Germline mutations in
mitochondrial DNA polymerase gamma (POLG1) induce
mitochondrial DNA (
mtDNA) mutations, depletion, and decrease oxidative phosphorylation. Earlier, we identified somatic mutations in POLG1 and the contribution of these mutations in human
cancer. However, a role for germline variations in POLG1 in human
cancers is unknown. In this study, we examined a role for disease associated germline variants of POLG1, POLG1 gene expression, copy number variation and regulation in human
cancers. We analyzed the mutations, expression and copy number variation in POLG1 in several
cancer databases and validated the analyses in primary
breast tumors and
breast cancer cell lines. We discovered
5-aza-2'-deoxycytidine led epigenetic regulation of POLG1,
mtDNA-encoded genes and increased mitochondrial respiration. We conducted comprehensive race based bioinformatics analyses of POLG1 gene in more than 33,000 European-Americans and 5,000 African-Americans. We identified a
mitochondrial disease causing missense variation in polymerase domain of POLG1
protein at
amino acid 1143 (E1143G) to be 25 times more prevalent in European-Americans (allele frequency 0.03777) when compared to African-American (allele frequency 0.00151) population. We identified T251I and P587L missense variations in
exonuclease and linker region of POLG1 also to be more prevalent in European-Americans. Expression of these variants increased
glucose consumption, decreased
ATP production and increased
matrigel invasion. Interestingly, conditional expression of these variants revealed that
matrigel invasion properties conferred by these germline variants were reversible suggesting a role of epigenetic regulators. Indeed, we identified a set of
miRNA whose expression was reversible after variant expression was turned off. Together, our studies demonstrate altered genetic and epigenetic regulation of POLG1 in human
cancers and suggest a role for POLG1 germline variants in promoting tumorigenic properties.