title: Mitochondrial DNA mutations in respiratory complex-I in never-smoker lung cancer patients contribute to lung cancer progression and associated with EGFR gene mutation.
abstract: 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.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland, USA. sdasgupta@vcu.edu
authors.forename: Santanu
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Ethan
authors.initials: E
authors.lastname: Soudry
authors.forename: Nitai
authors.initials: N
authors.lastname: Mukhopadhyay
authors.forename: Chunbo
authors.initials: C
authors.lastname: Shao
authors.forename: John
authors.initials: J
authors.lastname: Yee
authors.forename: Stephan
authors.initials: S
authors.lastname: Lam
authors.forename: Wan
authors.initials: W
authors.lastname: Lam
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
mesh_terms: D000368:Aged; D001955:British Columbia / Q000453:epidemiology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial; D018450:Disease Progression; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics*; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D016014:Linear Models; D008175:Lung Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018570:Risk Assessment; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects* / Q000208:ethnology; D013481:Superoxides / Q000378:metabolism; D014162:Transfection; D018631:ras Proteins / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; C117307:KRAS protein, human; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D013481:Superoxides; C481838:MT-ND5 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D042967:Electron Transport Complex I