Common germline MDR1/ABCB1 functional polymorphisms and haplotypes modify susceptibility to colorectal cancers with high microsatellite instability

被引:33
作者
Potocnik, Uros [1 ,2 ]
Glavac, Damjan [3 ]
Dean, Michael [4 ]
机构
[1] Univ Maribor, Fac Med, Ctr Human Mol Genet & Pharmacogen, SLO-2000 Maribor, Slovenia
[2] Univ Maribor, Fac Chem & Chem Engn, Lab Biochem Mol Biol & Gen, SLO-2000 Maribor, Slovenia
[3] Univ Ljubljana, Fac Med, Inst Pathol, Mol Genet Lab, Ljubljana 1000, Slovenia
[4] NCI, Lab Gen Divers, Frederick, MD 21702 USA
关键词
D O I
10.1016/j.cancergencyto.2008.01.023
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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/ABCB1gene, were identified in a proportion of previously untreated colorectal cancers (CRQ exhibiting high microsatellite instability (MSI-H), which suggested that MDR1/ABCB1acts 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/ABCB1gene, 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 HI (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. (C) 2008 Elsevier Inc. All rights reserved. (C) 2008 Elsevier Inc. All rights reserved.
引用
收藏
页码:28 / 34
页数:7
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