RESUMO
BACKGROUND AND AIMS: The enzyme MTHFR plays an important role in folate metabolism, and folate is implicated in carcinogenesis due to its role in DNA methylation, repair, and synthesis. We analyze the relationship of MTHFR C677T and A1298C polymorphisms with biological, clinicopathological, genetic and epigenetic features of tumors, and the patient outcome after treatment with 5-FU-based chemotherapy to determine the contribution of MTHFR genotypes in the risk of colorectal cancer (CRC) and in the response to therapy. METHODS: Genomic DNA of 143 Spanish sporadic CRC and 103 controls was analyzed by polymerase chain reaction/restriction fragment length polymorphism and sequencing. RESULTS: The C677T polymorphism has protective effect on CRC showing TT genotype an odds ratios of 0.06 (95% confidence interval (CI): 0.10-0.32) and the CT of 0.51 (95% CI: 0.3-0.87). MTHFR A1298C polymorphism is not associated with CRC risk. Patients with 1298CC and AC genotypes exhibit worse survival than those with the wild genotype (log rank, p = 0.001), whereas C677T genotypes do not affect patient survival (log rank, p = 0.92). MTHFR 677T allele carriers responded better to 5-FU-based chemotherapy than patients with the wild CC genotype (log rank, p = 0.05). The variant C allele of A1298C affects negatively the response to 5-FU-based chemotherapy (log rank, p = 0.009). CONCLUSIONS: The variant allele of the C677T has a protective effect on CRC development, whereas the variant allele of the A1298C does not produce any effect on disease risk. Both MTHFR polymorphisms are relevant and independent factors of patient outcome after 5FU-based treatment of CRC, and MTHFR genotyping may be of predictive benefit in selecting treatment regimens.
Assuntos
Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/genética , Epigênese Genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/enzimologia , Adenocarcinoma/mortalidade , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Estudos de Casos e Controles , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/mortalidade , Metilação de DNA , Feminino , Fluoruracila/administração & dosagem , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Seleção de Pacientes , Fenótipo , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: The mutator pathway implied in the development of colorectal cancer (CRC) is characterized by microsatellite instability (MSI). MSI tumors can be subdivided according to the level of instability: MSI-H (high), MSI-L (low) or stable MSS. MSI-H CRC displays a well described distinct phenotype, but the true biologic significance of MSI-L is still uncertain. The objective of this study was to further clarify if the MSI-L phenotype could reflect a distinct pathway of tumor development with a different clinical behavior. METHODS: We analyzed the clinicopathological and genetic variables of 156 patients with sporadic CRC in relation with the level of MSI of the tumors. RESULTS: We have found that MSI-L tumors are someway in the middle of MSI-H and MSS CRC, as they share some features with each of the other 2 subgroups: left side location, lower incidence of LOH at MSH2 as MSS and Dukes B (stage II TNM) like MSI-H. Moreover, MSI-L tumors show higher incidence of KRAS mutations. CONCLUSION: We believe that MSI-L tumors could be considered a distinct phenotype that develops through a "mild mutator pathway."
