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dc.contributor.authorDicks, Ed
dc.contributor.authorSong, Honglin
dc.contributor.authorRamus, Susan J
dc.contributor.authorOudenhove, Elke Van
dc.contributor.authorTyrer, Jonathan P
dc.contributor.authorIntermaggio, Maria P
dc.contributor.authorKar, Siddhartha
dc.contributor.authorHarrington, Patricia
dc.contributor.authorBowtell, David D
dc.contributor.authorGroup, Aocs Study
dc.contributor.authorCicek, Mine S
dc.contributor.authorCunningham, Julie M
dc.contributor.authorFridley, Brooke L
dc.contributor.authorAlsop, Jennifer
dc.contributor.authorJimenez-Linan, Mercedes
dc.contributor.authorPiskorz, Anna
dc.contributor.authorGoranova, Teodora
dc.contributor.authorKent, Emma
dc.contributor.authorSiddiqui, Nadeem
dc.contributor.authorPaul, James
dc.contributor.authorCrawford, Robin
dc.contributor.authorPoblete, Samantha
dc.contributor.authorLele, Shashi
dc.contributor.authorSucheston-Campbell, Lara
dc.contributor.authorMoysich, Kirsten B
dc.contributor.authorSieh, Weiva
dc.contributor.authorMcGuire, Valerie
dc.contributor.authorLester, Jenny
dc.contributor.authorOdunsi, Kunle
dc.contributor.authorWhittemore, Alice S
dc.contributor.authorBogdanova, Natalia
dc.contributor.authorDürst, Matthias
dc.contributor.authorHillemanns, Peter
dc.contributor.authorKarlan, Beth Y
dc.contributor.authorGentry-Maharaj, Aleksandra
dc.contributor.authorMenon, Usha
dc.contributor.authorTischkowitz, Marc
dc.contributor.authorLevine, Douglas
dc.contributor.authorBrenton, James D
dc.contributor.authorDörk, Thilo
dc.contributor.authorGoode, Ellen L
dc.contributor.authorGayther, Simon A
dc.contributor.authorPharoah, DP Paul
dc.description.abstractWe analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8×10-3). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 - were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin. We estimated mutation prevalence for each gene and tested for associations with disease risk. Mutations were identified in both cases and controls in all genes except MAD2L2, where we found no evidence of mutations in controls. In FANCM we observed a higher mutation frequency in HGSOC cases compared to controls (29/3,107 cases, 0.96 percent; 13/3,368 controls, 0.38 percent; P=0.008) with little evidence for association with other subtypes (6/1,491, 0.40 percent; P=0.82). The relative risk of HGSOC associated with deleterious FANCM mutations was estimated to be 2.5 (95% CI 1.3 - 5.0; P=0.006). In summary, whole exome sequencing of EOC cases with large-scale replication in case-control studies has identified FANCM as a likely novel susceptibility gene for HGSOC, with mutations associated with a moderate increase in risk. These data may have clinical implications for risk prediction and prevention approaches for high-grade serous ovarian cancer in the future and a significant impact on reducing disease mortality.
dc.rightsAttribution 4.0 International
dc.titleGermline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene.
dc.contributor.orcidDicks, Ed [0000-0002-0617-0401]
dc.contributor.orcidSong, Honglin [0000-0001-5076-7371]
dc.contributor.orcidTyrer, Jonathan [0000-0003-3724-4757]
dc.contributor.orcidTischkowitz, Marc [0000-0002-7880-0628]
dc.contributor.orcidBrenton, James [0000-0002-5738-6683]
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idCancer Research UK (C14303/A17197)
pubs.funder-project-idNational Cancer Institute (R01CA178535)
pubs.funder-project-idCancer Research UK (CB4150)

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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International