Molecular alterations in colorectal cancer

• Colorectal cancer is one of the most common causes to death due to cancer in the world. It is important to understand the molecular mechanisms behind tumour development for both prognostic and therapeutic applications. In this thesis, we have focused on genes and proteins related to tumour suppressor function, apoptosis and DNA repair in patients with colorectal adenocarcinomas. In Paper I, the pattern of mutations affecting the tumour suppressor p53 was investigated in 75 cases in order to determine whether there were any specific mutations in the cases with p53 accumulated in the cytoplasm. We found that the frequency and pattern of mutation were similar to those with nuclear p53 expression, suggesting that the prognostic importance of cytoplasmic p53 accumulation may depend on both mutational and non-mutational mechanisms. In Paper II we investigated the protein expression of the pro-apoptotic gene Bax from normal mucosa to primary tumour and to regional lymph node metastases in 135 patients. We further examined Bax mutations and the microsatellite status in the primary tumours. Bax expression was stronger from normal to tumour tissue, but decreased in the metastases. The matched cases with lower expression in the metastastases than in the primary tumour showed a more infiltrative growth pattern and more distal metastases. In paper III the mRNA expression of the pro-apoptotic gene Noxa was examined with real-time PCR and mutations searched for in 94 colorectal tumours and the corresponding normal mucosa. Noxa mRNA expression was weak in 9% and strong in 2% of the tumours and decreased in 9% and increased in 16% of the tumours compared to the normal mucosa. The expression was not related to clinicopathological features. We did not find any mutations in the gene. In Paper IV we studied the biological and clinicopathological importance of protein expression of the mismatch repair genes hMLHJ, hMSH2, hMSH3 and hMSH6 individually or combined in 301 colorectal cancers. When analysed individually, hMLH1 and hMSH2 were more important and the combined groups were more related to the mutator pathway, suggesting that the combined deficiencies of the proteins are more efficiently involved in the mutator pathway. Our result from comparing weak versus strong staining may suggest that the intensity of staining should be considered in future studies on the expression of mismatch repair proteins.

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