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Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot".


ABSTRACT: 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-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n=1,233 serous invasive cases; n=3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele>or=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.

SUBMITTER: Johnatty SE 

PROVIDER: S-EPMC2900295 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot".

Johnatty Sharon E SE   Beesley Jonathan J   Chen Xiaoqing X   Macgregor Stuart S   Duffy David L DL   Spurdle Amanda B AB   deFazio Anna A   Gava Natalie N   Webb Penelope M PM   Rossing Mary Anne MA   Doherty Jennifer Anne JA   Goodman Marc T MT   Lurie Galina G   Thompson Pamela J PJ   Wilkens Lynne R LR   Ness Roberta B RB   Moysich Kirsten B KB   Chang-Claude Jenny J   Wang-Gohrke Shan S   Cramer Daniel W DW   Terry Kathryn L KL   Hankinson Susan E SE   Tworoger Shelley S SS   Garcia-Closas Montserrat M   Yang Hannah H   Lissowska Jolanta J   Chanock Stephen J SJ   Pharoah Paul D PD   Song Honglin H   Whitemore Alice S AS   Pearce Celeste L CL   Stram Daniel O DO   Wu Anna H AH   Pike Malcolm C MC   Gayther Simon A SA   Ramus Susan J SJ   Menon Usha U   Gentry-Maharaj Aleksandra A   Anton-Culver Hoda H   Ziogas Argyrios A   Hogdall Estrid E   Kjaer Susanne K SK   Hogdall Claus C   Berchuck Andrew A   Schildkraut Joellen M JM   Iversen Edwin S ES   Moorman Patricia G PG   Phelan Catherine M CM   Sellers Thomas A TA   Cunningham Julie M JM   Vierkant Robert A RA   Rider David N DN   Goode Ellen L EL   Haviv Izhak I   Chenevix-Trench Georgia G  

PLoS genetics 20100708 7


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 a  ...[more]

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