Intratumor heterogeneity of k-ras and p53 mutations among human colorectaladenomas containing early cancer

The molecular pathways and the timing of genetic events during human colore ctal carcinogenesis are still not fully understood. We have addressed the i ntratumor heterogeneity of the mutational status of the k-ras oncogene and of the p53 on-cosuppressor gene during the adenoma-carcinoma sequence by in vestigating 26 human colorectal adenomas containing early cancer. An intrat umor comparative analysis was obtained among the adenomatous and carcinomat ous component pairs. Additionally, we have analyzed 17 adenomas having canc er in the near vicinity. The adenomatous components of the adenomas containing early cancer and the adenomas having cancer in the near vicinity had comparable frequencies for k-ras mutations (28 and 47%) but different for p53 mutations (52 and 7%, p- value = 0.01). Interestingly, the adenomatous and carcinomatous components of the adenomas containing early cancer were rarely heterogeneous for the k -ras mutational status (only in 13% of the cases) but were characterized by heterogeneity of the p53 status in 59% of the cases (p-value < 0.01). In a ddition, the mutations of p53 for the adenomatous components of the adenoma s containing early cancer were statistically significantly associated with severe dysplasia (p-value = 0.01). Intratumor homogeneity of k-ras status during the human colorectal adenoma- carcinoma sequence suggests that the role of k-ras is more related to tumor initiation than to tumor progression. On the contrary, intratumor heteroge neity of p53 mutations indicates that the type of the p53 mutations may als o be relevant for selection and expansion of new sub-clones leading to tumo r progression.