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 Dylan M. , Thompson Deborah J. , Aben Katja K.H. , Alsulimani Ahmad , Amant Frederic , Annibali Daniela , Attia John , Barricarte Aurelio , Beckmann Matthias W. , Berchuck Andrew , Bermisheva Marina , Bernardini Marcus Q. , Bischof Katharina , Bjorge Line , Bodelon Clara , Brand Alison H. , Brenton James D. , Brinton Louise A. , Bruinsma Fiona , Buchanan Daniel D. , Burghaus Stefanie , Butzow Ralf , Cai Hui , Carney Michael E. , Chanock Stephen J. , Chen Chu , Chen Xiao Qing , Chen Zhihua , Cook Linda S. , Cunningham Julie M. , De Vivo Immaculata , deFazio Anna , Doherty Jennifer A. , Dörk Thilo , du Bois Andreas , Dunning Alison M. , Dürst Matthias , Edwards Todd , Edwards Robert P. , Ekici Arif B. , Ewing Ailith , Fasching Peter A. , Ferguson Sarah , Flanagan James M. , Fostira Florentia , Fountzilas George , Friedenreich Christine M. , Gao Bo , Gaudet Mia M. , Gawełko Jan , Gentry-Maharaj Aleksandra , Giles Graham G. , Glasspool Rosalind , Goodman Marc T. , Gronwald Jacek , Harris Holly R. , Harter Philipp , Hein Alexander , Heitz Florian , Hildebrandt Michelle A.T. , Hillemanns Peter , Høgdall Estrid , Høgdall Claus K. , Holliday Elizabeth G. , Huntsman David G. , Huzarski Tomasz , Jakubowska Anna , Jensen Allan , Jones Michael E. , Karlan Beth Y. , Karnezis Anthony , Kelley Joseph L. , Khusnutdinova Elza , Killeen Jeffrey L. , Kjaer Susanne K. , Klapdor Rüdiger , Köbel Martin , Konopka Bozena , Konstantopoulou Irene , Kopperud Reidun K. , Koti Madhuri , Kraft Peter , Kupryjanczyk Jolanta , Lambrechts Diether , Larson Melissa C. , Le Marchand Loic , Lele Shashikant , Lester Jenny , Li Andrew J. , Liang Dong , Liebrich Clemens , Lipworth Loren , Lissowska Jolanta , Lu Lingeng , Lu Karen H. , Macciotta Alessandra , Mattiello Amalia , May Taymaa , McAlpine Jessica N. , McGuire Valerie , McNeish Iain A. , Menon Usha , Modugno Francesmary , Moysich Kirsten B. , Nevanlinna Heli , Odunsi Kunle , Olsson Håkan , Orsulic Sandra , Osorio Ana , Palli Domenico , Park-Simon Tjoung-Won , Pearce Celeste L. , Pejovic Tanja , Permuth Jennifer B. , Podgorska Agnieszka , Ramus Susan J. , Rebbeck Timothy R. , Riggan Marjorie J. , Risch Harvey A. , Rothstein Joseph H. , Runnebaum Ingo B. , Scott Rodney J. , Sellers Thomas A. , Senz Janine , Setiawan Veronica Wendy , Siddiqui Nadeem , Sieh Weiva , Spiewankiewicz Beata , Sutphen Rebecca , Swerdlow Anthony J. , Szafron Lukasz Michael , Teo Soo Hwang , Thompson Pamela J. , Thomsen Liv Cecilie Vestrheim , Titus Linda , Tone Alicia , Tumino Rosario , Turman Constance , Vanderstichele Adriaan , Edwards Digna Velez , Vergote Ignace , Vierkant Robert A. , Wang Zhaoming , Wang-Gohrke Shan , Webb Penelope M. ,   for the OPAL Study Group,   for the AOCS Group, White Emily , Whittemore Alice S. , Winham Stacey J. , Wu Xifeng , Wu Anna H. , Yannoukakos Drakoulis , Spurdle Amanda B. , O'Mara Tracy A. 
Published: November 2020

AbstractBackground: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 &lt; 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P &lt; 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.