 was fused to domain, a transmembrane domain, and a C-term NTRK3 exon 15 (Forghieri et al., 2011; Roberts et intracellular tyrosine kinase domain. Ligand for al., 2014). In one case ETV6 exon 4 was fused to NTRK3 is NTF3 (neurotrophin 3) (Knezevich 2004 NTRK3 exon 15 (Eguchi: et al., 1999), and in http://atlasgeneticsoncology.org/Genes/NTRK3ID4 another case, fusion transcripts contain ETV6 exons 33.html). 1 through 5 fused to NTRK3 exons 13b and 14b or NTRK3 exons 13 through 18 (Kralik et al., 2011). Result of the chromosomal Fusion Protein anomaly Description The SAM-PNT (sterile alpha motif- pointed) domain Hybrid Gene of ETV6 is fused to the PTK (Protein Tyrosine Description Kinase domain) of NTRK3. In solid tumors, ETV6 exon 5 - NTRK3 exon 15 Oncogenesis fusion is the most frequent: It leads to dimerization, and induction of CCND1 The fusion was exon 4 - exon 14 in most papillary (cyclin D1) and increased cell cycle progression. thyroid carcinoma ceases, but one exon 5 - exon 14 ETV6/NTRK3 also leads to constitutive activation fusion case was also found (Leeman-Neill et al., of the PI3K/AKT, RAS/RAF/MAPK, and PLCG pathways (Lannon and Sorensen, 2005). 2014)
To be noted
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 353 t(12;15)(p13;q25) ETV6/NTRK3 in solid tumors Huret JL
Therapeutic trials with TRK-(tropomyosin receptor than TrkC immunoreactivity for the diagnosis of congenital kinase) inhibitors are being developed with some fibrosarcoma J Pathol 2001 Jan;193(1):88-94 remarkable successes (Lange and Lo, 2018). Eguchi M, Eguchi-Ishimae M, Tojo A, Morishita K, Suzuki K, Sato Y, Kudoh S, Tanaka K, Setoyama M, Nagamura F, Asano S, Kamada N. Fusion of ETV6 to neurotrophin-3 References receptor TRKC in acute myeloid leukemia with Alassiri AH, Ali RH, Shen Y, Lum A, Strahlendorf C, Deyell t(12;15)(p13;q25) Blood 1999 Feb 15;93(4):1355-63 R, Rassekh R, Sorensen PH, Laskin J, Marra M, Yip S, Lee El Demellawy D, Cundiff CA, Nasr A, Ozolek JA, Elawabdeh CH, Ng TL. ETV6-NTRK3 Is Expressed in a Subset of ALK- N, Caltharp SA, Masoudian P, Sullivan KJ, de Nanassy J, Negative Inflammatory Myofibroblastic Tumors. Am J Surg Shehata BM. Congenital mesoblastic nephroma: a study of Pathol. 2016 Aug;40(8):1051-61 19 cases using immunohistochemistry and ETV6-NTRK3 Anderson J, Gibson S, Sebire NJ. Expression of ETV6- fusion gene rearrangement Pathology 2016 Jan;48(1):47- NTRK in classical, cellular and mixed subtypes of congenital 50 mesoblastic nephroma. Histopathology. 2006 Farmakis SG, Herman TE, Siegel MJ. Congenital infantile May;48(6):748-53 fibrosarcoma J Perinatol 2014 Apr;34(4):329-30 Andreasen S, Skálová A, Agaimy A, Bishop JA, Laco J, Forghieri F, Morselli M, Potenza L, Maccaferri M, Pedrazzi Leivo I, Franchi A, Larsen SR, Erentaite D, Ulhøi BP, von L, Paolini A, Bonacorsi G, Artusi T, Giacobbi F, Corradini G, Buchwald C, Melchior LC, Michal M, Kiss K. ETV6 Gene Barozzi P, Zucchini P, Marasca R, Narni F, Crescenzi B, Rearrangements Characterize a Morphologically Distinct Mecucci C, Falini B, Torelli G, Luppi M. Chronic eosinophilic Subset of Sinonasal Low-grade Non-intestinal-type leukaemia with ETV6-NTRK3 fusion transcript in an elderly Adenocarcinoma: A Novel Translocation-associated patient affected with pancreatic carcinoma Eur J Haematol Carcinoma Restricted to the Sinonasal Tract. Am J Surg 2011 Apr;86(4):352-5 Pathol. 2017 Nov;41(11):1552-1560 Ghilli M, Mariniello MD, Scatena C, Dosa L, Traficante G, Argani P, Fritsch MK, Shuster AE, Perlman EJ, Coffin CM. Tamburini A, Caporalini C, Buccoliero AM, Facchini F, Reduced sensitivity of paraffin-based RT-PCR assays for Colizzi L, Quattrini Li A, Landucci E, Manca G, Naccarato ETV6-NTRK3 fusion transcripts in morphologically defined AG, Caramella D, Favre C, Roncella M. Male secretory infantile fibrosarcoma Am J Surg Pathol 2001 breast cancer: case in a 6-year-old boy with a peculiar gene Nov;25(11):1461-4 duplication and review of the literature Breast Cancer Res Bayindir P, Guillerman RP, Hicks MJ, Chintagumpala MM. Treat 2018 Aug;170(3):445-454 Cellular mesoblastic nephroma (infantile renal Gu Z, Churchman M, Roberts K, Li Y, Liu Y, Harvey RC, fibrosarcoma): institutional review of the clinical, diagnostic McCastlain K, Reshmi SC, Payne-Turner D, Iacobucci I, imaging, and pathologic features of a distinctive neoplasm Shao Y, Chen IM, Valentine M, Pei D, Mungall KL, Mungall of infancy Pediatr Radiol 2009 Oct;39(10):1066-74 AJ, Ma Y, Moore R, Marra M, Stonerock E, Gastier-Foster Bourgeois JM, Knezevich SR, Mathers JA, Sorensen PH. JM, Devidas M, Dai Y, Wood B, Borowitz M, Larsen EE, Molecular detection of the ETV6-NTRK3 gene fusion Maloney K, Mattano LA Jr, Angiolillo A, Salzer WL, Burke differentiates congenital fibrosarcoma from other childhood MJ, Gianni F, Spinelli O, Radich JP, Minden MD, Moorman spindle cell tumors Am J Surg Pathol 2000 Jul;24(7):937- AV, Patel B, Fielding AK, Rowe JM, Luger SM, Bhatia R, 46 Aldoss I, Forman SJ, Kohlschmidt J, Mrózek K, Marcucci G, Bloomfield CD, Stock W, Kornblau S, Kantarjian HM, Cancer Genome Atlas Research Network. Integrated Konopleva M, Paietta E, Willman CL, Loh ML, Hunger SP, genomic characterization of papillary thyroid carcinoma Cell Mullighan CG. Genomic analyses identify recurrent MEF2D 2014 Oct 23;159(3):676-90 fusions in acute lymphoblastic leukaemia Nat Commun 2016 Nov 8;7:13331 Chiosea SI, Griffith C, Assaad A, Seethala RR. Clinicopathological characterization of mammary analogue Henno S, Loeuillet L, Henry C, D'Hervé D, Azzis O, Ferrer secretory carcinoma of salivary glands Histopathology 2012 J, Poulain P, Babut JM, Merlio JP, Jouan H, Dubus P. Sep;61(3):387-94 Cellular mesoblastic nephroma: morphologic, cytogenetic and molecular links with congenital fibrosarcoma Pathol Church AJ, Calicchio ML, Nardi V, Skalova A, Pinto A, Dillon Res Pract 2003;199(1):35-40 DA, Gomez-Fernandez CR, Manoj N, Haimes JD, Stahl JA, Dela Cruz FS, Tannenbaum-Dvir S, Glade-Bender JL, Kung Himori K, Hatori M, Watanabe M, Moriya T, Ogose A, AL, DuBois SG, Kozakewich HP, Janeway KA, Perez- Hashimoto H, Kokubun S. Infantile fibrosarcoma of thigh--a Atayde AR, Harris MH. Recurrent EML4-NTRK3 fusions in case report Ups J Med Sci 2005;110(1):85-93 infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy Mod Pathol Hoda RS, Brogi E, Pareja F, Nanjangud G, Murray MP, 2018 Mar;31(3):463-473 Weigelt B, Reis-Filho JS, Wen HY. Secretory carcinoma of the breast: clinicopathologic profile of 14 cases Connor A, Perez-Ordoñez B, Shago M, Skálová A, Weinreb emphasising distant metastatic potential Histopathology I. Mammary analog secretory carcinoma of salivary gland 2019 Aug;75(2):213-224 origin with the ETV6 gene rearrangement by FISH: expanded morphologic and immunohistochemical spectrum Hu X, Wang Q, Tang M, Barthel F, Amin S, Yoshihara K, of a recently described entity Am J Surg Pathol 2012 Lang FM, Martinez-Ledesma E, Lee SH, Zheng S, Verhaak Jan;36(1):27-34 RGW. TumorFusions: an integrative resource for cancer- associated transcript fusions Nucleic Acids Res 2018 Jan Diallo R, Tognon C, Knezevich SR, Sorensen P, Poremba 4;46(D1):D1144-D1149 C. Secretory carcinoma of the breast: a genetically defined carcinoma entity Verh Dtsch Ges Pathol 2003;87:193-203 Huang S, Liu Y, Su J, Liu J, Guo X, Mei F, Zheng J, Liao Dubus P, Coindre JM, Groppi A, Jouan H, Ferrer J, Cohen S. "Secretory" Carcinoma of the Skin Mimicking Secretory C, Rivel J, Copin MC, Leroy JP, de Muret A, Merlio JP. The Carcinoma of the Breast: Case Report and Literature detection of Tel-TrkC chimeric transcripts is more specific Review Am J Dermatopathol 2016 Sep;38(9):698-703
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 354 t(12;15)(p13;q25) ETV6/NTRK3 in solid tumors Huret JL
Ito Y, Ishibashi K, Masaki A, Fujii K, Fujiyoshi Y, Hattori H, Reshmi SC, Harvey RC, Roberts KG, Stonerock E, Smith Kawakita D, Matsumoto M, Miyabe S, Shimozato K, Nagao A, Jenkins H, Chen IM, Valentine M, Liu Y, Li Y, Shao Y, T, Inagaki H. Mammary analogue secretory carcinoma of Easton J, Payne-Turner D, Gu Z, Tran TH, Nguyen JV, salivary glands: a clinicopathologic and molecular study Devidas M, Dai Y, Heerema NA, Carroll AJ 3rd, Raetz EA, including 2 cases harboring ETV6-X fusion Am J Surg Borowitz MJ, Wood BL, Angiolillo AL, Burke MJ, Salzer WL, Pathol 2015 May;39(5):602-10 Zweidler-McKay PA, Rabin KR, Carroll WL, Zhang J, Loh ML, Mullighan CG, Willman CL, Gastier-Foster JM, Hunger Knezevich SR, Garnett MJ, Pysher TJ, Beckwith JB, Grundy SP. Targetable kinase gene fusions in high-risk B-ALL: a PE, Sorensen PH. ETV6-NTRK3 gene fusions and trisomy study from the Children's Oncology Group Blood 2017 Jun 11 establish a histogenetic link between mesoblastic 22;129(25):3352-3361 nephroma and congenital fibrosarcoma Cancer Res 1998 Nov 15;58(22):5046-8 Rizkalla H, Wildgrove H, Quinn F, Capra M, O'Sullivan MJ. Congenital fibrosarcoma of the ileum: case report with Kralik JM, Kranewitter W, Boesmueller H, Marschon R, molecular confirmation and literature review Fetal Pediatr Tschurtschenthaler G, Rumpold H, Wiesinger K, Erdel M, Pathol 2011;30(3):156-60 Petzer AL, Webersinke G. Characterization of a newly identified ETV6-NTRK3 fusion transcript in acute myeloid Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, leukemia Diagn Pathol 2011 Mar 15;6:19 Pei D, McCastlain K, Ding L, Lu C, Song G, Ma J, Becksfort J, Rusch M, Chen SC, Easton J, Cheng J, Boggs K, Lange AM, Lo HW. Inhibiting TRK Proteins in Clinical Santiago-Morales N, Iacobucci I, Fulton RS, Wen J, Cancer Therapy Cancers (Basel) 2018 Apr 4;10(4) Valentine M, Cheng C, Paugh SW, Devidas M, Chen IM, Lannon CL, Sorensen PH. ETV6-NTRK3: a chimeric protein Reshmi S, Smith A, Hedlund E, Gupta P, Nagahawatte P, tyrosine kinase with transformation activity in multiple cell Wu G, Chen X, Yergeau D, Vadodaria B, Mulder H, Winick lineages Semin Cancer Biol 2005 Jun;15(3):215-2 NJ, Larsen EC, Carroll WL, Heerema NA, Carroll AJ, Grayson G, Tasian SK, Moore AS, Keller F, Frei-Jones M, Leeman-Neill RJ, Kelly LM, Liu P, Brenner AV, Little MP, Whitlock JA, Raetz EA, White DL, Hughes TP, Guidry Auvil Bogdanova TI, Evdokimova VN, Hatch M, Zurnadzy LY, JM, Smith MA, Marcucci G, Bloomfield CD, Mrózek K, Nikiforova MN, Yue NJ, Zhang M, Mabuchi K, Tronko MD, Kohlschmidt J, Stock W, Kornblau SM, Konopleva M, Nikiforov YE. ETV6-NTRK3 is a common chromosomal Paietta E, Pui CH, Jeha S, Relling MV, Evans WE, Gerhard rearrangement in radiation-associated thyroid cancer DS, Gastier-Foster JM, Mardis E, Wilson RK, Loh ML, Cancer 2014 Mar 15;120(6):799-807 Downing JR, Hunger SP, Willman CL, Zhang J, Mullighan CG. Targetable kinase-activating lesions in Ph-like acute McCahon E, Sorensen PH, Davis JH, Rogers PC, Schultz lymphoblastic leukemia N Engl J Med 2014 Sep KR. Non-resectable congenital tumors with the ETV6- 11;371(11):1005-15 NTRK3 gene fusion are highly responsive to chemotherapy Med Pediatr Oncol 2003 May;40(5):288-92 Rubin BP, Chen CJ, Morgan TW, Xiao S, Grier HE, Kozakewich HP, Perez-Atayde AR, Fletcher JA. Congenital Miura K, Han G, Sano M, Tsutsui Y. Regression of mesoblastic nephroma t(12;15) is associated with ETV6- congenital fibrosarcoma to hemangiomatous remnant with NTRK3 gene fusion: cytogenetic and molecular relationship histological and genetic findings Pathol Int 2002 to congenital (infantile) fibrosarcoma Am J Pathol 1998 Sep;52(9):612-8 Nov;153(5):1451-8 Morerio C, Rapella A, Rosanda C, Tassano E, Conte M, Seshagiri S, Stawiski EW, Durinck S, Modrusan Z, Storm Gambini C, Panarello C. Differential diagnosis of congenital EE, Conboy CB, Chaudhuri S, Guan Y, Janakiraman V, fibrosarcoma Cancer Genet Cytogenet 2004 Jul Jaiswal BS, Guillory J, Ha C, Dijkgraaf GJ, Stinson J, Gnad 15;152(2):167-8 F, Huntley MA, Degenhardt JD, Haverty PM, Bourgon R, Nonaka D, Sun CC. Congenital fibrosacoma with Wang W, Koeppen H, Gentleman R, Starr TK, Zhang Z, metastasis in a fetus Pediatr Dev Pathol 2004 Mar- Largaespada DA, Wu TD, de Sauvage FJ. Recurrent R- Apr;7(2):187-91 spondin fusions in colon cancer Nature 2012 Aug 30;488(7413):660-4 PDQ Pediatric Treatment Editorial Board. Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ): Health Sheng WQ, Hisaoka M, Okamoto S, Tanaka A, Meis- Professional Version 2020 Jan 9 PDQ Cancer Information Kindblom JM, Kindblom LG, Ishida T, Nojima T, Hashimoto Summaries [Internet] H. Congenital-infantile fibrosarcoma A clinicopathologic study of 10 cases and molecular detection of the ETV6- Pinto A, Nosé V, Rojas C, Fan YS, Gomez-Fernandez C. NTRK3 fusion transcripts using paraffin-embedded tissues Searching for mammary analogue [corrected] secretory Am J Clin Pathol carcinoma of salivary gland among its mimics Mod Pathol 2014 Jan;27(1):30-7 Skálová A, Vanecek T, Simpson RH, Laco J, Majewska H, Baneckova M, Steiner P, Michal M. Mammary Analogue Punnett HH, Tomczak EZ, Pawel BR, de Chadarevian JP, Secretory Carcinoma of Salivary Glands: Molecular Sorensen PH. ETV6-NTRK3 gene fusion in metastasizing Analysis of 25 ETV6 Gene Rearranged Tumors With Lack congenital fibrosarcoma Med Pediatr Oncol 2000 of Detection of Classical ETV6-NTRK3 Fusion Transcript by Aug;35(2):137-9 Standard RT-PCR: Report of 4 Cases Harboring ETV6-X Gene Fusion Am J Surg Pathol 2016 Jan;40(1):3-13 Ramachandran C, Melnick SJ, Escalon E, Khatib Z, Jhabvala P, Fonseca HB, Smith S, Alamo A, Medina S. Skalova A, Michal M, Simpson RH. Newly described Cytogenetic and molecular characterization of a congenital salivary gland tumors Mod Pathol 2017 Jan;30(s1):S27-S43 mesoblastic nephroma Pediatr Dev Pathol 2001 Jul- Aug;4(4):402-11 Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer Nat Commun 2014 Ramphal R, Manson D, Viero S, Zielenska M, Gerstle T, Sep 10;5:4846 Pappo A. Retroperitoneal infantile fibrosarcoma: clinical, molecular, and therapeutic aspects of an unusual tumor Takahashi A, Kurosawa M, Uemura M, Kitazawa J, Hayashi Pediatr Hematol Oncol 2003 Dec;20(8):635-42 Y. Anaplastic lymphoma kinase-negative uterine inflammatory myofibroblastic tumor containing the ETV6-
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 355
t(12;15)(p13;q25) ETV6/NTRK3 in solid tumors Huret JL
NTRK3 fusion gene: a case report J Int Med Res 2018 Jones C, Boop FA, Broniscer A, Wetmore C, Gajjar A, Ding Aug;46(8):3498-3503 L, Mardis ER, Wilson RK, Taylor MR, Downing JR, Ellison DW, Zhang J, Baker SJ. The genomic landscape of diffuse Tognon C, Knezevich SR, Huntsman D, Roskelley CD, intrinsic pontine glioma and pediatric non-brainstem high- Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson grade glioma Nat Genet 2014 May;46(5):444-450 N, Horsman D, Poremba C, Sorensen PH. Expression of the ETV6-NTRK3 gene fusion as a primary event in human Yamamoto H, Yoshida A, Taguchi K, Kohashi K, Hatanaka secretory breast carcinoma Cancer Cell 2002 Y, Yamashita A, Mori D, Oda Y. ALK, ROS1 and NTRK3 Nov;2(5):367-76 gene rearrangements in inflammatory myofibroblastic tumours Histopathology 2016 Jul;69(1):72-83 Vasudev P, Onuma K. Secretory breast carcinoma: unique, triple-negative carcinoma with a favorable prognosis and Yeh I, Tee MK, Botton T, Shain AH, Sparatta AJ, Gagnon characteristic molecular expression Arch Pathol Lab Med A, Vemula SS, Garrido MC, Nakamaru K, Isoyama T, 2011 Dec;135(12):1606-10 McCalmont TH, LeBoit PE, Bastian BC. NTRK3 kinase fusions in Spitz tumours J Pathol 2016 Nov;240(3):282-290 Watanabe N, Kobayashi H, Hirama T, Kikuta A, Koizumi S, Tsuru T, Kaneko Y. Cryptic t(12;15)(p13;q26) producing the Zhang J, Wu G, Miller CP, Tatevossian RG, Dalton JD, ETV6-NTRK3 fusion gene and no loss of IGF2 imprinting in Tang B, Orisme W, Punchihewa C, Parker M, Qaddoumi I, congenital mesoblastic nephroma with trisomy 11: Boop FA, Lu C, Kandoth C, Ding L, Lee R, Huether R, Chen fluorescence in situ hybridization and IGF2 allelic X, Hedlund E, Nagahawatte P, Rusch M, Boggs K, Cheng expression analysis Cancer Genet Cytogenet 2002 Jul J, Becksfort J, Ma J, Song G, Li Y, Wei L, Wang J, Shurtleff 1;136(1):10-6 S, Easton J, Zhao D, Fulton RS, Fulton LL, Dooling DJ, Vadodaria B, Mulder HL, Tang C, Ochoa K, Mullighan CG, Wong V, Pavlick D, Brennan T, Yelensky R, Crawford J, Gajjar A, Kriwacki R, Sheer D, Gilbertson RJ, Mardis ER, Ross JS, Miller VA, Malicki D, Stephens PJ, Ali SM, Ahn H. Wilson RK, Downing JR, Baker SJ, Ellison DW; St. Jude Evaluation of a Congenital Infantile Fibrosarcoma by Children's Research Hospital-Washington University Comprehensive Genomic Profiling Reveals an LMNA- Pediatric Cancer Genome Project Whole-genome NTRK1 Gene Fusion Responsive to Crizotinib J Natl Cancer sequencing identifies genetic alterations in pediatric low- Inst 2015 Nov 12;108(1) grade gliomas Nat Genet Wu G, Diaz AK, Paugh BS, Rankin SL, Ju B, Li Y, Zhu X, Qu C, Chen X, Zhang J, Easton J, Edmonson M, Ma X, Lu This article should be referenced as such: C, Nagahawatte P, Hedlund E, Rusch M, Pounds S, Lin T, Huret JL. t(12;15)(p13;q25) ETV6/NTRK3 in solid Onar-Thomas A, Huether R, Kriwacki R, Parker M, Gupta tumors. Atlas Genet Cytogenet Oncol Haematol. 2020; P, Becksfort J, Wei L, Mulder HL, Boggs K, Vadodaria B, 24(9):351-356. Yergeau D, Russell JC, Ochoa K, Fulton RS, Fulton LL,
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 356
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS Instructions to Authors
Policies- Instructions to Authors See http://documents.irevues.inist.fr/bitstream/handle/2042/48486/Instructions-to-authors.pdf Manuscripts submitted to the Atlas must be submitted solely to the Atlas. The Atlas publishes "cards", "deep insights", "case reports", and "educational items". Cards are structured review articles. Detailed instructions for these structured reviews can be found at: http://AtlasGeneticsOncology.org/Forms/Gene_Form.html for reviews on genes, http://AtlasGeneticsOncology.org/Forms/Leukaemia_Form.html for reviews on leukaemias, http://AtlasGeneticsOncology.org/Forms/SolidTumour_Form.html for reviews on solid tumours, http://AtlasGeneticsOncology.org/Forms/CancerProne_Form.html for reviews on cancer-prone diseases. According to the length of the paper, cards are divided, into "reviews" (texts exceeding 2000 words), "mini reviews" (between), and "short communications" (texts below 400 words). Deep Insights are written as traditional papers, made of paragraphs with headings, at the author's convenience. Case Reports in haematological malignancies are dedicated to recurrent –but rare- chromosomes abnormalities in leukaemias/lymphomas; see http://atlasgeneticsoncology.org//BackpageAuthors.html#CASE_REPORTS . It is mandatory to use the specific "Submissionformfor Case reports": see http://AtlasGeneticsOncology.org/Reports/Case_Report_Submission.html. Educational Items must be didactic, give full information and be accompanied with iconography. Research articlesThe Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles. Authorship All authors should qualify for authorship according to the ICMJE criteria.
Editorial Ethics see http://documents.irevues.inist.fr/bitstream/handle/2042/56068/Policies-editorial-ethics.pdf for: Peer Review Process / Commissioned papers vs Unsolicited papers /Responsibility for the reviewers / Editorial responsibilities / Conflict of interest- Competing interests/ Privacy and Confidentiality - Iconography / Protection of Human Subjects and Animals in Research / Duplicate Publication/ Plagiarism / Retracting a publication
Subscription The Atlas is FREE! Costs/Page Charge There is NO page charge. PubMed Central Once the paper online, authors are encouraged to send their manuscript to PubMed Central http://www.ncbi.nlm.nih.gov/pmc/ with reference to the original paper in the Atlas in http://documents.irevues.inist.fr/handle/2042/15655
Corporate patronage, sponsorship and advertising Enquiries should be addressed to [email protected].
Rules, Copyright Notice and Disclaimer http://documents.irevues.inist.fr/bitstream/handle/2042/48487/Copyright-sponsorship.pdf Property As "cards" are to evolve with further improvements and updates from various contributors, the property of the cards belongs to the editor, and modifications will be made without authorization from the previous contributor (who may, nonetheless, be asked for refereeing); contributors are listed in an edit history manner. Authors keep the rights to use further the content of their papers published in the Atlas, provided that the source is cited. Copyright The information in the Atlas of Genetics and Cytogenetics in Oncology and Haematology is issued for general distribution. All rights are reserved. The information presented is protected under international conventions and under national laws on copyright and neighbouring rights. Commercial use is totally forbidden. Information extracted from the Atlas may be reviewed, reproduced or translated for research or private study but not for sale or for use in conjunction with commercial purposes. Any use of information from the Atlas should be accompanied by an acknowledgment of the Atlas as the source, citing the uniform resource locator (URL) of the article and/or the article reference, according to the Vancouver convention. Reference to any specific commercial products, process, or service by trade name, trademark, manufacturer, or otherwise, does not necessarily constitute or imply its endorsement, recommendation, or favouring. The views and opinions of contributors and authors expressed herein do not necessarily state or reflect those of the Atlas editorial staff or of the web site holder, and shall not be used for advertising or product endorsement purposes. The Atlas does not make any warranty, express or implied, including the warranties of merchantability and fitness for a particular purpose, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, and shall not be liable whatsoever for any damages incurred as a result of its use. In particular, information presented in the Atlas is only for research purpose, and shall not be used for diagnosis or treatment purposes. No responsibility is assumed for any injury and/or damage to persons or property for any use or operation of any methods products, instructions or ideas contained in the material herein. See also "Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication - Updated October 2004": http://www.icmje.org. http://AtlasGeneticsOncology.org © ATLAS - ISSN 1768-3262 Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS