Detection of low-fraction K-ras mutations in primary lung tumors using a sensitive method

Mutations in the K-ras gene are often identified in lung tumors and are implicated in the development of lung cancer. We used a sensitive method to analyze low-fraction mutations occurring in codon 12 of the K-ras gene in 114 primary lung tumors, including 77 adenocarcinomas, 31 squamous cell carcinomas and 6 adenosquamous carcinomas, which had previously been shown to be negative for codon 12 K-ras mutation in a first screening using less sensitive methods. Sixteen of these tumors were found to contain a low-fraction mutation, including 9 mutations among the adenocarcinomas, six mutations among the squamous cell carcinomas and one mutation among the adenosquamous carcinomas. Our study also showed that the occurrence of low-fraction mutation was associated with a positive smoking history, as was previously found for the occurrence of high-fraction mutation. Patients with low-fraction mutations were younger (mean age 58.8 years) than those with either high-fraction mutations (63.2 years) or no mutation (66 years). Patients with low-fraction mutations were more often stage I (8 of 10) than patients with either high fraction mutations (22 of 44) or no mutation (33 of 71). Moreover, the overall survival was better for the group with a low-fraction mutation than both the high-fraction mutation group and the group with no K-ras mutation, but due to small sample size, the difference was not statistically significant. Our results suggest that using highly sensitive methods of K-ras mutant detection in tumor DNA could obscure differences between patients in whom the mutation is found throughout the tumor, those in whom the mutation is only present in a small subpopulation and those who have no mutation.