Functional MDR1 polymorphisms (G2677T and C3435T) and TCF4 mutations in colorectal tumors with high microsatellite instability.

The multidrug resistance 1 (MDRI) gene and transcription factor 4(TCF4) gene are suggested to be involved in the WNT signalling pathway, the most important pathway altered in colorectal cancer. Mutations in both genes have been identified and associated with colorectal tumors exhibiting high microsatellite instability (MSI-H). In this study, we report on the distribution of functional polymorphisms in the MDR] gene and somatic frameshift mutations in the TCF4 gene coding mononucleotide repetition in 62 MSI-H colorectal tumors. Somatic frameshift mutations in(of) the TCF4 gene were identified in 24/62 (39%) of the studied MSI-H tumors. The estimated allele frequencies of functional polymorphisms in(of) exon 21 (2677 G>T, Ala893Ser) and exon 26(3435 C>T, Ilel 142I1e) of the MDR] gene were 0.42 and 0.46 in the controls and 0.54 (p=0.035) and 0.60 (p=0.017) in the MSI-H tumors. However, the allele frequency of both functional MDR] polymorphisms did not significantly differ between MSI-H tumors with TCF4 mutations and those without. These results support the involvement of the MDRI gene in the tumorgenesis of MSI-H tumors and also suggest that functional polymorphisms in the MDRI gene and mutations in the TCF4 gene are likely to occur independently in MSI-H tumors.