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POLE (DNA polymerase epsilon, catalytic subunit)

Written2018-05Enric Domingo
/ e-Mail Department of Oncology, University of Oxford, Oxford, United Kingdom / enric.domingo@oncology.ox.ac.uk

Keywords POLE; DNA repair; DNA replication; DNA replicase

(Note : for Links provided by Atlas : click)

Identity

Alias_namespolymerase (DNA directed), epsilon
polymerase (DNA) epsilon, catalytic subunit
Alias_symbol (synonym)POLE1
Other alias
HGNC (Hugo) POLE
LocusID (NCBI) 5426
Atlas_Id 41773
Location 12q24.33  [Link to chromosome band 12q24]
Location_base_pair Starts at 132623762 and ends at 132687524 bp from pter ( according to hg19-Feb_2009)  [Mapping POLE.png]
Local_order 132,623,762-132,687,359
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Description POLE gene is 63.6 kb long and composed of 49 coding exons, where the first and last one also have a UTR region.
Transcription The length of the transcript is 7840 bp and results in a protein of 2286 residues.

Protein

Description The POLE gene encodes for one of the four subunits that form Polε (DNA polymerase epsilon) together with POLE2, POLE3 and POLE4 genes. This protein is one of the main DNA replicases in eukaryotes and is responsible of the replication of the leading strand. POLE contains both the catalytic active site and the proofreading exonuclease domain (residues 223-517). Accordingly, the POLE gene confers to Polε both replicative and 3' to 5' repair capabilities for the new strand.
Expression Broadly expressed.
Localisation Nuclear.
Function Polε is responsible of the polymerization of the leading strand during DNA replication in yeast and humans. It also possesses 3' to 5' exonuclease capability to repair missincorporated nucleotides during DNA replication. Polε is also involved in DNA repair pathways such as mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER) or double-strand break repair.

Mutations

Germinal A few missense germline mutations in the proofreading domain of POLE have been shown to be pathogenic such as W347C, N363K, D368V, L424V, P436S or Y458F. These are quite rare in the population although for unclear reasons they are more common than similar germline mutations in the polymerase gene POLD1. These mutations affect the exonuclease repair of Polε hence resulting in a mutation rate increase of about 100-fold. Accordingly, these tumours are usually called ultramutated.
Somatic Pathogenic somatic mutations in the proofreading domain of POLE have been found in some tumour types at moderate or rare frequencies. Some mutations in the polymerase domain have been suggested to be drivers but further research is required to validate these results.

Implicated in

  
Entity Different human sporadic cancers
Note Somatic pathogenic mutations in the proofreading domain of POLE have been found in 8% of endometrial tumours and at lower frequencies in other tumour types such as colorectal, glioblastoma, ovary, prostate, breast or gastric cancer. These mutations seem to confer similar phenotypes regardless of the tumour tissue type. These are missense, heterozygous mutations where no second hit by either mutation or LOH seem to be required, and they are very early events, possibly initiating. Some mutations are hotspots such as P286R, S297F, V411L or S459F but other rarer mutations have also been identified (eg P286H/L, S297Y, F367S, L424V/I, P436R, M444K, A456P). These mutations affect the proofreading of the protein resulting in ultramutation with an overrepresentation of C>A. More specifically, POLE tumours have mutational signature 10 as reported by Alexandrov et al, with extremely prominent TCG>TTG and TCT>TAT substitutions and transcriptional strand bias. As a result, there is an overrepresentation of some specific missense mutations and nonsense mutations. In addition, it may explain why some cancer driver genes in POLE tumours tend to show mutations otherwise relatively uncommon such as R213X in TP53 or R88Q in PIK3CA. POLE tumours are hardly ever concomitant with microsatellite instability, although a few tumours with both phenotypes have been described, and do not seem to show chromosomal instability as their karyotype is nearly diploid.
Disease Patients with somatic POLE driver mutations are younger on average, although they have a broad range of ages. For colorectal cancer, most mutations are right-sided so they are relatively rare in rectal cancer.
Prognosis POLE tumours in endometrial cancer, colorectal cancer and glioblastoma show excellent prognosis in early disease. Similar patterns are expected in any other tumour type although it is not formally proven due to the low frequency of these mutations. Such good prognosis is because of very high immunogenicity with upregulation of immune checkpoint and other immunosuppressive genes. Accordingly, POLE proofreading pathogenic mutation is also a promising candidate biomarker for checkpoint blockade immunotherapy. They may also be sensitive to treatment with nucleoside analogs as they increase the mutation burden to a level where tumour cells are not viable.
  
  
Entity Proofreading-associated polyposis (PPAP)
Disease Autosomal dominant disease with high risk for endometrial and/or colorectal adenoma or carcinoma due to germline mutations in POLE or POLD1 genes.
Prognosis Probably good prognosis in early disease as found with POLE somatic mutations, although not formally proven. Similarly, these patients are likely to respond to checkpoint blockade immunotherapy.
  

Bibliography

Signatures of mutational processes in human cancer
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjörd JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jäger N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, López-Otín C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdés-Mas R, van Buuren MM, van 't Veer L, Vincent-Salomon A, Waddell N, Yates LR; Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR
Nature 2013 Aug 22;500(7463):415-21
PMID 23945592
 
POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance
Bellido F, Pineda M, Aiza G, Valdés-Mas R, Navarro M, Puente DA, Pons T, González S, Iglesias S, Darder E, Piñol V, Soto JL, Valencia A, Blanco I, Urioste M, Brunet J, Lázaro C, Capellá G, Puente XS, Valle L
Genet Med 2016 Apr;18(4):325-32
PMID 26133394
 
Comprehensive Analysis of Hypermutation in Human Cancer
Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, Davidson S, Edwards M, Elvin JA, Hodel KP, Zahurancik WJ, Suo Z, Lipman T, Wimmer K, Kratz CP, Bowers DC, Laetsch TW, Dunn GP, Johanns TM, Grimmer MR, Smirnov IV, Larouche V, Samuel D, Bronsema A, Osborn M, Stearns D, Raman P, Cole KA, Storm PB, Yalon M, Opocher E, Mason G, Thomas GA, Sabel M, George B, Ziegler DS, Lindhorst S, Issai VM, Constantini S, Toledano H, Elhasid R, Farah R, Dvir R, Dirks P, Huang A, Galati MA, Chung J, Ramaswamy V, Irwin MS, Aronson M, Durno C, Taylor MD, Rechavi G, Maris JM, Bouffet E, Hawkins C, Costello JF, Meyn MS, Pursell ZF, Malkin D, Tabori U, Shlien A
Cell 2017 Nov 16;171(5):1042-1056
PMID 29056344
 
DNA polymerase and δ exonuclease domain mutations in endometrial cancer
Church DN, Briggs SE, Palles C, Domingo E, Kearsey SJ, Grimes JM, Gorman M, Martin L, Howarth KM, Hodgson SV; NSECG Collaborators, Kaur K, Taylor J, Tomlinson IP
Hum Mol Genet 2013 Jul 15;22(14):2820-8
PMID 23528559
 
Prognostic significance of POLE proofreading mutations in endometrial cancer
Church DN, Stelloo E, Nout RA, Valtcheva N, Depreeuw J, ter Haar N, Noske A, Amant F, Tomlinson IP, Wild PJ, Lambrechts D, Jürgenliemk-Schulz IM, Jobsen JJ, Smit VT, Creutzberg CL, Bosse T
J Natl Cancer Inst 2014 Dec 12;107(1):402
PMID 25505230
 
Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study
Domingo E, Freeman-Mills L, Rayner E, Glaire M, Briggs S, Vermeulen L, Fessler E, Medema JP, Boot A, Morreau H, van Wezel T, Liefers GJ, Lothe RA, Danielsen SA, Sveen A, Nesbakken A, Zlobec I, Lugli A, Koelzer VH, Berger MD, Castellví-Bel S, Muñoz J; Epicolon consortium, de Bruyn M, Nijman HW, Novelli M, Lawson K, Oukrif D, Frangou E, Dutton P, Tejpar S, Delorenzi M, Kerr R, Kerr D, Tomlinson I, Church DN
Lancet Gastroenterol Hepatol 2016 Nov;1(3):207-216
PMID 28404093
 
Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition
Eggink FA, Van Gool IC, Leary A, Pollock PM, Crosbie EJ, Mileshkin L, Jordanova ES, Adam J, Freeman-Mills L, Church DN, Creutzberg CL, De Bruyn M, Nijman HW, Bosse T
Oncoimmunology 2016 Dec 9;6(2):e1264565
PMID 28344870
 
Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis
Erson-Omay EZ, alayan AO, Schultz N, Weinhold N, Omay SB, Özduman K, Köksal Y, Li J, Serin Harmanci A, Clark V, Carrión-Grant G, Baranoski J, alar C, Barak T, Coskun S, Baran B, Köse D, Sun J, Bakirciolu M, Moliterno Günel J, Pamir MN, Mishra-Gorur K, Bilguvar K, Yasuno K, Vortmeyer A, Huttner AJ, Sander C, Günel M
Neuro Oncol 2015 Oct;17(10):1356-64
PMID 25740784
 
Replicative DNA polymerase mutations in cancer
Heitzer E, Tomlinson I
Curr Opin Genet Dev 2014 Feb;24:107-13
PMID 24583393
 
Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy
Johanns TM, Miller CA, Dorward IG, Tsien C, Chang E, Perry A, Uppaluri R, Ferguson C, Schmidt RE, Dahiya S, Ansstas G, Mardis ER, Dunn GP
Cancer Discov 2016 Nov;6(11):1230-1236
PMID 27683556
 
Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas
Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, Kemp Z, Spain SL, Guarino E, Salguero I, Sherborne A, Chubb D, Carvajal-Carmona LG, Ma Y, Kaur K, Dobbins S, Barclay E, Gorman M, Martin L, Kovac MB, Humphray S; CORGI Consortium; WGS500 Consortium, Lucassen A, Holmes CC, Bentley D, Donnelly P, Taylor J, Petridis C, Roylance R, Sawyer EJ, Kerr DJ, Clark S, Grimes J, Kearsey SE, Thomas HJ, McVean G, Houlston RS, Tomlinson I
Nat Genet 2013 Feb;45(2):136-44
PMID 23263490
 
A panoply of errors: polymerase proofreading domain mutations in cancer
Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T, Tomlinson I, Church DN
Nat Rev Cancer 2016 Feb;16(2):71-81
PMID 26822575
 
Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response
Temko D, Van Gool IC, Rayner E, Glaire M, Makino S, Brown M, Chegwidden L, Palles C, Depreeuw J, Beggs A, Stathopoulou C, Mason J, Baker AM, Williams M, Cerundolo V, Rei M, Taylor JC, Schuh A, Ahmed A, Amant F, Lambrechts D, Smit VT, Bosse T, Graham TA, Church DN, Tomlinson I
J Pathol 2018 Mar 31
PMID 29604063
 
New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis
Valle L, Hernández-Illán E, Bellido F, Aiza G, Castillejo A, Castillejo MI, Navarro M, Seguí N, Vargas G, Guarinos C, Juarez M, Sanjuán X, Iglesias S, Alenda C, Egoavil C, Segura , Juan MJ, Rodriguez-Soler M, Brunet J, González S, Jover R, Lázaro C, Capellá G, Pineda M, Soto JL, Blanco I
Hum Mol Genet 2014 Jul 1;23(13):3506-12
PMID 24501277
 
Adjuvant Treatment for POLE Proofreading Domain-Mutant Cancers: Sensitivity to Radiotherapy, Chemotherapy, and Nucleoside Analogues
Van Gool IC, Rayner E, Osse EM, Nout RA, Creutzberg CL, Tomlinson IPM, Church DN, Smit VTHBM, de Wind N, Bosse T, Drost M
Clin Cancer Res 2018 Mar 20
PMID 29559562
 
POLE proofreading mutation, immune response and prognosis in endometrial cancer
van Gool IC, Bosse T, Church DN
Oncoimmunology 2015 Aug 12;5(3):e1072675
PMID 27141333
 

Citation

This paper should be referenced as such :
Domingo E
POLE (DNA polymerase epsilon, catalytic subunit);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/POLEID41773ch12q24.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(12;12)(q24;q24) POLE/FBRSL1


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  Colon: Colorectal adenocarcinoma
t(12;12)(q23;q24) POLE/ANKS1B


External links

Nomenclature
HGNC (Hugo)POLE   9177
LRG (Locus Reference Genomic)LRG_789
Cards
AtlasPOLEID41773ch12q24
Entrez_Gene (NCBI)POLE  5426  DNA polymerase epsilon, catalytic subunit
AliasesCRCS12; FILS; POLE1
GeneCards (Weizmann)POLE
Ensembl hg19 (Hinxton)ENSG00000177084 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000177084 [Gene_View]  ENSG00000177084 [Sequence]  chr12:132623762-132687524 [Contig_View]  POLE [Vega]
ICGC DataPortalENSG00000177084
TCGA cBioPortalPOLE
AceView (NCBI)POLE
Genatlas (Paris)POLE
WikiGenes5426
SOURCE (Princeton)POLE
Genetics Home Reference (NIH)POLE
Genomic and cartography
GoldenPath hg38 (UCSC)POLE  -     chr12:132623762-132687524 -  12q24.33   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)POLE  -     12q24.33   [Description]    (hg19-Feb_2009)
EnsemblPOLE - 12q24.33 [CytoView hg19]  POLE - 12q24.33 [CytoView hg38]
Mapping of homologs : NCBIPOLE [Mapview hg19]  POLE [Mapview hg38]
OMIM174762   615083   615139   
Gene and transcription
Genbank (Entrez)AF128542 AF128544 AK025087 AK093003 AK128248
RefSeq transcript (Entrez)NM_006231
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)POLE
Cluster EST : UnigeneHs.524871 [ NCBI ]
CGAP (NCI)Hs.524871
Alternative Splicing GalleryENSG00000177084
Gene ExpressionPOLE [ NCBI-GEO ]   POLE [ EBI - ARRAY_EXPRESS ]   POLE [ SEEK ]   POLE [ MEM ]
Gene Expression Viewer (FireBrowse)POLE [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5426
GTEX Portal (Tissue expression)POLE
Human Protein AtlasENSG00000177084-POLE [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ07864   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ07864  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ07864
Splice isoforms : SwissVarQ07864
Catalytic activity : Enzyme2.7.7.7 [ Enzyme-Expasy ]   2.7.7.72.7.7.7 [ IntEnz-EBI ]   2.7.7.7 [ BRENDA ]   2.7.7.7 [ KEGG ]   
PhosPhoSitePlusQ07864
Domains : Interpro (EBI)DNA-dir_DNA_pol_B    DNA-dir_DNA_pol_B_exonuc    DNA-dir_DNA_pol_B_multi_dom    DNA_pol_e_suA_C    POL2    RNaseH-like_dom   
Domain families : Pfam (Sanger)DNA_pol_B (PF00136)    DNA_pol_B_exo1 (PF03104)    DUF1744 (PF08490)   
Domain families : Pfam (NCBI)pfam00136    pfam03104    pfam08490   
Domain families : Smart (EMBL)DUF1744 (SM01159)  POLBc (SM00486)  
Conserved Domain (NCBI)POLE
DMDM Disease mutations5426
Blocks (Seattle)POLE
SuperfamilyQ07864
Human Protein Atlas [tissue]ENSG00000177084-POLE [tissue]
Peptide AtlasQ07864
HPRD07177
IPIIPI00939602   IPI00940894   IPI01019102   IPI00000898   IPI00797203   IPI00744598   IPI00790334   IPI01012998   IPI01013454   IPI01013828   
Protein Interaction databases
DIP (DOE-UCLA)Q07864
IntAct (EBI)Q07864
FunCoupENSG00000177084
BioGRIDPOLE
STRING (EMBL)POLE
ZODIACPOLE
Ontologies - Pathways
QuickGOQ07864
Ontology : AmiGOG1/S transition of mitotic cell cycle  G1/S transition of mitotic cell cycle  nucleotide binding  DNA synthesis involved in DNA repair  DNA binding  chromatin binding  DNA-directed DNA polymerase activity  protein binding  nucleus  nucleoplasm  nucleoplasm  plasma membrane  DNA replication  DNA replication initiation  leading strand elongation  base-excision repair, gap-filling  nucleotide-excision repair, DNA gap filling  zinc ion binding  single-stranded DNA 3'-5' exodeoxyribonuclease activity  epsilon DNA polymerase complex  telomere maintenance via semi-conservative replication  DNA replication proofreading  embryonic organ development  4 iron, 4 sulfur cluster binding  nucleic acid phosphodiester bond hydrolysis  
Ontology : EGO-EBIG1/S transition of mitotic cell cycle  G1/S transition of mitotic cell cycle  nucleotide binding  DNA synthesis involved in DNA repair  DNA binding  chromatin binding  DNA-directed DNA polymerase activity  protein binding  nucleus  nucleoplasm  nucleoplasm  plasma membrane  DNA replication  DNA replication initiation  leading strand elongation  base-excision repair, gap-filling  nucleotide-excision repair, DNA gap filling  zinc ion binding  single-stranded DNA 3'-5' exodeoxyribonuclease activity  epsilon DNA polymerase complex  telomere maintenance via semi-conservative replication  DNA replication proofreading  embryonic organ development  4 iron, 4 sulfur cluster binding  nucleic acid phosphodiester bond hydrolysis  
Pathways : KEGGDNA polymerase    Purine metabolism    Pyrimidine metabolism   
REACTOMEQ07864 [protein]
REACTOME PathwaysR-HSA-68962 [pathway]   
NDEx NetworkPOLE
Atlas of Cancer Signalling NetworkPOLE
Wikipedia pathwaysPOLE
Orthology - Evolution
OrthoDB5426
GeneTree (enSembl)ENSG00000177084
Phylogenetic Trees/Animal Genes : TreeFamPOLE
HOVERGENQ07864
HOGENOMQ07864
Homologs : HomoloGenePOLE
Homology/Alignments : Family Browser (UCSC)POLE
Gene fusions - Rearrangements
Fusion : MitelmanPOLE/ANKS1B [12q24.33/12q23.1]  
Fusion PortalPOLE 12q24.33 ANKS1B 12q23.1 BLCA
Fusion : QuiverPOLE
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPOLE [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)POLE
dbVarPOLE
ClinVarPOLE
1000_GenomesPOLE 
Exome Variant ServerPOLE
ExAC (Exome Aggregation Consortium)ENSG00000177084
GNOMAD BrowserENSG00000177084
Genetic variants : HAPMAP5426
Genomic Variants (DGV)POLE [DGVbeta]
DECIPHERPOLE [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPOLE 
Mutations
ICGC Data PortalPOLE 
TCGA Data PortalPOLE 
Broad Tumor PortalPOLE
OASIS PortalPOLE [ Somatic mutations - Copy number]
Cancer Gene: CensusPOLE 
Somatic Mutations in Cancer : COSMICPOLE  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPOLE
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch POLE
DgiDB (Drug Gene Interaction Database)POLE
DoCM (Curated mutations)POLE (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)POLE (select a term)
intoGenPOLE
NCG5 (London)POLE
Cancer3DPOLE(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM174762    615083    615139   
Orphanet22105    23548   
DisGeNETPOLE
MedgenPOLE
Genetic Testing Registry POLE
NextProtQ07864 [Medical]
TSGene5426
GENETestsPOLE
Target ValidationPOLE
Huge Navigator POLE [HugePedia]
snp3D : Map Gene to Disease5426
BioCentury BCIQPOLE
ClinGenPOLE
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5426
Chemical/Pharm GKB GenePA277
Clinical trialPOLE
Miscellaneous
canSAR (ICR)POLE (select the gene name)
Probes
Litterature
PubMed109 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePOLE
EVEXPOLE
GoPubMedPOLE
iHOPPOLE
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Jun 22 17:16:43 CEST 2018

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