Abstract 2009: Clinical value of pathogenic mitochondrial mutations in oral cavity squamous cell carcinoma.
Authors: Hsieh Ling-Ling , Lai Chih-Hsiung , Huang Shiang-Fu , Liao Chun-Ta , Chen I-How , Wang Hung-Ming 
Published: August 2014

Mitochondria appear to have a central role in two of the basic cancer cellular hallmarks made by Hanahan and Weinberg: reprogramming of energy metabolism and glucose-shortage induced apoptosis. Somatic mutations in 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. In the present study, we screened the entire mitochondrial genome of 300 oral cavity squamous cell carcinomas (OSCC) with their matched control tissues by direct sequencing. We found that 240 (80%) OSCC tumor tissues had one or more somatic mutations and 85 % (203/240) of somatic mutation occurs in the control region (D-loop region) of mitochondrial genome, 47.1% (113/240) in the coding region, 13.8% (33/240) in rRNA and 8.3% (20/240) cases with in tRNA. Overall, 645 somatic mutations at 329 unique nucleotide positions were identified and 355 (55.0%) of 645 somatic mutations were located in the D-loop. The relative mutation frequency (mutations/nucleotides) in the D-loop was 15.6-fold higher than in the other regions (355/1121 versus 290/15448). The highest mutation was in the D310 polycytidine stretch region, where 165 (25.6%, 165/645) mutations were found. Among the 10 somatic mtDNA hot mutation sites, 6 are known mono-/di-nucleotide repeat length polymorphic sites, namely nucleotide position 310-317 (D310, also known as hypervariable region 1), 514-523 (CA repeat), 568-576 (C stretch 1), 956-965 (12S RNA), 5895-5899 (C stretch 2) and 16180-16195 (hypervariable region 2. We found that the mutation frequency at these 6 mono-/di-nucleotide repeat length polymorphic sites was strongly associated with the number of the repeat length and status of heteroplasmy. In the total 645 mutations, most common mutation type was base substitution (58.3%, 376/645), and transition mutation (G:C &gt; A:T and A:T &gt; G:C) accounted for the most mutations (94.7%, 356/376). The total and pathogenic mutation load for mitochondrial respiratory complexes was 1.10% and 0.76%, respectively. No significant association was found between somatic mtDNA mutations in whole mitochondrial genome and the clinicopathological features. However, we found that individuals with p53 R allele had higher frequency of pathogenic somatic mtDNA mutation than those with PP genotype. The Kaplan-Meier plot analysis indicated that pathogenic somatic mtDNA mutations was associated with poor disease-free survival (p = 0.02) and this phenomenon still existed after adjusting for tumor stage, differentiation and age at diagnosis (hazard ratio = 1.557; 95% confidence interval = 1.058 - 2.292); while, there was no difference in overall survival. Taken together, these data suggest that pathogenic somatic mtDNA mutations may play important roles in the aggressiveness of OSCCs.

Citation Format: Ling-Ling Hsieh, Chih-Hsiung Lai, Shiang-Fu Huang, Chun-Ta Liao, I-How Chen, Hung-Ming Wang. Clinical value of pathogenic mitochondrial mutations in oral cavity squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2009. doi:10.1158/1538-7445.AM2013-2009