Yonsei Med J.  2013 Jul;54(4):865-874. 10.3349/ymj.2013.54.4.865.

The Impact of Cigarette Smoking on the Frequency of and Qualitative Differences in KRAS Mutations in Korean Patients with Lung Adenocarcinoma

• Kim HR
• Ahn JR
• Lee JG
• Bang DH
• Ha SJ
• Hong YK
• Kim SM
• Nam KC
• Rha SY
• Soo RA
• Riely GJ
• Kim JH
• Cho BC

• KMID: 2158219
• DOI: http://doi.org/10.3349/ymj.2013.54.4.865

Abstract

PURPOSE
This study was designed to determine the relationship of cigarette smoking to the frequency and qualitative differences among KRAS mutations in lung adenocarcinomas from Korean patients.
MATERIALS AND METHODS
Detailed smoking histories were obtained from 200 consecutively enrolled patients with lung adenocarcinoma according to a standard protocol. EGFR (exons 18 to 21) and KRAS (codons 12/13) mutations were determined via direct-sequencing.
RESULTS
The incidence of KRAS mutations was 8% (16 of 200) in patients with lung adenocarcinoma. KRAS mutations were found in 5.8% (7 of 120) of tumors from never-smokers, 15% (6 of 40) from former-smokers, and 7.5% (3 of 40) from current-smokers. The frequency of KRAS mutations did not differ significantly according to smoking history (p=0.435). Never-smokers were significantly more likely than former or current smokers to have a transition mutation (G-->A or C-->T) rather than a transversion mutation (G-->T or G-->C) that is known to be smoking-related (p=0.011). In a Cox regression model, the adjusted hazard ratios for the risk of progression with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were 0.24 (95% CI, 0.14-0.42; p<0.001) for the EGFR mutation and 1.27 (95% CI, 0.58-2.79; p=0.537) for the KRAS mutation.
CONCLUSION
Cigarette smoking did not influence the frequency of KRAS mutations in lung adenocarcinomas in Korean patients, but influenced qualitative differences in the KRAS mutations.

Keyword

EGFR; KRAS; pulmonary adenocarcinoma; cigarette smoking; EGFR-tyrosine kinase inhibitors

MeSH Terms

Adenocarcinoma/drug therapy/etiology/*genetics/pathology
Adult
Aged
Aged, 80 and over
Asian Continental Ancestry Group/genetics
Female
Humans
Incidence
Lung Neoplasms/drug therapy/etiology/*genetics/pathology
Male
Middle Aged
*Mutation
Mutation Rate
Proportional Hazards Models
Proto-Oncogene Proteins/*genetics
Receptor, Epidermal Growth Factor/antagonists & inhibitors/genetics
Smoking/adverse effects/*genetics
Treatment Outcome
ras Proteins/*genetics
Proto-Oncogene Proteins
Receptor, Epidermal Growth Factor
ras Proteins

Figure

• 

  Fig. 1 Frequency of KRAS mutation according to smoking history.

• 

  Fig. 2 Kaplan-Meier survival plots for patients with three tumor genotypes in metastatic lung adenocarcinoma treated with EGFR tyrosine kinase inhibitors (TKIs): EGFR mutation (n=41), KRAS mutation (n=8), and WT/WT (n=47). (A) Median OS with EGFR TKI treatment (26.7 months for EGFR mutation vs. 8.2 months for WT/WT vs. 9.2 months for KRAS mutant, p=0.001). (B) Median PFS (12.8 months for EGFR mutation vs. 1.2 months for KRAS mutation vs. 1.9 months for WT/WT, p<0.001).

• 

  Supplementary Fig. 1 Comparison of median values for various factors regarding cigarette-smoking according to KRAS mutation status. The number of y-axis represents the number according to the variables in x-axis (age at first cigarette, pack-years, smoke years, cigarettes per day, and smoke free year), respectively.

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