Clinical value of mitochondrial mutations in colorectal cancer

  • Lièvre A
  • Chapusot C
  • Bouvier A
 et al. 
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Abstract

PURPOSE: Prognostic factors that could select high-risk recurrence colorectal cancer patients and predict chemosensitivity are needed. Since mutations of mitochondrial DNA (mtDNA) have been described in different types of cancers and since they may play a role in response to anticancer agents, we investigated in a population-based series of colorectal cancer patients the clinical value of mtDNA mutations. PATIENTS AND METHODS: The displacement loop (D-loop) region of mtDNA was sequenced on a series of 365 patients recorded in the Digestive Cancer Registry of Côte-d'Or (France) between 1998 and 2000. Clinicopathologic characteristics were correlated to the presence of a D-loop mutation. Survival rates were compared with the log-rank test. A multivariate survival analysis was performed. RESULTS: D-loop mutations were found in 38.3% of the tumors. The 3-year survival rate was 53.5% in patients with D-loop mutation versus 62.1% in patients without (P = .05). After adjustment for age, stage, and microsatellite instability status, the relative risk of death in patients with D-loop mutation was 1.40 (95% CI, 1.02 to 1.93; P = .034) as compared with those without. In stage III colon cancers, adjuvant chemotherapy was beneficial only for patients without D-loop mutation (3-year survival, 78.3% v 45.4%, P < .02). In those with D-loop mutation who received adjuvant chemotherapy, the relative risk of death was 4.30 (95% CI, 1.23 to 15.00; P < .02). CONCLUSION: The D-loop region is a hotspot for somatic mutations in colorectal tumors. Moreover, presence of tumor D-loop mutation appears to be a factor of poor prognosis in colorectal patients and a factor of resistance to fluorouracil-based adjuvant chemotherapy in stage III colon cancers.

Author-supplied keywords

  • Antineoplastic Combined Chemotherapy Protocols
  • Base Sequence
  • Case-Control Studies
  • Colorectal Neoplasms
  • Confidence Intervals
  • DNA Mutational Analysis
  • DNA: Mitochondrial
  • Female
  • Gene Expression Regulation: Neoplastic
  • Humans
  • Male
  • Molecular Sequence Data
  • Multivariate Analysis
  • Mutation
  • Pharmacogenetics
  • Polymerase Chain Reaction
  • Prognosis
  • Proportional Hazards Models
  • Reference Values
  • Sampling Studies
  • Sensitivity and Specificity
  • Survival Analysis
  • Tissue Culture Techniques
  • Treatment Outcome
  • Tumor Markers: Biological

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Authors

  • A Lièvre

  • C Chapusot

  • A M Bouvier

  • F Zinzindohoué

  • F Piard

  • P Roignot

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