Abstract 1845: Genetic analyses of MGMT in familial gliomas and colorectal cancer

Abstract DNA repair is an important area of research in cancer biology. The O6-methylguanine DNA methyltransferase (MGMT) enzyme is one of the key players in this area. When deregulated affects DNA repair capacity and it is involved in cancer formation. In eukaryotes the MGMT enzyme is the first line of defense against the adverse effects of DNA alkyl-lesions that are potent mutagenic and cytotoxic lesions. Evidence for MGMT suppressing cancer susceptibility in humans include the loss of expression by epigenetic silencing in a variety of human cancers, including > 30% of colorectal, brain, lung, lymphoma, head and neck cancers. Moreover, these cancers frequently show higher incidence of G to A transitions mutations in oncogene v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and in the tumour suppressor gene tumour protein p53 (TP53) compared to tumours with normal MGMT expression. A single report has described somatic mutations in MGMT gene. However, there are several reports of individual differences in MGMT activity. A few germline variants affecting this gene have been described, but the functional relevance of these nucleotides changes is unclear. There are many familial colorectal cancers (CCR) and familial gliomas for which it has not been described an associated germline mutation. In order to see if MGMT tumour suppressor gene could be genetically involved on that, we did a germline screening of 78 CCR probands and 8 gliomas probands from familial cases. As control we also did the screening of 80 normal DNAs lymphocytes from healthy volunteers. For that we performed direct sequencing of all MGMT exons. We found polymorphisms (SNPs) already described, where are included the three common non-synonymous SNPs Leu84Phe, Ile143Val and Lys178Arg. The frequency of SNPs in probands lymphocytes was the same as in normal DNA lymphocytes. The study is ongoing and further extensive research is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1845.