Article

Frequency and Distinctive Spectrum of KRAS Mutations in Never Smokers with Lung Adenocarcinoma

Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Clinical Cancer Research (Impact Factor: 8.72). 10/2008; 14(18):5731-4. DOI: 10.1158/1078-0432.CCR-08-0646
Source: PubMed

ABSTRACT

KRAS mutations are found in approximately 25% of lung adenocarcinomas in Western countries and, as a group, have been strongly associated with cigarette smoking. These mutations are predictive of poor prognosis in resected disease as well as resistance to treatment with erlotinib or gefitinib.
We determined the frequency and type of KRAS codon 12 and 13 mutations and characterized their association with cigarette smoking history in patients with lung adenocarcinomas.
KRAS mutational analysis was done on 482 lung adenocarcinomas, 81 (17%) of which were obtained from patients who had never smoked cigarettes. KRAS mutations were found in 15% (12 of 81; 95% confidence intervals, 8-24%) of tumors from never smokers. Similarly, 22% (69 of 316; 95% confidence intervals, 17-27%) of tumors from former smokers, and 25% (21 of 85; 95% confidence intervals, 16-35%) of tumors from current smokers had KRAS mutations. The frequency of KRAS mutation was not associated with age, gender, or smoking history. The number of pack years of cigarette smoking did not predict an increased likelihood of KRAS mutations. Never smokers were significantly more likely than former or current smokers to have a transition mutation (G-->A) rather than the transversion mutations known to be smoking-related (G-->T or G-->C; P < 0.0001).
Based on our data, KRAS mutations are not rare among never smokers with lung adenocarcinoma and such patients have a distinct KRAS mutation profile. The etiologic and biological heterogeneity of KRAS mutant lung adenocarcinomas is worthy of further study.

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    • "MUT KRAS occurs in approximately 20% of NSCLC cases at diagnosis, more frequently in Caucasian population, adenocarcinomas, males and current smokers[25,26]. About 90% of KRAS mutations occur in exon 2 (codon 12 and 13), while exon 3 (codon 61) is less frequently involved[26,27]; in never-smokers with lung adenocarcinoma, MUT KRAS is more frequently a transition (G to A) compared to transversion in current smokers[25]. Colo-rectal cancer cells with MUT KRAS treated with anti-EGFR monoclonal antibodies are able to escape growth inhibition by several mechanisms, including MUT RAS[28]. "
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    • "KRAS mutations are present in approximately 30% of lung adenocarcinomas and less commonly in squamous NSCLC (~5%) (28). They are found more frequently in Caucasians with lung cancer than in the Asian population and in current- or ex-smokers when compared with never-smokers (29, 110). Most KRAS mutations in NSCLC are single amino acid substitutions in codon 12 (80%) and to a lesser extent in codons 13 and 61 (30). "
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    • "This observation is not in line with previous studies [31] [37] [38] [40] [42] where G12D appeared to be the most frequent mutation among never-smokers compared with other codon 12 mutation subtypes. Although the reasons for this discrepancy between the above studies and our cohort are unclear, the difference might be explained by ethnic factors since we analysed patients only of Caucasian background whereas the above studies included mixed US cohorts [31] [38] [40] or patients with East-Asian [37] [42] origin. Nevertheless, our finding raises the possibility that not all subtypes of codon 12 mutations are associated with smoking in Caucasian lung adenocarcinoma patients. "
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