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Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

2016; Springer Science+Business Media; Volume: 135; Issue: 7 Linguagem: Inglês

10.1007/s00439-016-1663-9

1432-1203

Gabriel Cuéllar-Partida, Yi Lu, Suzanne C. Dixon‐Suen, Peter A. Fasching, Alexander Hein, Stefanie Burghaus, Matthias W. Beckmann, Diether Lambrechts, Els Van Nieuwenhuysen, Ignace Vergote, Adriaan Vanderstichele, Jennifer A. Doherty, Mary Anne Rossing, Jenny Chang‐Claude, Anja Rudolph, Shan Wang‐Gohrke, Marc T. Goodman, Natalia Bogdanova, Thilo Dörk, Matthias Dürst, Peter Hillemanns, Ingo B. Runnebaum, Natalia Antonenkova, Ralf Bützow, Arto Leminen, Heli Nevanlinna, Liisa M. Pelttari, Robert P. Edwards, Joseph L. Kelley, Francesmary Modugno, Kirsten B. Moysich, Roberta B. Ness, Rikki A. Cannioto, Estrid Høgdall, Claus Høgdall, Allan Jensen, Graham G. Giles, Fiona Bruinsma, Susanne K. Kjær, Michelle A.T. Hildebrandt, Dong Liang, Karen H. Lu, Xifeng Wu, Maria Bisogna, Fanny Dao, Douglas A. Levine, Daniel W. Cramer, Kathryn L. Terry, Shelley S. Tworoger, Meir J. Stampfer, Stacey A. Missmer, Line Bjørge, Helga B. Salvesen, Reidun Kristin Kopperud, Katharina Bischof, Katja K.H. Aben, Lambertus A. Kiemeney, Leon F.A.G. Massuger, Angela Brooks‐Wilson, Sara H. Olson, Valerie McGuire, Joseph H. Rothstein, Weiva Sieh, Alice S. Whittemore, Linda S. Cook, Nhu D. Le, C. Blake Gilks, Jacek Gronwald, Anna Jakubowska, Jan Lubiński, Tomasz Kluz, Honglin Song, Jonathan P. Tyrer, Nicolas Wentzensen, Louise A. Brinton, Britton Trabert, Jolanta Lissowska, Esther M. John, Steven A. Narod, Catherine Phelan, Hoda Anton‐Culver, Argyrios Ziogas, Diana Eccles, Ian Campbell, Simon A. Gayther, Aleksandra Gentry‐Maharaj, Usha Menon, Susan J. Ramus, Anna H. Wu, Agnieszka Dansonka‐Mieszkowska, Jolanta Kupryjańczyk, Agnieszka Timorek, Lukasz M. Szafron, Julie M. Cunningham, Brooke L. Fridley, Stacey J. Winham, Elisa V. Bandera, Elizabeth M. Poole, Terry K. Morgan, Ellen L. Goode, Joellen M. Schildkraut, Celeste Leigh Pearce, Andrew Berchuck, Paul D.P. Pharoah, Penelope M. Webb, Georgia Chenevix‐Trench, Harvey A. Risch, Stuart MacGregor,

RNA modifications and cancer

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ( $$h^{ 2}_{\rm{g}}$$ = 8.8 ± 1.1 %), endometrioid ( $$h^{ 2}_{\rm{g}}$$ = 3.2 ± 1.6 %), clear cell ( $$h^{ 2}_{\rm{g}}$$ = 6.7 ± 3.3 %) and all EOC ( $$h^{ 2}_{\rm{g}}$$ = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.