title: 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).
  
  
  CONCLUSIONS
  We provide novel evidence to suggest that variants in mitochondrial biogenesis genes may influence EOC susceptibility.
  
  
  CONCLUSIONS
  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.
authors: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida 33612-9416, USA.
authors: Jennifer
authors: J
authors: Permuth-Wey
authors: Y Ann
authors: YA
authors: Chen
authors: Ya-Yu
authors: YY
authors: Tsai
authors: Zhihua
authors: Z
authors: Chen
authors: Xiaotao
authors: X
authors: Qu
authors: Johnathan M
authors: JM
authors: Lancaster
authors: Heather
authors: H
authors: Stockwell
authors: Getachew
authors: G
authors: Dagne
authors: Edwin
authors: E
authors: Iversen
authors: Harvey
authors: H
authors: Risch
authors: Jill
authors: J
authors: Barnholtz-Sloan
authors: Julie M
authors: JM
authors: Cunningham
authors: Robert A
authors: RA
authors: Vierkant
authors: Brooke L
authors: BL
authors: Fridley
authors: Rebecca
authors: R
authors: Sutphen
authors: John
authors: J
authors: McLaughlin
authors: Steven A
authors: SA
authors: Narod
authors: Ellen L
authors: EL
authors: Goode
authors: Joellen M
authors: JM
authors: Schildkraut
authors: David
authors: D
authors: Fenstermacher
authors: Catherine M
authors: CM
authors: Phelan
authors: Thomas A
authors: TA
authors: Sellers
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics; D002288:Adenocarcinoma, Mucinous / Q000235:genetics; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D016022:Case-Control Studies; D018284:Cystadenocarcinoma, Serous / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics; D005260:Female; D050259:Genes, Mitochondrial / Q000235:genetics*; D005838:Genotype; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics*; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004272:DNA, Mitochondrial; D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; D051267:NF-E2-Related Factor 2; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C105178:MTERF1 protein, human; C495635:NFE2L2 protein, human; C495633:NRF1 protein, human; C486497:PPARGC1A protein, human; C517660:CAMK2D protein, human