20.500.12556/DKUM-26177 Common germline MDR1/ABCB1 functional polymorphisms and haplotypes modify susceptibility to colorectal cancers with high microsatellite instability Altered expression of P-glycoprotein (P-gp) encoded by the multidrug resistance (MDR1/ABCB1) gene, as well as somatic mutations and hypermethylation in the MDR1/ABCB1 gene, were identified in a proportion of previously untreated colorectal cancers (CRC) exhibiting high microsatellite instability (MSI-H), which suggested that MDR1/ABCB1 acts as a candidate gene contributing to the initiation and progression of MSI-H tumors. Here we report germline functional single nucleotide polymorphisms (SNPs) and haplotypes in the MDR1/ABCB1 gene, which could contribute to genetic risk or increase susceptibility to MSI-H cancers. We have confirmed disease association by comparing the MDR1/ABCB1 genotype, allele, and haplotype frequencies between healthy controls and patients with MSI-H tumors. In particular, carriers of the T/T genotype in exon 12 (1236 C>T) SNP and the T/T genotype in exon 21 (2677G>T) SNP were most significantly associated with a higher risk for developing MSI-H CRC compared to controls (P=0.01, OR=3.182 and P=0.005, OR=3.594, respectively). The most significant MSI-H-associated risk haplotypes include the most frequent haplotype H1 (T-C-T-T) defined by SNPs in exon 12, intron 13 (rs2235035), exon 21, and exon 26 (3435 C>T; P=0.004, OR= 0.476). Our results suggest that ABCB1/MDR1 is a novel low-penetrance gene for susceptibility to MSI-H tumors. The present study provides additional evidence for the role that the MDR1/ABCB1 gene plays in the initiation and progression of MSI-H CRC development. true false false Angleški jezik Angleški jezik Neznano 2012-05-31 12:06:30 2012-05-31 12:06:30 2022-04-15 03:41:01 2024-01-03 03:21:30 2008 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 61 12265494 0165-4608 URN:SI:UM:DK:UNSDLDWY http://dx.doi.org/10.1016/j.cancergencyto.2008.01.023 1 https://dk.um.si/Dokument.php?lang=slv&id=35118 Fakulteta za kemijo in kemijsko tehnologijo 0 0 0