title: Somatic mutations in mitochondrial genome and their potential roles in the progression of human gastric cancer.
abstract: BACKGROUND
  Somatic mutation in mitochondrial DNA (mtDNA) has been proposed to contribute to initiation and progression of human cancer. In our previous study, high frequency of somatic mutations was found in the D-loop region of mtDNA of gastric cancers. However, it is unclear whether somatic mutations occur in the coding region of mtDNA of gastric cancers.
  
  
  METHODS
  Using DNA sequencing, we studied 31 gastric cancer specimens and corresponding non-cancerous stomach tissues. Moreover, a human gastric cancer SC-M1 cell line was treated with oligomycin to induce mitochondrial dysfunction. Cisplatin sensitivity and cell migration were analyzed.
  
  
  RESULTS
  We identified eight somatic mutations in the coding region of mtDNAs of seven gastric cancer samples (7/31, 22.6%). Patients with somatic mutations in the entire mtDNA of gastric cancers did not show significant association with their clinicopathologic features. Among the eight somatic mutations, five point mutations (G3697A, G4996A, G9986A, C12405T and T13015C) are homoplasmic and three mutations (5895delC, 7472insC and 12418insA) are heteroplasmic. Four (4/8, 50%) of these somatic mutations result in amino acid substitutions in the highly conserved regions of mtDNA, which potentially lead to mitochondrial dysfunction. In addition, in vitro experiments in SC-M1 cells revealed that oligomycin-induced mitochondrial dysfunction promoted resistance to cisplatin and enhanced cell migration. N-acetyl cysteine was effective in the prevention of the oligomycin-enhanced migration, which suggests that reactive oxygen species generated by defective mitochondria may be involved in the enhanced migration of SC-M1 cells.
  
  
  CONCLUSIONS
  Our results suggest that somatic mtDNA mutations and mitochondrial dysfunction may play an important role in the malignant progression of gastric cancer.
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan 112, ROC.
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Hung
authors.forename: Chew-Wun
authors.initials: CW
authors.lastname: Wu
authors.forename: Pen-Hui
authors.initials: PH
authors.lastname: Yin
authors.forename: Chun-Ju
authors.initials: CJ
authors.lastname: Chang
authors.forename: Anna Fen-Yau
authors.initials: AF
authors.lastname: Li
authors.forename: Chin-Wen
authors.initials: CW
authors.lastname: Chi
authors.forename: Yau-Huei
authors.initials: YH
authors.lastname: Wei
authors.forename: Hsin-Chen
authors.initials: HC
authors.lastname: Lee
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000368:Aged; D019943:Amino Acid Substitution; D018929:Cell Culture Techniques / Q000379:methods; D002465:Cell Movement; D017931:DNA Primers; D004272:DNA, Mitochondrial / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005260:Female; D054629:Genome, Mitochondrial / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000473:pathology / Q000502:physiology; D009154:Mutation; D010101:Oxygen Consumption; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion; D013270:Stomach / Q000503:physiopathology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D017931:DNA Primers; D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm; D000255:Adenosine Triphosphate