Mitochondrial DNA (
mtDNA) mutations were reported in different
cancers. However, the nature and role of
mtDNA mutation in never-smoker
lung cancer patients including patients with
epidermal growth factor receptor (EGFR) and KRAS gene mutation are unknown. In the present study, we sequenced entire mitochondrial genome (16.5 kb) in matched normal and
tumors obtained from 30 never-smoker and 30 current-smoker
lung cancer patients, and determined the
mtDNA content. All the patients' samples were sequenced for KRAS (exon 2) and EGFR (exon 19 and 21) gene mutation. The impact of forced overexpression of a
respiratory complex-I gene mutation was evaluated in a
lung cancer cell line. We observed significantly higher (P = 0.006)
mtDNA mutation in the never-smokers compared to the current-smoker
lung cancer patients.
MtDNA mutation was significantly higher (P = 0.026) in the never-smoker Asian compared to the current-smoker Caucasian patients' population.
MtDNA mutation was significantly (P = 0.007) associated with EGFR gene mutation in the never-smoker patients. We also observed a significant increase (P = 0.037) in
mtDNA content among the never-smoker
lung cancer patients. The majority of the coding
mtDNA mutations targeted
respiratory complex-I and forced overexpression of one of these mutations resulted in increased in vitro proliferation, invasion, and
superoxide production in
lung cancer cells. We observed a higher prevalence and new relationship between
mtDNA alterations among never-smoker
lung cancer patients and EGFR gene mutation. Moreover, a representative mutation produced strong growth effects after forced overexpression in
lung cancer cells. Signature
mtDNA mutations provide a basis to develop novel
biomarkers and therapeutic strategies for never-smoker
lung cancer patients.