MOLECULAR STAGING OF NON-SMALL-CELL LUNG-CANCER ACCORDING TO K-RAS GENOTYPES

We have previously demonstrated a strong association between K-ras gen e mutations, as determined by PCR followed by allele-specific oligonuc leotide hybridization (ASO-h), and survival in non small cell lung can cer patients, The purpose of this study was to determine the relations hip between tumor aggressiveness and specific-type K-ras point mutatio ns in non-small cell lung cancer, We developed procedures to examine t he status of the K-ras gene by ASO-h and by single-strand conformation polymorphism assay of DNA obtained from formalin-fixed paraffin-embed ded tumors, K-ras point mutations at codons 12 and 61 were assessed in 275 consecutively treated stage I-IV non-small cell lung cancers, Amo ng patients with stage I disease, median survival time was 41.5 months in those whose tumors had no evidence of K-ras mutations and 27 month s in those with K-ras 12 mutations; among patients with stage IIIA dis ease, median survival time was 7 months in those with K-ras codon 12 a spartic and serine mutations and 15 months for those with other K-ras mutations (P = 0.01), In a multivariate analysis, specific-type K-rns codon 12 point mutation remained a strong predictive factor (hazard ra tio for death, 2.06; 95% confidence interval, 1.11-3.81; P = 0.02) aft er adjustment for other evaluated factors, including TNM stage and his tology, Thus, we concluded that in patients with non-small cell lung c ancer, specific K-ras 12 point mutations detected by DNA amplification and either ASO-h or single-strand conformation polymorphism methods p redicted a significantly increased risk of recurrence and death, indep endently of stage and histology.