DNA methylation in hereditary and sporadic colorectal carcinomas with mismatch repair defect

Colorectal cancer is caused by the progressive accumulation of genetic and epigenetic changes. Hereditary colorectal nonpolyposis cancer (Lynch syndrome - LS) is characterized by high level of microsatellite instability (MSI) as a consequence of DNA mismatch repair defect. To investigate the role of epigenetic changes in LS development, we evaluated MLH1 specific and gene nonspecific hypermethylation in hereditary tumors. We documented that the rather randomly distributed weak methylation patterns in these tumors indicate no significant role of epigenetic events in LS etiology, in contrast to widespread hypermethylation in sporadic unstabile tumors. These differences in methylation can lead to more effective molecular diagnosis of this disease. Moreover, in the relation of MSI evaluation, we found insertion/deletion mutations in MRE11 and RAD50 repeats in several LS patients. Such alterations can lead to MRE11/RAD50/NBS1 protein complex destabilization and additional defect of DNA double-strand break repair.