Variation in K‐ras Codon 12 Point Mutation Rate with Histological Atypia within Individual Colorectal Tumors

To elucidate genetic alteration in relation to morphology and also to confirm more directly the proposed adenoma‐carcinoma sequence, we analyzed thirty‐eight colorectal “cancer in adenoma” lesions exhibiting areas of different atypia, in terms of K‐ras codon 12 point mutation. The mutation incidence was 26.3% (10/38) for all cancerous areas. Well‐differentiated and very well‐differentiated carcinoma exhibited values of 17.6% (3/17) and 30.4% (7/23), respectively (statistically not significant). Positive cases of adenoma with severe atypia and adenoma with moderate or slight atypia were 26.7% (8/30) and 8.3% (3/36) respectively (statistically significant). Thus, K‐ras point mutation, as indicated previously, may play an important role in the early stages of colorectal tumorigenesis. As for the nature of the mutation, GGT(Gly) to GAT(Asp) was the most frequent (80%). Eight cases had mutations concurrently in different areas of the same tumor and in all of these the mutation was homogeneous (6 cases to GAT, 1 case to TGT and 1 case to GTT). This provides genetic support for the “adenoma‐carcinoma sequence” theory proposed on the basis of morphological considerations. All lesions with a mutation were of polypoid type, and no mutation was found in the flat type.