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Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk.

ABSTRACT: BACKGROUND:Mitochondria contribute to oxidative stress, a phenomenon implicated in ovarian carcinogenesis. We hypothesized that inherited variants in mitochondrial-related genes influence epithelial ovarian cancer (EOC) susceptibility. METHODS:Through a multicenter study of 1,815 Caucasian EOC cases and 1,900 controls, we investigated associations between EOC risk and 128 single nucleotide polymorphisms (SNPs) from 22 genes/regions within the mitochondrial genome (mtDNA) and 2,839 nuclear-encoded SNPs localized to 138 genes involved in mitochondrial biogenesis (BIO, n = 35), steroid hormone metabolism (HOR, n = 13), and oxidative phosphorylation (OXP, n = 90) pathways. Unconditional logistic regression was used to estimate OR and 95% CI between genotype and case status. Overall significance of each gene and pathway was evaluated by using Fisher's method to combine SNP-level evidence. At the SNP level, we investigated whether lifetime ovulation, hormone replacement therapy (HRT), and cigarette smoking were confounders or modifiers of associations. RESULTS:Interindividual variation involving BIO was most strongly associated with EOC risk (empirical P = 0.050), especially for NRF1, MTERF, PPARGC1A, ESRRA, and CAMK2D. Several SNP-level associations strengthened after adjustment for nongenetic factors, particularly for MTERF. Statistical interactions with cigarette smoking and HRT use were observed with MTERF and CAMK2D SNPs, respectively. Overall variation within mtDNA, HOR, and OXP was not statistically significant (empirical P > 0.10). CONCLUSION:We provide novel evidence to suggest that variants in mitochondrial biogenesis genes may influence EOC susceptibility. IMPACT:A deeper understanding of the complex mechanisms implicated in mitochondrial biogenesis and oxidative stress may aid in developing strategies to reduce morbidity and mortality from EOC.

SUBMITTER: Permuth-Wey J

PROVIDER: S-EPMC3111851 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk.

Permuth-Wey Jennifer J Chen Y Ann YA Tsai Ya-Yu YY Chen Zhihua Z Qu Xiaotao X Lancaster Johnathan M JM Stockwell Heather H Dagne Getachew G Iversen Edwin E Risch Harvey H Barnholtz-Sloan Jill J Cunningham Julie M JM Vierkant Robert A RA Fridley Brooke L BL Sutphen Rebecca R McLaughlin John J Narod Steven A SA Goode Ellen L EL Schildkraut Joellen M JM Fenstermacher David D Phelan Catherine M CM Sellers Thomas A TA

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20110329 6

<h4>Background</h4>Mitochondria contribute to oxidative stress, a phenomenon implicated in ovarian carcinogenesis. We hypothesized that inherited variants in mitochondrial-related genes influence epithelial ovarian cancer (EOC) susceptibility.<h4>Methods</h4>Through a multicenter study of 1,815 Caucasian EOC cases and 1,900 controls, we investigated associations between EOC risk and 128 single nucleotide polymorphisms (SNPs) from 22 genes/regions within the mitochondrial genome (mtDNA) and 2,839 ...[more]

PMID: 21447778

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Project description:BACKGROUND:Mitochondria are the site of oxidative phosphorylation, a process which generates reactive oxygen species (ROS). Elevated ROS levels can lead to oxidative stress, a cellular state implicated in carcinogenesis. It is hypothesized that alternations in mitochondrial (MT) DNA, including heritable MT single nucleotide polymorphisms (MT-SNPs), have the potential to change the capacity of MT function, leading to increased oxidative stress and cancer risk. We investigated if common MT-SNPs and/or haplogroups and are associated with invasive serous ovarian cancer (OvCa) risk. METHODS:A panel of 64 MT-SNPs designed to tag all common variation in the European MT genome (minor allele frequency (MAF) >1%, r^2 >0.8) was genotyped in study participants of European descent using the Sequenom MassARRAY iPlex Gold® system (Sequenom Inc, CA, USA). Invasive serous OvCa cases (n?=?405) and frequency age-matched controls (n?=?445) were drawn from a population-based case-control study of OvCa in western Canada. Binary logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (C.I.) for carriage of the minor versus major allele by case-control status. MitoTool was used to test the relationship between European haplogroup status and case-control status using Fisher's exact test. RESULTS:The most significant disease-SNP association was for rs2857285, a synonymous MT-SNP in ND4 (OR?=?4.84, 95% CI: 1.03-22.68, P?=?0.045). After adjustment for multiple testing using a Bonferroni correction of the Type 1 error this MT-SNP was not significant. No other MT-SNP had a P-value?<?0.05. European haplogroup status was not associated with case status. Most MT-SNPs (73%) genotyped had a MAF <5%. CONCLUSION:Common European MT-SNPs (MAF?>?5%) and haplogroups were not associated with invasive serous OvCa risk in this study; however, most European MT-SNPs have a low MAF (<5%), which we were underpowered to adequately assess. Larger studies are needed to clarify the role of low MAF MT-SNPs (MAF?<?5%) in invasive serous OvCa risk.

Dataset Information

Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk.

Publications

Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk.

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