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Distinct Epidermal Growth Factor Receptor and KRAS Mutation Patterns in Non–Small Cell Lung Cancer Patients with Different Tobacco Exposure and Clinicopathologic Features

Authors' Affiliations: Departments of ¹ Pathology, ² Dental Public Health, ³ Medicine, University of Hong Kong; Departments of ⁴ Cardiothoracic Surgery and ⁵ Pathology, Grantham Hospital; ⁶ Department of Cardiothoracic Surgery, Queen Elizabeth Hospital, Hong Kong, Republic of China; and ⁷ Hamon Centre for Therapeutic Oncology Research and ⁸ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas

Requests for reprints: Maria P. Wong, Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, Republic of China. E-mail: mwpik{at}hkucc.hku.hk.

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.

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