K-RAS-2 G-C AND G-T TRANSVERSIONS CORRELATE WITH DNA ANEUPLOIDY IN COLORECTAL ADENOMAS

Background/Aims: K-ras-2 mutations and DNA content heterogeneity represent early events of human colorectal tumor progression. The aim of the study was to investigate if specific K-ras-2 mutations in 58 human sporadic adenomas were correlated with DNA aneuploidization and cell proliferation. Methods: Multiparameter flow cytometry, based on scatter parameters and PNA content, was performed using 4,6-diamidino-2-phenilindole- 2-hydrochloride-strained nuclei obtained from adenoma fragments with either mild-moderate or severe dysplasia. K-ras-2 polymerase chain reaction and spectrum analysis were performed using sorted DNA specific epithelial subclones. Results: We detected six G-A transitions; and four G-C and two G-T transversions. The DNA aneuploid subclones were 25 with DNA index Values in the near diploid region (DNA index < 1.3) for the vast majority of cases (80%). DNA aneuploidy among the mutated adenomas with G-A transitions was 1 of 6 (17%) and 6 of 6 (100%) among G-C and G-T transversions. Although DNA aneuploidy and high S-phase values were also present among K-ras-2 wild-type adenomas, their statistical associations with K-ras-2 status were P < 0.005 and P < 0.05, respectively. Conclusions: The present series of sporadic colorectal adenomas indicates that codon 12 G-C and G-T K-ras-2 transversion mutations and DNA aneuploidy are correlated. The underlying mechanisms that explain such association remain to be investigated.