title: Significance of somatic mutations and content alteration of mitochondrial DNA in esophageal cancer.
abstract: BACKGROUND
  The roles of mitochondria in energy metabolism, the generation of ROS, aging, and the initiation of apoptosis have implicated their importance in tumorigenesis. In this study we aim to establish the mutation spectrum and to understand the role of somatic mtDNA mutations in esophageal cancer.
  
  
  METHODS
  The entire mitochondrial genome was screened for somatic mutations in 20 pairs (18 esophageal squamous cell carcinomas, one adenosquamous carcinoma and one adenocarcinoma) of tumor/surrounding normal tissue of esophageal cancers, using temporal temperature gradient gel electrophoresis (TTGE), followed by direct DNA sequencing to identify the mutations.
  
  
  RESULTS
  Fourteen somatic mtDNA mutations were identified in 55% (11/20) of tumors analyzed, including 2 novel missense mutations and a frameshift mutation in ND4L, ATP6 subunit, and ND4 genes respectively. Nine mutations (64%) were in the D-loop region. Numerous germline variations were found, at least 10 of them were novel and five were missense mutations, some of them occurred in evolutionarily conserved domains. Using real-time quantitative PCR analysis, the mtDNA content was found to increase in some tumors and decrease in others. Analysis of molecular and other clinicopathological findings does not reveal significant correlation between somatic mtDNA mutations and mtDNA content, or between mtDNA content and metastatic status.
  
  
  CONCLUSIONS
  Our results demonstrate that somatic mtDNA mutations in esophageal cancers are frequent. Some missense and frameshift mutations may play an important role in the tumorigenesis of esophageal carcinoma. More extensive biochemical and molecular studies will be necessary to determine the pathological significance of these somatic mutations.
authors.affiliation: Institute for Molecular and Human Genetics, Georgetown University Medical Center, Washington DC, USA. dt33@georgetown.edu
authors.forename: Duan-Jun
authors.initials: DJ
authors.lastname: Tan
authors.forename: Julia
authors.initials: J
authors.lastname: Chang
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Liu
authors.forename: Ren-Kui
authors.initials: RK
authors.lastname: Bai
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Wang
authors.forename: Kun-Tu
authors.initials: KT
authors.lastname: Yeh
authors.forename: Lee-Jun C
authors.initials: LJ
authors.lastname: Wong
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D018196:Carcinoma, Adenosquamous / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D004586:Electrophoresis; D004938:Esophageal Neoplasms / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D017382:Reactive Oxygen Species; D017422:Sequence Analysis, DNA; D013696:Temperature
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D004247:DNA