Mitochondrial DNA mutations in respiratory complex-I in never-smoker lung cancer patients contribute to lung cancer progression and associated with EGFR gene mutation

Santanu Dasgupta, Ethan Soudry, Nitai Mukhopadhyay, Chunbo Shao, John Yee, Stephan Lam, Wan Lam, Wei Zhang, Adi F. Gazdar, Paul B. Fisher, David Sidransky

Research output: Contribution to journalArticle

43 Citations (Scopus)

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 (16.5kb) 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.

Original languageEnglish (US)
Pages (from-to)2451-2460
Number of pages10
JournalJournal of Cellular Physiology
Volume227
Issue number6
DOIs
StatePublished - Jun 2012

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erbB-1 Genes
Electron Transport Complex I
Mitochondrial DNA
Epidermal Growth Factor Receptor
Lung Neoplasms
Genes
Mutation
Cells
Exons
Biomarkers
Superoxides
Tumors
Mitochondrial Genome

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

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Mitochondrial DNA mutations in respiratory complex-I in never-smoker lung cancer patients contribute to lung cancer progression and associated with EGFR gene mutation. / Dasgupta, Santanu; Soudry, Ethan; Mukhopadhyay, Nitai; Shao, Chunbo; Yee, John; Lam, Stephan; Lam, Wan; Zhang, Wei; Gazdar, Adi F.; Fisher, Paul B.; Sidransky, David.

In: Journal of Cellular Physiology, Vol. 227, No. 6, 06.2012, p. 2451-2460.

Research output: Contribution to journalArticle

Dasgupta, S, Soudry, E, Mukhopadhyay, N, Shao, C, Yee, J, Lam, S, Lam, W, Zhang, W, Gazdar, AF, Fisher, PB & Sidransky, D 2012, 'Mitochondrial DNA mutations in respiratory complex-I in never-smoker lung cancer patients contribute to lung cancer progression and associated with EGFR gene mutation', Journal of Cellular Physiology, vol. 227, no. 6, pp. 2451-2460. https://doi.org/10.1002/jcp.22980
Dasgupta, Santanu ; Soudry, Ethan ; Mukhopadhyay, Nitai ; Shao, Chunbo ; Yee, John ; Lam, Stephan ; Lam, Wan ; Zhang, Wei ; Gazdar, Adi F. ; Fisher, Paul B. ; Sidransky, David. / Mitochondrial DNA mutations in respiratory complex-I in never-smoker lung cancer patients contribute to lung cancer progression and associated with EGFR gene mutation. In: Journal of Cellular Physiology. 2012 ; Vol. 227, No. 6. pp. 2451-2460.
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