title: Common germline MDR1/ABCB1 functional polymorphisms and haplotypes modify susceptibility to colorectal cancers with high microsatellite instability.
abstract: 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.
authors.affiliation: Center for Human Molecular Genetics and Pharmacogenomics, Medical Faculty, University of Maribor, Slomskov trg 15, 2000 Maribor, Slovenia. uros.potocnik@uni-mb.si
authors.forename: Uros
authors.initials: U
authors.lastname: Potocnik
authors.forename: Damjan
authors.initials: D
authors.lastname: Glavac
authors.forename: Michael
authors.initials: M
authors.lastname: Dean
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D053842:Microsatellite Instability; D020641:Polymorphism, Single Nucleotide
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1