title: Inherited common variants in mitochondrial DNA and invasive serous epithelial ovarian cancer risk.
abstract: 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%.
  
  
  CONCLUSIONS
  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.
authors.forename: Madalene A
authors.initials: MA
authors.lastname: Earp
authors.affiliation: Canada's Michael Smith Genome Sciences Center, BC Cancer Agency, Vancouver, BC, Canada. abrooks-wilson@bcgsc.ca.
authors.forename: Angela
authors.initials: A
authors.lastname: Brooks-Wilson
authors.forename: Linda
authors.initials: L
authors.lastname: Cook
authors.forename: Nhu
authors.initials: N
authors.lastname: Le
mesh_terms: D000368:Aged; D000483:Alleles; D002170:Canada; D000077216:Carcinoma, Ovarian Epithelial; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D040582:Inheritance Patterns; D016015:Logistic Models; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology; D009245:NADH Dehydrogenase / Q000235:genetics; D009375:Neoplasms, Glandular and Epithelial / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D016017:Odds Ratio; D010051:Ovarian Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D017382:Reactive Oxygen Species / Q000378:metabolism; D012306:Risk; D044465:White People
chemical_list: D004272:DNA, Mitochondrial; C098483:NADH dehydrogenase subunit 4; D017382:Reactive Oxygen Species; D009245:NADH Dehydrogenase