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 , 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. , Vivo Immaculata De , deFazio Anna , Doherty Jennifer A. , Dörk Thilo , Bois Andreas du , 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 ,   OPAL Study Group,   AOCS Group, 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. , Marchand Loic Le , Lele Shashikant B. , 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 , 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 , Scott Rodney J. , Sellers Thomas A. , Senz Janine , Setiawan V. Wendy , Siddiqui Nadeem , Sieh Weiva , Spiewankiewicz Beata , Sutphen Rebecca , Swerdlow Anthony J. , Szafron Lukasz , 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. , White Emily , Whittemore Alice S. , Winham Stacey J. , Wu Xifeng , Wu Anna H. , Yannoukakos Drakoulis , Spurdle Amanda B. , O’Mara Tracy A. 
Published: May 2020

Accumulating evidence suggests a relationship between endometrial cancer and epithelial ovarian cancer. For example, endometrial cancer and epithelial ovarian cancer share epidemiological risk factors and molecular features observed across histotypes are held in common (e.g. serous, endometrioid and clear cell). Independent genome-wide association studies (GWAS) for endometrial cancer and epithelial ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. Using GWAS summary statistics, we explored the shared genetic etiology between endometrial cancer and epithelial ovarian cancer. Genetic correlation analysis using LD Score regression revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses by stratified by subtype. We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified at a sub-genome wide threshold (P < 5 × 10−7). Integration with promoter-associated HiChIP chromatin loops from immortalized endometrium and epithelial ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.