Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features

Clin Cancer Res. 2006 Mar 1;12(5):1647-53. doi: 10.1158/1078-0432.CCR-05-1981.

Abstract

Purpose: This study evaluated the mutational profile of epidermal growth factor receptor (EGFR) and KRAS in non-small cell lung cancers in Hong Kong and determined their relation with smoking history and other clinicopathologic features.

Experimental design: Mutational profile of exons 18 to 21 of EGFR and codons 12, 13, and 61 of KRAS were determined in 215 adenocarcinomas, 15 squamous cell (SCC), and 11 EBV-associated lymphoepithelioma-like carcinomas (LELC).

Results: EGFR mutations were prevalent in adenocarcinomas (115 of 215), uncommon in LELC (1 of 11), and not found in SCC (P < 0.001). Among adenocarcinomas, mutations were associated with nonsmokers (83 of 111; P < 0.001), female gender (87 of 131; P < 0.001), and well-differentiated (55 of 86) compared with poorly differentiated (11 of 41) tumors (P < 0.001). Decreasing mutation rates with increasing direct tobacco exposure was observed, with 74.8% (83 of 111) in nonsmokers, 61.1% (11 of 18) in passive, 35.7% (10 of 28) in previous, and 19.0% (11 of 58) in current smokers. There were 53% amino acid substitutions, 43% in-frame deletions, and 4% insertions. Complex patterns with 13% double mutations, including five novel substitutions, were observed. For KRAS, mutations occurred in adenocarcinoma only (21 of 215) and were associated with smokers (11 of 58; P = 0.003), men (14 of 84; P = 0.009) and poorly differentiated (7 of 41) compared with well-differentiated (4 of 86) tumors (P = 0.037). EGFR and KRAS mutations occurred in mutually exclusive tumors. Regression analysis showed smoking history was the significant determinant for both mutations, whereas gender was a confounding factor.

Conclusion: This study shows EGFR mutations are prevalent in lung adenocarcinoma and suggests that it plays an increasing oncogenic role with decreasing direct tobacco damage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / diagnosis
  • Adenocarcinoma / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Substitution
  • Carcinoma, Non-Small-Cell Lung / diagnosis
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Squamous Cell / diagnosis
  • Carcinoma, Squamous Cell / genetics
  • Cell Differentiation
  • DNA Mutational Analysis
  • ErbB Receptors / genetics*
  • Exons
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, ras / genetics*
  • Herpesviridae Infections / complications
  • Herpesviridae Infections / genetics
  • Herpesviridae Infections / pathology
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / immunology
  • Herpesvirus 4, Human / isolation & purification
  • Hong Kong
  • Humans
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / genetics*
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Solitary Pulmonary Nodule / diagnosis
  • Solitary Pulmonary Nodule / genetics
  • Solitary Pulmonary Nodule / virology
  • Tobacco Smoke Pollution

Substances

  • Tobacco Smoke Pollution
  • ErbB Receptors