Citations 2
Inherited Variants in Mitochondrial Biogenesis Genes May Influence Epithelial Ovarian Cancer Risk
Permuth‐Wey, Jennifer, Chen, Y. Ann , Tsai, Ya-Yu, Chen, Zhihua , Qu, Xiaotao , Lancaster, Johnathan M., Stockwell, Heather, Dagne, Getachew , Iversen, Edwin S., Barnholtz‐Sloan, Jill S. , Cunningham, Julie M. , Vierkant, Robert A. , Sutphen, Rebecca , McLaughlin, John, Narod, Steven A., Goode, Ellen L. , Schildkraut, Joellen M. , Fenstermacher, David, Phelan, Catherine M., Sellers, Thomas A. , Risch, Harvey A. , Fridley, Brooke L. , McLaughlin, John, Vierkant, Robert A , Barnholtz-Sloan, Jill S
Cancer Epidemiology, Biomarkers & Prevention | June 7, 2011 | Volume: 20 | Issue: 6 | Pages: 1131-1145
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. Cancer Epidemiol Biomarkers Prev; 20(6); 1131–45. ©2011 AACR.
LIN28B Polymorphisms Influence Susceptibility to Epithelial Ovarian Cancer
Permuth‐Wey, Jennifer, Tsai, Ya-Yu, Lin, Hui‐Yi , Chen, Y. Ann , Barnholtz‐Sloan, Jill S. , Birrer, Michael J. , Bloom, Gregory, Chen, Zhihua , Cunningham, Julie M. , Dagne, Getachew , Ebbert-Syfrett, Judith, Fenstermacher, David, García‐Closas, Montserrat , Gayther, Simon A. , Bosquet, Jesús González , Goode, Ellen L. , Iversen, Edwin S., Kong, William, McLaughlin, John, Menon, Usha , Monteiro, Álvaro N.A. , Narod, Steven A., Phelan, Catherine M., Qu, Xiaotao , Ramus, Susan J. , Schildkraut, Joellen M. , Song, Honglin , Stockwell, Heather, Sutphen, Rebecca , Terry, Kathryn L. , Vierkant, Robert A. , Wentzensen, Nicolas , Lancaster, Johnathan M., Cheng, Jin Q. , Sellers, Thomas A. , Kim, Donghwa , Chanock, Stephen Jacob , Cramer, Daniel W. , Fridley, Brooke L. , Ge, William H. , Gentry‐Maharaj, Aleksandra , Jim, Heather , McLaughlin, John, Pharoah, Paul D.P. , Risch, Harvey A. , Tyrer, Jonathan P. , Ramus, Susan J , Vierkant, Robert A , Menon, Usha , Monteiro, Alvaro N , Barnholtz-Sloan, Jill S , Lin, Hui-Yi , García-Closas, Montserrat , Bosquet, Jesus Gonzalez
Cancer Research | April 12, 2011 | Volume: 71 | Issue: 11 | Pages: 3896-3903
Abstract Defective microRNA (miRNA) biogenesis contributes to the development and progression of epithelial ovarian cancer (EOC). In this study, we examined the hypothesis that single nucleotide polymorphisms (SNP) in miRNA biogenesis genes may influence EOC risk. In an initial investigation, 318 SNPs in 18 genes were evaluated among 1,815 EOC cases and 1,900 controls, followed up by a replicative joint meta-analysis of data from an additional 2,172 cases and 3,052 controls. Of 23 SNPs from 9 genes associated with risk (empirical P < 0.05) in the initial investigation, the meta-analysis replicated 6 SNPs from the DROSHA, FMR1, LIN28, and LIN28B genes, including rs12194974 (G>A), an SNP in a putative transcription factor binding site in the LIN28B promoter region (summary OR = 0.90, 95% CI: 0.82–0.98; P = 0.015) which has been recently implicated in age of menarche and other phenotypes. Consistent with reports that LIN28B overexpression in EOC contributes to tumorigenesis by repressing tumor suppressor let-7 expression, we provide data from luciferase reporter assays and quantitative RT-PCR to suggest that the inverse association among rs12194974 A allele carriers may be because of reduced LIN28B expression. Our findings suggest that variants in LIN28B and possibly other miRNA biogenesis genes may influence EOC susceptibility. Cancer Res; 71(11); 3896–903. ©2011 AACR.