Johnatty, Sharon E2; Beesley, Jonathan2; Chen, Xiaoqing2; Macgregor, Stuart2; Duffy, David L2; Spurdle, Amanda B2; deFazio, Anna2; Gava, Natalie2; Webb, Penelope M2; Rossing, Mary Anne2; Doherty, Jennifer Anne2; Goodman, Marc T2; Lurie, Galina2; Thompson, Pamela J2; Wilkens, Lynne R2; Ness, Roberta B2; Moysich, Kirsten B2; Chang-Claude, Jenny2; Wang-Gohrke, Shan2; Cramer, Daniel W2; Terry, Kathryn L2; Hankinson, Susan E2; Tworoger, Shelley S2; Garcia-Closas, Montserrat2; Yang, Hannah2; Lissowska, Jolanta2; Chanock, Stephen J2; Pharoah, Paul D2; Song, Honglin2; Whitemore, Alice S2; Pearce, Celeste L2; Stram, Daniel O2; Wu, Anna H2; Pike, Malcolm C2; Gayther, Simon A2; Ramus, Susan J2; Menon, Usha2; Gentry-Maharaj, Aleksandra2; Anton-Culver, Hoda2; Ziogas, Argyrios2; Hogdall, Estrid2; Kjaer, Susanne K1; Hogdall, Claus1; Berchuck, Andrew2; Schildkraut, Joellen M2; Iversen, Edwin S2; Moorman, Patricia G2; Phelan, Catherine M2; Sellers, Thomas A2; Cunningham, Julie M2; Vierkant, Robert A2; Rider, David N2; Goode, Ellen L2; Haviv, Izhak2; Chenevix-Trench, Georgia2
1 Gynækologisk Klinik, Juliane Marie Centre, Rigshospitalet, The Capital Region of Denmark2 unknown
We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-alleleor=0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p=0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.