| Title: | Common germline MDR1/ABCB1 functional polymorphisms and haplotypes modify susceptibility to colorectal cancers with high microsatellite instability |
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| Authors: | ID Potočnik, Uroš (Author)
ID Glavač, Damjan (Author)
ID Dean, Michael (Author) |
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| Files: |  http://dx.doi.org/10.1016/j.cancergencyto.2008.01.023
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| Language: | English |
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| Work type: | Unknown |
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| Typology: | 1.01 - Original Scientific Article |
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| Organization: | FKKT - Faculty of Chemistry and Chemical Engineering
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| 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. |
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| Year of publishing: | 2008 |
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| PID: | 20.500.12556/DKUM-26177  |
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| UDC: | 61 |
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| ISSN on article: | 0165-4608 |
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| COBISS.SI-ID: | 12265494 |
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| NUK URN: | URN:SI:UM:DK:UNSDLDWY |
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| Publication date in DKUM: | 31.05.2012 |
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| Views: | 1693 |
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| Downloads: | 95 |
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| Metadata: |    |
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| Categories: | Misc.
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