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Title: Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.
Authors: Glubb DM,  Thompson DJ,  Aben KKH,  Alsulimani A,  Amant F,  Annibali D,  Attia J,  Barricarte A,  Beckmann MW,  Berchuck A,  Bermisheva M,  Bernardini MQ,  Bischof K,  Bjorge L,  Bodelon C,  Brand AH,  Brenton JD,  Brinton LA,  Bruinsma F,  Buchanan DD,  Burghaus S,  Butzow R,  Cai H,  Carney ME,  Chanock SJ,  Chen C,  Chen XQ,  Chen Z,  Cook LS,  Cunningham JM,  De Vivo I,  deFazio A,  Doherty JA,  Dörk T,  du Bois A,  Dunning AM,  Dürst M,  Edwards T,  Edwards RP,  Ekici AB,  Ewing A,  Fasching PA,  Ferguson S,  Flanagan JM,  Fostira F,  Fountzilas G,  Friedenreich CM,  Gao B,  Gaudet MM,  Gawełko J,  Gentry-Maharaj A,  Giles GG,  Glasspool R,  Goodman MT,  Gronwald J,  Harris HR,  Harter P,  Hein A,  Heitz F,  Hildebrandt MAT,  Hillemanns P,  Høgdall E,  Høgdall CK,  Holliday EG,  Huntsman DG,  Huzarski T,  Jakubowska A,  Jensen A,  Jones ME,  Karlan BY,  Karnezis A,  Kelley JL,  Khusnutdinova E,  Killeen JL,  Kjaer SK,  Klapdor R,  Köbel M,  Konopka B,  Konstantopoulou I,  Kopperud RK,  Koti M,  Kraft P,  Kupryjanczyk J,  Lambrechts D,  Larson MC,  Le Marchand L,  Lele S,  Lester J,  Li AJ,  Liang D,  Liebrich C,  Lipworth L,  Lissowska J,  Lu L,  Lu KH,  Macciotta A,  Mattiello A,  May T,  McAlpine JN,  McGuire V,  McNeish IA,  Menon U,  Modugno F,  Moysich KB,  Nevanlinna H,  Odunsi K,  Olsson H,  Orsulic S,  Osorio A,  Palli D,  Park-Simon TW,  Pearce CL,  Pejovic T,  Permuth JB,  Podgorska A,  Ramus SJ,  Rebbeck TR,  Riggan MJ,  Risch HA,  Rothstein JH,  Runnebaum IB,  Scott RJ,  Sellers TA,  Senz J,  Setiawan VW,  Siddiqui N,  Sieh W,  Spiewankiewicz B,  Sutphen R,  Swerdlow AJ,  Szafron LM,  Teo SH,  Thompson PJ,  Thomsen LCV,  Titus L,  Tone A,  Tumino R,  Turman C,  Vanderstichele A,  Edwards DV,  Vergote I,  Vierkant RA,  Wang Z,  Wang-Gohrke S,  Webb PM,  OPAL Study Group,  AOCS Group,  White E,  Whittemore AS,  Winham SJ,  Wu X,  Wu AH,  Yannoukakos D,  Spurdle AB,  O'Mara TA
Journal: Cancer Epidemiol Biomarkers Prev
Date: 2021 Jan
Branches: CGR, ITEB, OD, TDRP
PubMed ID: 33144283
PMC ID: not available
Abstract: BACKGROUND: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. METHODS: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. RESULTS: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10-9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10-7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. CONCLUSIONS: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. IMPACT: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.