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

Jennifer Permuth-Wey, Y. Ann Chen, Ya Yu Tsai, Zhihua Chen, Xiaotao Qu, Johnathan M. Lancaster, Heather Stockwell, Getachew Dagne, Edwin Iversen, Harvey Risch, Jill Barnholtz-Sloan, Julie M Cunningham, Robert A. Vierkant, Brooke L. Fridley, Rebecca Sutphen, John McLaughlin, Steven A. Narod, Ellen L Goode, Joellen M. Schildkraut, David Fenstermacher & 2 others Catherine M. Phelan, Thomas A. Sellers

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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.

Original languageEnglish (US)
Pages (from-to)1131-1145
Number of pages15
JournalCancer Epidemiology Biomarkers and Prevention
Volume20
Issue number6
DOIs
StatePublished - Jun 2011

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Mitochondrial Genes
Organelle Biogenesis
Single Nucleotide Polymorphism
Hormone Replacement Therapy
Mitochondrial DNA
Oxidative Stress
Smoking
Genes
Mitochondrial Genome
Oxidative Phosphorylation
Ovulation
Multicenter Studies
Ovarian epithelial cancer
Mitochondria
Carcinogenesis
Logistic Models
Steroids
Genotype
Hormones
Morbidity

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Permuth-Wey, J., Chen, Y. A., Tsai, Y. Y., Chen, Z., Qu, X., Lancaster, J. M., ... Sellers, T. A. (2011). Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk. Cancer Epidemiology Biomarkers and Prevention, 20(6), 1131-1145. https://doi.org/10.1158/1055-9965.EPI-10-1224

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; Risch, Harvey; Barnholtz-Sloan, Jill; Cunningham, Julie M; Vierkant, Robert A.; Fridley, Brooke L.; Sutphen, Rebecca; McLaughlin, John; Narod, Steven A.; Goode, Ellen L; Schildkraut, Joellen M.; Fenstermacher, David; Phelan, Catherine M.; Sellers, Thomas A.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 20, No. 6, 06.2011, p. 1131-1145.

Research output: Contribution to journalArticle

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 2011, 'Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk', Cancer Epidemiology Biomarkers and Prevention, vol. 20, no. 6, pp. 1131-1145. https://doi.org/10.1158/1055-9965.EPI-10-1224
Permuth-Wey, Jennifer ; Chen, Y. Ann ; Tsai, Ya Yu ; Chen, Zhihua ; Qu, Xiaotao ; Lancaster, Johnathan M. ; Stockwell, Heather ; Dagne, Getachew ; Iversen, Edwin ; Risch, Harvey ; Barnholtz-Sloan, Jill ; Cunningham, Julie M ; Vierkant, Robert A. ; Fridley, Brooke L. ; Sutphen, Rebecca ; McLaughlin, John ; Narod, Steven A. ; Goode, Ellen L ; Schildkraut, Joellen M. ; Fenstermacher, David ; Phelan, Catherine M. ; Sellers, Thomas A. / Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk. In: Cancer Epidemiology Biomarkers and Prevention. 2011 ; Vol. 20, No. 6. pp. 1131-1145.
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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.",
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T1 - Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk

AU - Permuth-Wey, Jennifer

AU - Chen, Y. Ann

AU - Tsai, Ya Yu

AU - Chen, Zhihua

AU - Qu, Xiaotao

AU - Lancaster, Johnathan M.

AU - Stockwell, Heather

AU - Dagne, Getachew

AU - Iversen, Edwin

AU - Risch, Harvey

AU - Barnholtz-Sloan, Jill

AU - Cunningham, Julie M

AU - Vierkant, Robert A.

AU - Fridley, Brooke L.

AU - Sutphen, Rebecca

AU - McLaughlin, John

AU - Narod, Steven A.

AU - Goode, Ellen L

AU - Schildkraut, Joellen M.

AU - Fenstermacher, David

AU - Phelan, Catherine M.

AU - Sellers, Thomas A.

PY - 2011/6

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N2 - 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.

AB - 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.

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