Presentation Abstract

Abstract Number: 2835
Presentation Title: Mitochondrial genetic variants influence ovarian cancer risk
Presentation Time: Monday, Apr 19, 2010, 2:00 PM - 5:00 PM
Location: Exhibit Hall A-C, Poster Section 36
Poster Section: 36
Poster Board Number: 5
Author Block: Jennifer Permuth-Wey1, Ya-Yu Tsai1, Y. Ann Chen1, Zhihua Chen1, Johnathan M. Lancaster1, Edwin Iverson2, Harvey Risch3, Jill Barnholtz-Sloan4, Julie M. Cunningham5, Robert A. Vierkant5, Brooke L. Fridley5, David Fenstermacher1, Rebecca Sutphen1, Steven A. Narod6, Ellen L. Goode5, Joellen M. Schildkraut2, Thomas A. Sellers1, Catherine M. Phelan1. 1H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 2Duke University School of Medicine, Durham, NC; 3Yale University, New Haven, CT; 4Case Comprehensive Cancer Center, Case School of Medicine, Cleveland, OH; 5Mayo Clinic College of Medicine, Rochester, MN; 6Women's College Hospital, Toronto, ON, Canada
Abstract Body: Mitochondria have been implicated in carcinogenesis because of their central role in apoptosis, free radical production, and cellular energy metabolism. Although studies have identified somatic mitochondrial DNA mutations in ovarian cancers, little attention has been directed to the possible role of germline mitochondrial variants in mitochondrial dysfunction and subsequent ovarian cancer development.
Through an ongoing epithelial ovarian cancer genome-wide association study of 1,856 invasive cases (59% with serous carcinomas) and 1,912 controls (frequency-matched on age, race, and study site), we genotyped 138 SNPs tagging variation in the maternally-inherited mitochondrial genome (mtDNA) to evaluate the hypothesis that single nucleotide polymorphisms (SNPs) in mtDNA are associated with ovarian cancer risk. All subjects were non-Hispanic, non-Jewish Caucasians, and were genotyped with the Illumina 610-quad Beadchip. Samples and SNPs with call rates less than 95% were excluded. Subjects with ambiguous gender, unresolved identical genotypes, and less than 80% European ancestry were excluded. For each SNP, logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) between carriers of the minor versus major maternally-inherited allele and case status. Subgroup analysis was conducted to estimate allele-specific risks between serous-only cases and controls. Haplotype analysis was performed for regions containing statistically significant SNPs (p<0.05).
Two rare SNPs, C16329T in the displacement loop gene (MT-D-loop) (OR: 6.72, 95%CI: 1.5-29.8, p=0.004; minor allele frequency (MAF)=0.001) and C15905T in the tRNA threonine gene (MT-TT) (OR: 1.60, 95%CI: 1.1-2.3, p=0.009; MAF=0.027), were associated with increased ovarian cancer risk; whereas T6777C in the cytochrome c oxidase subunit 1 gene (MT-CO1) (OR: 0.68, 95%CI: 0.51-0.91, p=0.009; MAF=0.063) was associated with decreased risk. All three SNPs remained statistically significant after adjustment for multiple comparisons within the mitochondrial SNPs using permutation testing. C16329T and T6777C were also significantly associated among cases with serous histology, with ORs (95% CIs) of 6.13 (1.2-29.6) and 0.61 (0.43-0.87), respectively. Haplotype analysis for each of the three regions investigated revealed significant haplotype-disease associations; however, findings suggest that the respective associations were driven by the most significant SNP(s) listed above.
This is the first large-scale epidemiologic study to provide evidence that SNPs in mitochondrial genes may be novel risk factors for ovarian cancer. Future investigation of additional mitochondrial variants (i.e. nuclear-encoded mitochondrial proteins) is necessary to more comprehensively investigate this association. Furthermore, replication of the most promising SNPs in a larger population is warranted to validate these findings.