Earp, Madalene A4; Kelemen, Linda E4; Magliocco, Anthony M4; Swenerton, Kenneth D4; Chenevix-Trench, Georgia4; Lu, Yi4; Hein, Alexander4; Ekici, Arif B4; Beckmann, Matthias W4; Fasching, Peter A4; Lambrechts, Diether4; Despierre, Evelyn4; Vergote, Ignace4; Lambrechts, Sandrina4; Doherty, Jennifer A4; Rossing, Mary Anne4; Chang-Claude, Jenny4; Rudolph, Anja4; Friel, Grace4; Moysich, Kirsten B4; Odunsi, Kunle4; Sucheston-Campbell, Lara4; Lurie, Galina4; Goodman, Marc T4; Carney, Michael E4; Thompson, Pamela J4; Runnebaum, Ingo B4; Dürst, Matthias4; Hillemanns, Peter4; Dörk, Thilo4; Antonenkova, Natalia4; Bogdanova, Natalia4; Leminen, Arto4; Nevanlinna, Heli4; Pelttari, Liisa M4; Butzow, Ralf4; Bunker, Clareann H4; Modugno, Francesmary4; Edwards, Robert P4; Ness, Roberta B4; du Bois, Andreas4; Heitz, Florian4; Schwaab, Ira4; Harter, Philipp4; Karlan, Beth Y4; Walsh, Christine4; Lester, Jenny4; Jensen, Allan5; Kjær, Susanne K6; Høgdall, Claus K6; Høgdall, Estrid4; Lundvall, Lene4; Sellers, Thomas A4; Fridley, Brooke L4; Goode, Ellen L4; Cunningham, Julie M4; Vierkant, Robert A4; Giles, Graham G4; Baglietto, Laura4; Severi, Gianluca4; Southey, Melissa C4; Liang, Dong4; Wu, Xifeng4; Lu, Karen4; Hildebrandt, Michelle A T4; Levine, Douglas A4; Bisogna, Maria4; Schildkraut, Joellen M4; Iversen, Edwin S4; Weber, Rachel Palmieri4; Berchuck, Andrew4; Cramer, Daniel W4; Terry, Kathryn L4; Poole, Elizabeth M4; Tworoger, Shelley S4; Bandera, Elisa V4; Chandran, Urmila4; Orlow, Irene4; Olson, Sara H4; Wik, Elisabeth4; Salvesen, Helga B4; Bjorge, Line4; Halle, Mari K4; van Altena, Anne M4; Aben, Katja K H4; Kiemeney, Lambertus A4; Massuger, Leon F A G4; Pejovic, Tanja4; Bean, Yukie T4; Cybulski, Cezary4; Gronwald, Jacek4; Lubinski, Jan4; Wentzensen, Nicolas4; Brinton, Louise A4; Lissowska, Jolanta4; Garcia-Closas, Montserrat4; Dicks, Ed4; Dennis, Joe4; Easton, Douglas F4; Song, Honglin4; Tyrer, Jonathan P4; Pharoah, Paul D P4; Eccles, Diana4; Campbell, Ian G4; Whittemore, Alice S4; McGuire, Valerie4; Sieh, Weiva4; Rothstein, Joseph H4; Flanagan, James M4; Paul, James4; Brown, Robert4; Phelan, Catherine M4; Risch, Harvey A4; McLaughlin, John R4; Narod, Steven A4; Ziogas, Argyrios4; Anton-Culver, Hoda4; Gentry-Maharaj, Aleksandra4; Menon, Usha4; Gayther, Simon A4; Ramus, Susan J4; Wu, Anna H4; Pearce, Celeste L4; Pike, Malcolm C4; Dansonka-Mieszkowska, Agnieszka4; Rzepecka, Iwona K4; Szafron, Lukasz M4; Kupryjanczyk, Jolanta4; Cook, Linda S4; Le, Nhu D4; Brooks-Wilson, Angela4
1 Department of Public Health, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Public Health, Department of Public Health, Faculty of Health and Medical Sciences, Københavns Universitet3 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet4 unknown5 Department of Public Health, Faculty of Health and Medical Sciences, Københavns Universitet6 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.
Human Genetics, 2014, Vol 133, Issue 5, p. 481-497
Alleles; DNA; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Polymorphism, Single Nucleotide; Quality Control; Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.