Faculty publish Inherited Variants in Mitochondrial Biogenesis Genes May Influence Epithelial Ovarian Cancer Risk.

| EPI-BIO, Our Research

Permuth-Wey J, Chen YA, Tsai YY, Chen Z, Qu X, Lancaster JM, Stockwell H,
Dagne G, Iversen E, Risch H, Barnholtz-Sloan J, Cunningham JM, Vierkant RA,
Fridley BL, Sutphen R, McLaughlin J, Narod SA, Goode EL, Schildkraut JM,
Fenstermacher D, Phelan CM, Sellers TA. Inherited Variants in Mitochondrial
Biogenesis Genes May Influence Epithelial Ovarian Cancer Risk. Cancer Epidemiol
Biomarkers Prev. 2011 Mar 29. [Epub ahead of print] PubMed PMID: 21447778.


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 multi-center 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 odds ratios (OR) and 95% confidence intervals (CI) between genotype and case status. Overall significance of each gene and pathway was evaluated 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: Inter-individual 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 non-genetic 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).

CONCLUSIONS: 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.

PMID: 21447778 [PubMed – as supplied by publisher]