Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Madalene A. Earp, Linda E. Kelemen, Anthony M. Magliocco, Kenneth D. Swenerton, Georgia Chenevix-Trench, Yi Lu, Alexander Hein, Arif B Ekici, Matthias W. Beckmann, Peter A. Fasching, Diether Lambrechts, Evelyn Despierre, Ignace Vergote, Sandrina Lambrechts, Jennifer Anne Doherty, Mary Anne Rossing, Jenny Chang-Claude, Anja Rudolph, Grace Friel, Kirsten B MoysichKunle Odunsi, Lara E. Sucheston-Campbell, Galina Lurie, Marc T Goodman, Michael E. Carney, Pamela J Thompson, Ingo B Runnebaum, Matthias Dürst, Peter Hillemanns, Thilo Dörk, Natalia Antonenkova, Natalia Bogdanova, Arto Leminen, Heli Nevanlinna, Liisa M Pelttari, Ralf Butzow, Clareann H Bunker, Francesmary Modugno, Robert P. Edwards, Roberta B Ness, Andreas Du Bois, Florian Heitz, Ira Schwaab, Philipp Harter, Beth Y. Karlan, Christine S Walsh, Jenny Lester, Allan Jensen, Susanne K. Kjær, Claus K. Høgdall, Estrid Høgdall, Lene Lundvall, Thomas A Sellers, Brooke L. Fridley, Ellen L Goode, Julie M. Cunningham, Robert A Vierkant, Graham G. Giles, Laura Baglietto, Gianluca Severi, Melissa C. Southey, Dong Liang, Xifeng Wu, Karen Lu, Michelle A T Hildebrandt, Douglas A. Levine, Maria Bisogna, Joellen M Schildkraut, Edwin S. Iversen, Rachel Palmieri Weber, Andrew Berchuck, Daniel W. Cramer, Kathryn L Terry, Elizabeth M Poole, Shelley S Tworoger, Elisa V. Bandera, Urmila Chandran, Irene Orlow, Sara H Olson, Elisabeth Wik, Helga Birgitte Salvesen, Line Bjorge, Mari K. Halle, Anne Mvan Altena, Katja K.H. Aben, Lambertus A. Kiemeney, Leon F A G Massuger, Tanja Pejovic, Yukie Tarumi Bean, Cezary Cybulski, Jacek Gronwald, Jan Lubinski, Nicolas Wentzensen, Louise A. Brinton, Jolanta Lissowska, Montserrat Garcia-Closas, Ed Dicks, Joe Dennis, Douglas F Easton, Honglin Song, Jonathan P. Tyrer, Paul D P Pharoah, Diana M Eccles, Ian G. Campbell, Alice S Whittemore, Valerie McGuire, Weiva Sieh, Joseph H Rothstein, James M. Flanagan, James Paul, Robert Brown, Catherine M Phelan, Harvey A Risch, John R McLaughlin, Steven A Narod, Argyrios Ziogas, Hoda Anton-Culver, Aleksandra Gentry-Maharaj, Usha N Menon, Simon A Gayther, Susan J Ramus, Anna H Wu, Celeste L Pearce, Malcolm C Pike, Agnieszka Dansonka-Mieszkowska, Iwona K Rzepecka, Lukasz M. Szafron, Jolanta Kupryjanczyk, Linda S. Cook, Nhu D. Le, Angela Brooks-Wilson, Australian Cancer Study, Australian Ovarian Cancer Study Group, on behalf of the Ovarian Cancer Association Consortium

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17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)481-497
Number of pages17
JournalHuman Genetics
Volume133
Issue number5
DOIs
Publication statusPublished - May 2014
Externally publishedYes

Cite this

Earp, M. A., Kelemen, L. E., Magliocco, A. M., Swenerton, K. D., Chenevix-Trench, G., Lu, Y., Hein, A., Ekici, A. B., Beckmann, M. W., Fasching, P. A., Lambrechts, D., Despierre, E., Vergote, I., Lambrechts, S., Doherty, J. A., Rossing, M. A., Chang-Claude, J., Rudolph, A., Friel, G., ... on behalf of the Ovarian Cancer Association Consortium (2014). Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA. Human Genetics, 133(5), 481-497. https://doi.org/10.1007/s00439-013-1383-3