Prognostic value of K-ras mutations and allelic imbalance on chromosome 18q in patients with resected colorectal cancer

PURPOSE: We designed this study to assess the frequency of K-ras mutations in patients with resected colorectal tumors and their association with surv ival. A second objective was to analyze the prognostic value of different K -ras genotypes. In a subgroup of patients we also investigated the presence of allelic imbalance on chromosome 18q and its relationship to clinical ou tcome. METHODS: One hundred fourteen colorectal tumors resected between 198 3 and 1986 were analyzed to detect K-ras point mutations at codons 12, 13, and 61 by polymerase chain reaction followed by allele specific oligonucleo tide hybridization. A subgroup of 77 tumors was further screened to detect loss of heterozygosity on chromosome 18q using three polymorphic microsatel lite markers (D18S67, D18S474 and D18S58). RESULTS: K-ras mutations were de tected in 29 percent (33/114) of patients. K-ras mutations correlated with age and preoperative carcinoembryonic antigen levels, and there was some in dication that they may be linked to poor survival, especially in Stage II t umors, where a subgroup of patients with aspartic and serine mutations show ed significantly reduced survival (P = 0.03) compared with K-ras-negative p atients. 18q loss of heterozygosity was present in 39 percent (25/63) of tu mors. A multivariate analysis of Stage II tumors showed that 18q loss of he terozygosity was significantly associated with a worse prognosis (P = 0.006 ). A significant decrease in survival was identified in ten patients harbor ing both genetic alterations (K-i mutations and 18q loss of heterozygosity; P = 0.02). CONCLUSIONS: In colorectal tumors, K-ras mutations and 18q loss of heterozygosity are two genetic markers which may identify patients with more aggressive behavior, mainly in Stage II tumors. These findings warran t further research, because they can be useful in customizing adjuvant chem otherapy.