A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity

Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Science (Impact Factor: 33.61). 02/2007; 315(5811):525-8. DOI: 10.1126/science.1135308
Source: PubMed


Synonymous single-nucleotide polymorphisms (SNPs) do not produce altered coding sequences, and therefore they are not expected to change the function of the protein in which they occur. We report that a synonymous SNP in the Multidrug Resistance 1 (MDR1) gene, part of a haplotype previously linked to altered function of the MDR1 gene product P-glycoprotein (P-gp), nonetheless results in P-gp with altered drug and inhibitor interactions. Similar mRNA and protein levels, but altered conformations, were found for wild-type and polymorphic P-gp. We hypothesize that the presence of a rare codon, marked by the synonymous polymorphism, affects the timing of cotranslational folding and insertion of P-gp into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.

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    • "Since it is a synonymous SNP, no change in amino acid of the protein occurs. For a long time, it was assumed that synonymous SNPs were inconsequential , but the assumption has been questioned in a number of studies [25] [26]. It is now believed that synonymous SNPs can result "
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    ABSTRACT: Objectives: Epidermal growth factor receptor (EGFR) mutations are important predictors of treatment response to tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, some patients with mutations do not respond and some patients without mutations show response. We therefore need additional biomarkers to improve the selection of these patients for treatment. A promising candidate could be germline genetic variations in the EGFR gene that can alter protein expression or function and may influence the response to TKIs. Thus, the aim of this study was to evaluate the predictive role of genetic variations in the EGFR gene in advanced NSCLC patients treated with a TKI. Materials and methods: Genotypes for -216G>T, -191C>A and 181946C>T in the EGFR gene were retrospectively evaluated by DNA sequencing and allele-specific PCR analysis in 331 Caucasian patients with advanced NSCLC. Genotypes were correlated with clinical characteristics, toxicity and outcome. A multivariate analysis was performed using Cox proportional hazards model while adjusting for clinically relevant factors including EGFR mutation status. Results: 181946CT or TT genotypes showed an association with clinical outcome compared with patients with the 181946CC genotype (disease control rate (DCR), 68% versus 52%; P=0.049; progression-free survival (PFS), adjusted hazard ratio (HR)=0.74 (95% confidence interval (CI): 0.55-0.99); overall survival (OS), adjusted HR=0.73 (95% CI: 0.54-0.97)). Subgroup analysis demonstrated that the association may be most relevant in EGFR mutation-positive patients (PFS, adjusted HR=0.43 (95% CI: 0.22-0.82); OS, adjusted HR=0.47 (95% CI: 0.24-0.93)). Conclusion: The 181946C>T polymorphisms in the EGFR gene seems to be a potential predictor of higher DCR, longer PFS and OS in advanced NSCLC patients treated with erlotinib, especially in EGFR mutation-positive patients. Thus, this SNP may be a new potential tool for selection of patients for treatment. Prospective randomized studies are wanted to confirm our data.
    Lung cancer (Amsterdam, Netherlands) 09/2015; DOI:10.1016/j.lungcan.2015.09.003 · 3.96 Impact Factor
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    • "To confirm reproducibility, genotyping was repeated for 10% of the samples yielding 100% identity. ABCB1/rs1045652 [45] [46] [47] [48], ABCB1/rs1128503 [49], ABCG2/rs2231142 [50] [51] [52], ABCG2/rs2231137 [53],ABCG2/rs2622604 [53], ABCC2/rs2273697[54], ABCC2/17222723 [55] and ABCC2/rs717620 [54] were all selected based on their documented functionality from a literature search; and ABCG2/rs3789243 was chosen based on its association with inflammatory bowel disease [56], CRC [29] and low mRNA levels in morphologically normal intestinal tissue from patients with adenoma [24]. "
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    ABSTRACT: The ATP-binding cassette (ABC) transporter family transports various molecules across the enterocytes in the gut protecting the intestine against potentially harmful substances. Moreover, ABC transporters are involved in mucosal immune defence through interaction with cytokines. The study aimed to assess whether polymorphisms in ABCB1, ABCC2 and ABCG2 were associated with risk of colorectal cancer (CRC) and to investigate gene-environment (dietary factors, smoking and use of non-steroidal anti-inflammatory drugs) and gene-gene interactions between previously studied polymorphisms in IL1B and IL10 and ABC transporter genes in relation to CRC risk. We used a Danish prospective case-cohort study of 1010 CRC cases and 1829 randomly selected participants from the Danish Diet, Cancer and Health cohort. Incidence rate ratios were calculated based on Cox' proportional hazards model. None of the polymorphisms were associated with CRC, but ABCB1 and ABCG2 haplotypes were associated with risk of CRC. ABCB1/rs1045642 interacted with intake of cereals and fiber (p-Value for interaction (Pint) = 0.001 and 0.01, respectively). In a three-way analysis, both ABCB1/rs1045642 and ABCG2/rs2231137 in combination with IL10/rs3024505 interacted with fiber intake in relation to risk of CRC (Pint = 0.0007 and 0.009). Our results suggest that the ABC transporters P-glycoprotein/multidrug resistance 1 and BRCP, in cooperation with IL-10, are involved in the biological mechanism underlying the protective effect of fiber intake in relation to CRC. These results should be replicated in other cohorts to rule out chance findings.
    Scandinavian Journal of Gastroenterology 06/2015; 50(12):1-13. DOI:10.3109/00365521.2015.1056224 · 2.36 Impact Factor
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    • "The nonsynonymous mutation in ABCB1 G2677T can result in a distinct amino acid change (Ala > Ser), which exhibited lower substrate specificity and reduced drugstimulated ATPase activity as compared to the wild type [23]. The ABCB1 C3435T is a synonymous mutation but the variant can alter protein expression by affecting translation efficacy [24]. Since ABCB1 3435TT was first reported to be significantly associated with reduced ABCB1 expression in intestine compared to the CC homozygotes, numerous studies have investigated the association of ABCB1 genotype/haplotype with expression/function of the transporter in different tissues [25]. "
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    ABSTRACT: Genetic polymorphisms in ABC (ATP-binding cassette) transporter genes are associated with differential responses to chemotherapy in various cancers including pancreatic cancer. In this study, four SNPs in the ABCB1, ABCC1, and ABCG2 genes were investigated in normal and pancreatic cancerous specimens. The expression of the three transporters was also analyzed. The TT genotypes of G2677T and C3435T in ABCB1 gene were associated with lower risk of developing pancreatic cancer (P = 0.013, OR = 0.35 and P = 0.015, OR = 0.29, resp.). To our knowledge, this is the first report of the common polymorphisms in the ABCB1 gene affecting the genetic risk of developing pancreatic cancer. Moreover, the expression of ABCB1 in 2677TT and 3435TT carriers was lower compared to the wild-type homozygotes and heterozygotes. A cell viability assay, using standard pancreatic cancer cell lines, revealed that the ABCB1 2677TT-3455TT haplotype was more sensitive than the other haplotypes to gemcitabine. Conclusion. Polymorphisms in ABCB1 G2677T and G3435T were associated with differential susceptibility to pancreatic cancer and may predict responses to chemotherapy.
    Gastroenterology Research and Practice 10/2014; 2014(19 Supplement):414931. DOI:10.1155/2014/414931 · 1.75 Impact Factor
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