Potocnik Uros, Glavac Damjan, Dean Michael
Center for Human Molecular Genetics and Pharmacogenomics, Medical Faculty, University of Maribor, Slomskov trg 15, 2000 Maribor, Slovenia.
Cancer Genet Cytogenet. 2008 May;183(1):28-34. doi: 10.1016/j.cancergencyto.2008.01.023.
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.
在一部分先前未经治疗且表现出高微卫星不稳定性（MSI-H）的结直肠癌（CRC）中，发现了多药耐药（MDR1/ABCB1）基因编码的P-糖蛋白（P-gp）表达改变，以及MDR1/ABCB1基因的体细胞突变和高甲基化，这表明MDR1/ABCB1作为一个候选基因，在MSI-H肿瘤的发生和发展中起作用。在此，我们报告了MDR1/ABCB1基因中的种系功能性单核苷酸多态性（SNP）和单倍型，它们可能导致遗传风险或增加对MSI-H癌症的易感性。我们通过比较健康对照与MSI-H肿瘤患者之间的MDR1/ABCB1基因型、等位基因和单倍型频率，证实了疾病关联。特别是，与对照组相比，外显子12（1236 C→T）SNP的T/T基因型携带者和外显子21（2677G→T）SNP的T/T基因型携带者发生MSI-H CRC的风险显著更高（分别为P = 0.01，OR = 3.182和P = 0.005，OR = 3.594）。与MSI-H相关的最显著风险单倍型包括由外显子12、内含子13（rs2235035）、外显子21和外显子26中的SNP定义的最常见单倍型H1（T-C-T-T；P = 0.004，OR = 0.476）。我们的结果表明，ABCB1/MDR1是一个新的对MSI-H肿瘤易感性具有低外显率的基因。本研究为MDR1/ABCB1基因在MSI-H CRC发生和发展中的作用提供了额外证据。
