Clinical significance in oral cavity squamous cell carcinoma of pathogenic somatic mitochondrial mutations

PLoS One. 2013 Jun 14;8(6):e65578. doi: 10.1371/journal.pone.0065578. Print 2013.


Somatic mutations affecting the mitochondrial DNA (mtDNA) have been frequently observed in human cancers and proposed as important oncological biomarkers. However, the clinical significance of mtDNA mutations in cancer remains unclear. This study was therefore performed to explore the possible clinical use in assessing oral squamous cell carcinoma (OSCC) of pathogenic mtDNA mutations. The entire mitochondrial genome of 300 OSCC with their matched control DNAs was screened by direct sequencing and criteria were set to define a pathogenic somatic mutation. The patients' TP53 R72P genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. The relationships between pathogenic somatic mutations, clinicopathogical features, TP53 R72P genotype and clinical prognosis were analyzed. Overall, 645 somatic mtDNA mutations were identified and 91 of these mutations were defined as pathogenic. About one quarter (74/300) of the OSCC tumor samples contained pathogenic mutations. Individuals with the TP53 R allele had a higher frequency of pathogenic somatic mutation than those with the PP genotype. Kaplan-Meier analysis indicated that TP53 R allele patients with pathogenic somatic mutations demonstrated a significant association with a poorer disease-free survival than other individuals (HR = 1.71; 95% CI, 1.15-2.57; p = 0.009) and this phenomenon still existed after adjusting for mtDNA haplogroup, tumor stage with treatment regimens, differentiation and age at diagnosis (HR = 1.59; 95% CI, 1.06-2.40; p = 0.03). Subgroup analyses showed that this phenomenon was limited to patients who received adjuvant radiotherapy/chemo-radiotherapy after surgery. The results strongly indicated that pathogenic mtDNA mutations are a potential prognostic marker for OSCCs. Furthermore, functional mitochondria may play an active role in cancer development and the patient's response to radiotherapy/chemo-radiotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / mortality
  • DNA, Mitochondrial / genetics
  • Disease-Free Survival
  • Electron Transport Chain Complex Proteins / genetics
  • Genes, Mitochondrial*
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Haplotypes
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Mitochondria / genetics*
  • Mouth Neoplasms / genetics*
  • Mouth Neoplasms / mortality
  • Mutation, Missense
  • Point Mutation
  • Polymorphism, Restriction Fragment Length
  • Proportional Hazards Models
  • Sequence Analysis, DNA
  • Tumor Suppressor Protein p53 / genetics*


  • DNA, Mitochondrial
  • Electron Transport Chain Complex Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53

Grant support

This study was supported by Grant NSC95-2314-B-182-049-MY3 and NSC98-2314-B-182-046-MY3 from the National Science Council, Executive Yuan, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.