SPECIFIC K-RAS2 MUTATIONS IN HUMAN SPORADIC COLORECTAL ADENOMAS ARE ASSOCIATED WITH DNA NEAR-DIPLOID ANEUPLOIDY AND INHIBITION OF PROLIFERATION

Recent studies indicate that p21ras proteins mediate their multiple ce ll functions through interactions with multiple effecters and that the number of new effecters is growing. We recently reported that K-ras2 mutations in human colorectal adenomas were associated with chromosome instability and proliferation changes. In the present study, we exten d these previous observations. Hereditary and multiple (n greater than or equal to 5) adenomas and adenomas with early cancer were excluded. Dysplasia was moderate in 91 cases and high in 25, and the median ade noma size was 1.5 cm, K-ras2 spectrum analysis was done by sequence-sp ecific oligonucleotide hybridization using nuclear suspensions provide d by analysis and sorting of multiparameter now cytometry. In particul ar, tissue inflammatory cells were separated for DNA diploid tumors, w hereas DNA aneuploid epithelial subclones were analyzed separately. K- ras2 mutations and DNA aneuploidy were both detected in 29 of 116 (25% ) cases. DNA aneuploid index was in the near-diploid region in the maj ority of cases. DNA aneuploidy was strongly associated with G-->C/T tr ansversions, An association was also found between low S-phase values and G-->A transitions. These findings were confirmed using multivariat e logistic regression analysis to account for the effects of size, dys plasia, site, type, age, and sex. These data suggest that specific K-r as2 mutations in a subgroup of human sporadic colorectal adenomas play a role in chromosome instability and, contrary to expectations, are a ssociated with inhibition of proliferation.