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Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide. Almost 60% of the cases occur in developed regions. CRC arises from a multistep process that involves an accumulation of mutations /epimutations in tumor suppressor genes and protooncogenes. DNA methylation is an important control program that modulates gene expression in the organism. Genome-wide hypomethylation and promoter-specific hypermethylation are thought to contribute to age-related pathologies. Moreover female sex hormones have been implicated in the etiology of several women's cancers and may participate in different pathways associated with distinct DNA methylation signatures. Folates are essential nutrients whose metabolism is required for the production of S-adenosylmethionine (SAM), the major intracellular methylating agent, and for the synthesis of DNA and RNA precursors. Impairments in folate metabolism might result in increased frequency of point mutations as well as altered methylation of tumor suppressor genes, thereby contributing to cancer initiation and progression. Reduced folate levels have been associated with increased CRC risk in healthy people, whilst increased folate availability is believed to enhance CRC progression in individuals harbouring preneoplastic lesions. There is increasing interest in understanding the correlation among folate availability, its metabolism, and the methylation levels of tumor suppressor genes in CRC tissues. For this purpose we collected 104 CRC patients and searched for correlation among clinico-pathological characteristics, common polymorphisms of genes participating in folate metabolism (MTHFR 677C>T, MTHFR 1298A>C, MTR 2756A>G, MTRR 66A>G, TYMS 28bp repeats, TYMS 1494 6bp del, RFC1 80A>G, DNMT3B -149 C>T, and DNMT -579 G>T) and promoter methylation of APC, MGMT, hMLH1, RASSF1A, CDKN2A, tumor suppressor genes. Genotyping was performed by means of PCR/RFLP technique and DNA methylation analyses by means of methylation-sensitive high resolution melting (MS-HRM). A precise value of gene promoter methylation was obtained by means of an algorithm recently developed by us. MGMT and hMLH1 methylation levels showed a significant positive correlation with aging and female gender. Moreover, some interesting correlation among folate metabolism polymorphisms and promoter methylation levels were found. No significant association among promoter methylation and CRC location, stage and tumor size was found. Only a borderline association between TNM stage IV and increased hMLH1 methylation and TNM stage III and a higher RASSF1A methylation (with respect to the other stages) have been observed. The study of epigenetic marks to better understand colorectal carcinogenesis and to identify new tools for diagnosis and prognosis as well as for therapeutic interventions is then extremely promising.