title: Mitochondrial DNA mutations in preneoplastic lesions of the gastrointestinal tract: a biomarker for the early detection of cancer.
abstract: BACKGROUND
  Somatic mutations of mitochondrial DNA (mtDNA) are common in many human cancers. We have described an oligonucleotide microarray ("MitoChip") for rapid sequencing of the entire mitochondrial genome (Zhou et al, J Mol Diagn 2006), facilitating the analysis of mtDNA mutations in preneoplastic lesions. We examined 14 precancerous lesions, including seven Barrett esophagus biopsies, with or without associated dysplasia; four colorectal adenomas; and three inflammatory colitis-associated dysplasia specimens. In all cases, matched normal tissues from the corresponding site were obtained as germline control. MitoChip analysis was performed on DNA obtained from cryostat-embedded specimens.
  
  
  RESULTS
  A total of 513,639 bases of mtDNA were sequenced in the 14 samples, with 490,224 bases (95.4%) bases assigned by the automated genotyping software. All preneoplastic lesions examined demonstrated at least one somatic mtDNA sequence alteration. Of the 100 somatic mtDNA alterations observed in the 14 cases, 27 were non-synonymous coding region mutations (i.e., resulting in an amino acid change), 36 were synonymous, and 37 involved non-coding mtDNA. Overall, somatic alterations most commonly involved the COI, ND4 and ND5 genes. Notably, somatic mtDNA alterations were observed in preneoplastic lesions of the gastrointestinal tract even in the absence of histopathologic evidence of dysplasia, suggesting that the mitochondrial genome is susceptible at the earliest stages of multistep cancer progression.
  
  
  CONCLUSIONS
  Our findings further substantiate the rationale for exploring the mitochondrial genome as a biomarker for the early diagnosis of cancer, and confirm the utility of a high-throughput array-based platform for this purpose from a clinical applicability standpoint.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Washington, DC. gsui1@jhmi.edu
authors.forename: Guoping
authors.initials: G
authors.lastname: Sui
authors.forename: Shaoyu
authors.initials: S
authors.lastname: Zhou
authors.forename: Jean
authors.initials: J
authors.lastname: Wang
authors.forename: Marcia
authors.initials: M
authors.lastname: Canto
authors.forename: Edward E
authors.initials: EE
authors.lastname: Lee
authors.forename: James R
authors.initials: JR
authors.lastname: Eshleman
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Montgomery
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Califano
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
mesh_terms: D001331:Automation; D014408:Biomarkers, Tumor; D001706:Biopsy; D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm; D018450:Disease Progression; D005770:Gastrointestinal Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D018895:Microsatellite Repeats; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm