RESUMEN
Microsatellite instability (MSI) is an important factor in tumor development and is a hypermutable phenotype caused by the loss of DNA mismatch repair activity. It is important to identify tumors with microsatellite instability as the patients have a better prognosis and differ with response to chemotherapy. Limited data are available on the incidence of MSI in Indian colorectal cancers (CRCs). The objectives of this study were to identify the extent of MSI in Indian CRC patients below 50 years and to determine promoter methylation status of hMLH1 and hMSH2 in relation to MSI. A total of 450 patients were diagnosed with CRC, out of which 91 individuals were recruited as per Bethesda guidelines and were tested for instability by the NCI-recommended Bethesda panel (BAT25, BAT26, D2S123, D5S346, and D17S2720) using labeled primers. The fragments were separated and analyzed on a Beckman GeXP sequencer. Promoter methylation status was determined by restriction enzyme digestion and PCR. MSI (high and low) was seen in 48.4% (44/91) of CRC patients, out of which microsatellite instability-high (MSI-H) was detected in 13.2% (12/91) and microsatellite instability-low (MSI-L) in 35.2% (32/91) and the rest were microsatellite stable (MSS), 51.6% (47/91). Majority of the MSI-H tumors were adenocarcinomas (10/12), in the rectum (8/12), and moderately or poorly differentiated (12/12). Promoter hypermethylation was seen in 75% of the MSI-H, 56.24% of MSI-L, and only 23.4% of MSS individuals. MSI (high and low) was associated with 48.4% of CRC patients, and a significantly higher proportion of promoter hypermethylation of hMLH1 and hMSH2 genes was associated with instable tumors.
Asunto(s)
Neoplasias Colorrectales/genética , Metilación de ADN , Inestabilidad de Microsatélites , Regiones Promotoras Genéticas , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Neoplasias Colorrectales/patología , Femenino , Humanos , India , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Invasividad Neoplásica , Estadificación de Neoplasias , Proteínas Nucleares/genéticaRESUMEN
BACKGROUND: Researchers have determined that Indians face a higher risk of heart disease, despite the fact that nearly half of them are vegetarians and lack many of the other traditional risk factors. In the below-30 age group, coronary artery disease mortality among Indians is three-fold higher than in the whites in United Kingdom and ten-fold higher than the Chinese in Singapore. High levels of homocysteine have been widely linked to the early onset of heart diseases in other populations, although a definite proof among Indians is lacking, which needs to be investigated by way of screening for factors responsible for high homocysteine levels. OBJECTIVE: To screen for genetic factors responsible for hyperhomocysteinemia and the risk for premature coronary artery disease. MATERIALS AND METHODS: A total of 100 individuals with proven premature coronary artery disease and 200 age-and-sex matched controls were screened for polymorphisms in Methylenetetrahydrofolate reductase (MTHFR) (C677T) Methionine synthase (MS) genes (A2756G, C2758G), and the B12 and Folate levels were estimated. RESULTS: Results from the mutational analysis revealed that in the study group, seven individuals had a polymorphism for the C677T allele in the MTHFR gene (one homozygous and six heterozygous) (Fischer's Exact test P > 0.046) (OR: 0.2711 95% CI 0.0774 to 0.9491). Six were heterozygous for the A2756G polymorphism in the MS gene (Fischer's Exact test P > 0.0012). None showed a polymorphism at the C2758G allele in the MS gene. Four controls showed heterozygosity for the C677T polymorphism and none for the MS gene. The B12 and Folate levels were significantly lower in the study group as compared to the controls. CONCLUSIONS: It is important to know which factors determine the total homocysteine concentrations. In the general population, the most important modifiable determinants of tHcy are folate intake and coffee consumption. Smoking and alcohol consumption are also associated with the total homocysteine concentrations, but more research is necessary to elucidate whether these relations are not originating from residual confounding due to other lifestyle factors.