Different genetic pathways involved in colorectal cancer

Abstract

Colorectal cancer (CRC) is one of the three leading causes of cancer mortality worldwide with an incidence of approximately one million cases and a mortality of 500 000 annually. Identification of different pathways involved in tumorigenesis of both familial and sporadic colorectal cancer may led to a major breakthrough in the prevention of this potentially curable disease.

It has been reported that HNPCC patients have a better prognosis than sporadic colorectal cancer cases. Approximately 13% of sporadic and >90% of HNPCC tumors show microsatellite instability (MSI). In an attempt to explore if MSI phenotype carries prognostic information, we examined 181 sporadic cases using microsatellite markers. No correlation between MSI status and age or gender was found. Survival analysis at 5-10 years follow-up showed a weak favorable clinical course for MSI positive cases. However, the differences in prognosis between microsatellite stable and -unstable cases was not statistically significant. These results indicate that MSI phenotype as such is not an independent prognostic factor.

We also searched for other differences between MSI positive and -negative sporadic colorectal tumors. The possibility that these two types of tumors may evolve through different tumorigenesis pathways, were tested by studying the frequency of different gene alterations in MSI and MSS (microsatellite stable) tumors. The prevalence of mutation in the APC, KRAS, TP53, (beta)-catenin and TGF(beta)R2 known to be involved in CRC tumor development was examined using different techniques. A high frequency of MSS tumors showed mutations in the TGF(beta)R2, whereas none of the MSS tumors did. A highly statistically significant negative association was found between MSI and alteration in APC and TP53. Our results strongly support the idea that carcinogenesis in MSI and MSS colorectal cancer develops through different pathways.

To find out the best strategy to select mismatch repair gene mutations carrier for further analysis, immunohistochemical testing was compared to MSI test. It was found that Immunohistochemistry could identify most cases with germline mutations in hMLH1 and hMSH2. However, some missense and even truncating mutations will be missed. Cases with hMLH1 promoter methylation will result in false positive results. These results suggested that MSI test is a better method in predicting mismatch repair gene carriers.

Inactivating mutations have been found in the cell-cell adhesion molecule E-cadherin in gastric and breast cancer. We searched for E-cadherin alterations in familial gastric and colon cancer. One E-cadherin germline alteration was found in two cases with familial colon and gastric cancer, leading to the substitution of Alanine to Threonine (Ala592Thr). This variant segregates with disease in one family with colon, gastric and breast cancer, although, the penetrance was not complete. A somatic mutation, exon 2 (49-CgA) was also found in a tumor from a patient with familial breast cancer. An allelic association study of the Ala592Thr variant in was performed in a series of cancer cases (colon, breast, gastric). The study did not support the correlation of this variant with an increased risk for breast cancer. However, an association between this alteration and an aggressive phenotype in breast cancer cases was suggested.