Dataset Information

Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer.

ABSTRACT: The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r(2) = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07-1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01-1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region.

SUBMITTER: Schildkraut JM

PROVIDER: S-EPMC2666150 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer.

Schildkraut Joellen M JM Goode Ellen L EL Clyde Merlise A MA Iversen Edwin S ES Moorman Patricia G PG Berchuck Andrew A Marks Jeffrey R JR Lissowska Jolanta J Brinton Louise L Peplonska Beata B Cunningham Julie M JM Vierkant Robert A RA Rider David N DN Chenevix-Trench Georgia G Webb Penelope M PM Beesley Jonathan J Chen Xiaoqing X Phelan Catherine C Sutphen Rebecca R Sellers Thomas A TA Pearce Leigh L Wu Anna H AH Van Den Berg David D Conti David D Elund Christopher K CK Anderson Rebecca R Goodman Marc T MT Lurie Galina G Carney Michael E ME Thompson Pamela J PJ Gayther Simon A SA Ramus Susan J SJ Jacobs Ian I Krüger Kjaer Susanne S Hogdall Estrid E Blaakaer Jan J Hogdall Claus C Easton Douglas F DF Song Honglin H Pharoah Paul D P PD Whittemore Alice S AS McGuire Valerie V Quaye Lydia L Anton-Culver Hoda H Ziogas Argyrios A Terry Kathryn L KL Cramer Daniel W DW Hankinson Susan E SE Tworoger Shelley S SS Calingaert Brian B Chanock Stephen S Sherman Mark M Garcia-Closas Montserrat M

Cancer research 20090310 6

The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent ...[more]

PMID: 19276375

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Project description:Thyroid cancer (TC) is the most common endocrine malignancy and its incidence continues to rise worldwide. Ionizing radiation exposure is the best established etiological factor. Heritability is high; however, despite valuable contribution from recent genome-wide association studies, the current understanding of genetic susceptibility to TC remains limited. Several studies suggest that altered function or expression of the DNA mismatch repair (MMR) system may contribute to TC pathogenesis. Therefore, the present study aimed to evaluate the potential role of a panel of MMR single nucleotide polymorphisms (SNPs) on the individual susceptibility to well-differentiated TC (DTC). A case-control study was performed involving 106 DTC patients and 212 age- and gender-matched controls, who were all Caucasian Portuguese. Six SNPs present in distinct MMR genes (MLH1 rs1799977, MSH3 rs26279, MSH4 rs5745325, PMS1 rs5742933, MLH3 rs175080 and MSH6 rs1042821) were genotyped through TaqMan® assays and genotype-associated risk estimates were calculated. An increased risk was observed in MSH6 rs1042821 variant homozygotes [adjusted odds ratio (OR)=3.42, 95% CI: 1.04-11.24, P=0.04, under the co-dominant model; adjusted OR=3.84, 95% CI: 1.18-12.44, P=0.03, under the recessive model]. The association was especially evident for the follicular histotype and female sex. The association was also apparent when MSH6 was analysed in combination with other MMR SNPs such as MSH3 rs26279. Interestingly, two other SNP combinations, both containing the MSH6 heterozygous genotype, were associated with a risk reduction, suggesting a protective effect for these genotype combinations. These data support the idea that MMR SNPs such as MSH6 rs1042821, alone or in combination, may contribute to DTC susceptibility. This is coherent with the limited evidence available. Nevertheless, further studies are needed to validate these findings and to establish the usefulness of these SNPs as genetic susceptibility biomarkers for DTC so that, in the near future, cancer prevention policies may be optimized under a personalized medicine perspective.

Dataset Information

Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer.

Publications

Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer.

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