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. 2014 May;133(5):481-97.
doi: 10.1007/s00439-013-1383-3. Epub 2013 Nov 5.

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

Madalene A Earp  1 , Linda E Kelemen, Anthony M Magliocco, Kenneth D Swenerton, Georgia Chenevix-Trench; Australian Cancer Study; Australian Ovarian Cancer Study Group; Yi Lu, Alexander Hein, Arif B Ekici, Matthias W Beckmann, Peter A Fasching, Diether Lambrechts, Evelyn Despierre, Ignace Vergote, Sandrina Lambrechts, Jennifer A Doherty, Mary Anne Rossing, Jenny Chang-Claude, Anja Rudolph, Grace Friel, Kirsten B Moysich, Kunle Odunsi, Lara 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 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 B Salvesen, Line Bjorge, Mari K Halle, Anne M van Altena, Katja K H Aben, Lambertus A Kiemeney, Leon F A G Massuger, Tanja Pejovic, Yukie T 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 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 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; Ovarian Cancer Association Consortium
Affiliations

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

Madalene A Earp et al. Hum Genet. 2014 May.

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.

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Figures

Figure 1
Figure 1
Forest plots of the study specific and summary odds ratios and 95% confidence intervals for the association between mucinous ovarian cancer risk and five SNPs nominated by our pool-based GWAS: (A) rs11108890 (B) rs933518 (C) rs17106154 (D) rs970651, and (E) rs7981902. Study-specific odds ratios, 95% confidence intervals, and P-values are based on logistic regression assuming an additive genetic mode, adjusting for the first 5 eigenvalues from principal components analysis. Summary odds ratios and 95% confidence intervals are from fixed effects meta-analysis and include the OVA study site. Forest plots were generated using the rmeta library implemented in the R project; association analyses were performed using PLINK
Figure 1
Figure 1
Forest plots of the study specific and summary odds ratios and 95% confidence intervals for the association between mucinous ovarian cancer risk and five SNPs nominated by our pool-based GWAS: (A) rs11108890 (B) rs933518 (C) rs17106154 (D) rs970651, and (E) rs7981902. Study-specific odds ratios, 95% confidence intervals, and P-values are based on logistic regression assuming an additive genetic mode, adjusting for the first 5 eigenvalues from principal components analysis. Summary odds ratios and 95% confidence intervals are from fixed effects meta-analysis and include the OVA study site. Forest plots were generated using the rmeta library implemented in the R project; association analyses were performed using PLINK
Figure 2
Figure 2
Forest plots of the study specific and summary odds ratios and 95% confidence intervals for the association between endometrioid/clear cell ovarian cancer risk and three SNPs nominated by our pool-based GWAS: (A) rs2190503 (B) rs6593140 and (C) rs2329554. Study-specific odds ratios, 95% confidence intervals, and P-values are based on logistic regression assuming an additive genetic mode, adjusting for the first 5 eigenvalues from principal components analysis. Summary odds ratios and 95% confidence intervals are from fixed effects meta-analysis and include the OVA study site. Forest plots were generated using the rmeta library implemented in the R project; association analyses were performed using PLINK
Figure 3
Figure 3
Forest plot of the study specific and summary odds ratios and 95% confidence intervals for the association between low malignant potential serous ovarian cancer risk and one SNP nominated by our pool-based GWAS, rs9609538. Study-specific odds ratios, 95% confidence intervals, and P-values are based on logistic regression assuming an additive genetic model, adjusting for the first 5 eigenvalues from principal components analysis. Summary odds ratios and 95% confidence intervals are from fixed effects meta-analysis and include the OVA study site. Forest plots were generated using the rmeta library implemented in the R project; association analyses were performed using PLINK. The MDA and TOR study sites are not plotted; neither study had any LMP serous ovarian cancer cases or controls
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