Show simple item record

dc.contributor.authorLitchfield, Ken
dc.contributor.authorLevy, Men
dc.contributor.authorOrlando, Gen
dc.contributor.authorLoveday, Cen
dc.contributor.authorLaw, PJen
dc.contributor.authorMigliorini, Gen
dc.contributor.authorHolroyd, Aen
dc.contributor.authorBroderick, Pen
dc.contributor.authorKarlsson, Ren
dc.contributor.authorHaugen, TBen
dc.contributor.authorKristiansen, Wen
dc.contributor.authorNsengimana, Jen
dc.contributor.authorFenwick, Ken
dc.contributor.authorAssiotis, Ien
dc.contributor.authorKote-Jarai, Zen
dc.contributor.authorDunning, Alisonen
dc.contributor.authorMuir, Ken
dc.contributor.authorPeto, Jen
dc.contributor.authorEeles, Ren
dc.contributor.authorEaston, Douglasen
dc.contributor.authorDudakia, Den
dc.contributor.authorOrr, Nen
dc.contributor.authorPashayan, Nen
dc.contributor.authorUK Testicular Cancer Collaboration,en
dc.contributor.authorPRACTICAL Consortium,en
dc.contributor.authorBishop, DTen
dc.contributor.authorReid, Aen
dc.contributor.authorHuddart, RAen
dc.contributor.authorShipley, Jen
dc.contributor.authorGrotmol, Ten
dc.contributor.authorWiklund, Fen
dc.contributor.authorHoulston, RSen
dc.contributor.authorTurnbull, Cen
dc.date.accessioned2017-08-16T10:47:51Z
dc.date.available2017-08-16T10:47:51Z
dc.date.issued2017-07-01en
dc.identifier.issn1061-4036
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/266476
dc.description.abstractGenome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.
dc.description.sponsorshipWe acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre. Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) (U19 CA 148537 for Elucidating Loci Involved in Prostate cancer Susceptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I). Additional analytical support was provided by NIH NCI U01 CA188392. The PRACTICAL consortium was supported by Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692 and C16913/A6135; the European Commission’s Seventh Framework Programme grant agreement 223175 (HEALTH-F2-2009-223175) (D.F.E., R.E. and Z.K.-J.); and the NIH Cancer Post-Cancer GWAS initiative grant 1 U19 CA 148537-01 (the GAME-ON initiative). We thank the following for funding support: the Institute of Cancer Research and the Everyman Campaign, the Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), the Orchid Cancer Appeal, the National Cancer Research Network UK and the National Cancer Research Institute (NCRI) UK. We are grateful for NIHR funding to the Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust. We acknowledge funding from the Swedish Cancer Society (CAN2011/484 and CAN2012/823), the Norwegian Cancer Society (grants 418975-71081-PR-2006-0387 and PK01-2007- 0375) and the Nordic Cancer Union (grant S-12/07). This study was supported by the Movember Foundation and the Institute of Cancer Research. K.L. is supported by a PhD fellowship from Cancer Research UK. R.S.H. and P.B. are supported by Cancer Research UK (C1298/A8362 Bobby Moore Fund for Cancer Research UK).
dc.languageengen
dc.language.isoenen
dc.publisherSpringer Nature
dc.subjectGene expression profilingen
dc.subjectGenome-wide association studiesen
dc.subjectGerm cell tumoursen
dc.titleIdentification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumoren
dc.typeArticle
prism.endingPage1140
prism.issueIdentifier7en
prism.publicationDate2017en
prism.publicationNameNature Geneticsen
prism.startingPage1133
prism.volume49en
dc.identifier.doi10.17863/CAM.12655
dcterms.dateAccepted2017-05-16en
rioxxterms.versionofrecord10.1038/ng.3896en
rioxxterms.versionAMen
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-07-01en
dc.contributor.orcidDunning, Alison [0000-0001-6651-7166]
dc.contributor.orcidEaston, Douglas [0000-0003-2444-3247]
dc.identifier.eissn1546-1718
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (A10123)
pubs.funder-project-idNational Cancer Institute (NCI) (U19CA148537)
cam.issuedOnline2017-06-12en
rioxxterms.freetoread.startdate2017-12-12


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record