Association of DNA sequence variation in mitochondrial DNA polymerase with mitochondrial DNA synthesis and risk of oral cancer

Gene. 2016 Jan 10;575(2 Pt 3):650-4. doi: 10.1016/j.gene.2015.09.039. Epub 2015 Sep 25.


Enzymes responsible for mitochondrial (mt) DNA synthesis and transcription are encoded by nuclear genome and inherited mutations in these genes may play important roles in enhancing risk of precancer and cancer. Here, genetic variations in 23 functionally relevant tagSNPs in 6 genes responsible for mtDNA synthesis and transcription were studied in 522 cancer and 241 precancer (i.e. leukoplakia) patients and 525 healthy controls using Illumina Golden Gate assay to explore association with risk of oral precancer and cancer. Two SNPs, rs41553913 at POLRMT and rs9905016 at POLG2, significantly increased risk of oral leukoplakia and cancer, respectively, at both genotypic and allelic levels. Gene-environment interaction models also revealed that tobacco habits and SNPs at POLG2 and TFAM may modulate risk of both leukoplakia and cancer. In silico analysis of published data-set also revealed that variant heterozygote (TC) significantly increased transcription of POLG2 compared to wild genotype (p=0.03). Cancer tissues having variant allele genotypes (TC+CC) at POLG2 contained 1.6 times (p<0.01) more mtDNA compared to cancer tissues having wild genotype (TT). In conclusion, polymorphisms at POLG2 and POLRMT increased risk of oral cancer and leukoplakia, respectively, probably modulating synthesis and activity of the enzymes. Enhanced synthesis of mtDNA in cancer tissues may have implication in carcinogenesis, but the mechanism is yet to be explored.

Keywords: Association; DNA polymerase γ2; DNA sequence variation; Mitochondrial DNA content; Oral precancer and cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • DNA, Mitochondrial / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Directed DNA Polymerase / genetics*
  • DNA-Directed RNA Polymerases / genetics*
  • Female
  • Gene-Environment Interaction
  • Genetic Predisposition to Disease
  • Humans
  • Leukoplakia, Oral / genetics*
  • Male
  • Middle Aged
  • Mitochondria / genetics
  • Mitochondrial Proteins / genetics
  • Mouth Neoplasms / genetics*
  • Polymorphism, Single Nucleotide*
  • Risk Factors
  • Smoking / adverse effects
  • Transcription Factors / genetics
  • Young Adult


  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • TFAM protein, human
  • Transcription Factors
  • DNA-Directed RNA Polymerases
  • POLRMT protein, human
  • DNA-Directed DNA Polymerase
  • POLG2 protein, human