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The MDR1/ABCB1 gene rs 1045642 polymorphism in colorectal cancer.

ABSTRACT: Introduction:Colorectal cancer (CRC) is one of the most frequently diagnosed tumors in Western countries. CRC is a heterogeneous group of tumors with regards to its molecular pathogenesis and genetic factors. Both genetic variations and anthropometric factors may affect morbidity in CRC patients. The aim of this study was to assess the impact of multidrug resistance 1/ATP-binding cassette sub-family B member 1 gene (MDR1/ABCB1) polymorphism rs1045642 and general anthropometric factors on the CRC risk. Material and methods:The study included 250 patients who underwent colonoscopy and polypectomy between 2006 and 2013 in a single endoscopy unit in Warsaw, Poland. Results:The CRC was diagnosed in 50 individuals, and 200 patients were included in the control group. Cases and controls were matched for mean age and sex (p > 0.05). Factors that were found to significantly increase the risk of CRC were ulcerative colitis (8/35 in the CRC group vs. 8/181 in the control group; p = 0.001), family history of CRC (11/33 vs. 26/172; p = 0.05), and diabetes mellitus (12/34 vs. 28/170; p = 0.04). Allele T of the rs 1045642 polymorphism was more frequently present in CRC cases (in both a co-dominant and recessive model) and in males (in a co-dominant model), although these associations were not statistically significant (p > 0.05). Conclusions:The MDR1/ABCB1 gene polymorphism rs 1045642 may be involved in the pathogenesis of CRC and this relationship may be sex-specific for males. However, further population studies are necessary to assess this relationship.

SUBMITTER: Mrozikiewicz-Rakowska B

PROVIDER: S-EPMC6963158 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The MDR1/ABCB1 gene rs 1045642 polymorphism in colorectal cancer.

Mrozikiewicz-Rakowska Beata B Malinowski Marian M Nehring Piotr P Bartkowiak-Wieczorek Joanna J Bogacz Anna A Żurawińska-Grzelka Ewa E Krasnodębski Przemysław P Muszyński Jacek J Grzela Tomasz T Przybyłkowski Adam A Czupryniak Leszek L

Archives of medical science : AMS 20190926 1

<h4>Introduction</h4>Colorectal cancer (CRC) is one of the most frequently diagnosed tumors in Western countries. CRC is a heterogeneous group of tumors with regards to its molecular pathogenesis and genetic factors. Both genetic variations and anthropometric factors may affect morbidity in CRC patients. The aim of this study was to assess the impact of multidrug resistance 1/ATP-binding cassette sub-family B member 1 gene (MDR1/ABCB1) polymorphism rs1045642 and general anthropometric factors on ...[more]

PMID: 32051713

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Project description:ObjectiveTo analyse the single-nucleotide polymorphisms (SNPs): ABCB1(1236C>T), ABCB1(2677G>T/A), ABCB1(3435C>T) and haplotypes in the ABCB1/MDR1 gene, which could contribute to genetic risk of colorectal cancer (CRC). Disease association between the ABCB1/MDR1 genotype, allele, haplotype frequencies and histological features, such as TNM classification, localization of primary carcinoma, grade of malignancy, histological type of tumour, lymphoid infiltration and vessel invasion were estimated. In this study, the potential role of SNPs of the ABCB1/MDR1 gene as a prognostic marker for CRC was analysed.Materials and methodsTumour specimens of 95 patients with CRC were studied. Using automated sequencing or PCR-RFLP method, DNA for three common SNPs of ABCB1/MDR1 was extracted and analysed. The results of genotyping and haplotype analysis with histopathological features, grading and clinical staging of neoplasms were correlated.ResultsA statistically significant higher frequency of T(1236) allele in T1/T2 (89.7%), M0 groups (81.6%) and I/II clinical staging (82.7%) in comparison with T3/T4 (68.2%), M1 groups (47.4%) and III/IV clinical staging (65.1%) was detected. Furthermore, multivariate analysis according to Cox's proportional hazard model indicated that the T(1236) allele is a good, independent prognostic factor and the presence of this allele decreases the risk of death in comparison with a group without this allele (HR = 0.26; p = 0.0424). In addition, a statistically significant higher frequency of C(3435) allele and significant differences in the C(3435) allele distribution in N1/N2 group (91.7% and 62.5%, respectively) than N0 group (71.2% and 44.9%, respectively) was found. Each of the eight possible haplotypes was noted in M0 or I/II group and only seven in M1 or III/IV group. Haplotype T(1236)-G(2677)-C(3435) only in less advanced CRC subjects (9.6% in I/II and 9.2% in M0 group) was detected. In addition, significant differences in haplotype distributions between M0 or I/II and M1 or III/IV group were found (p = 0.01 and p = 0.05, respectively).ConclusionsThese results suggest association between T(1236) allele and T(1236)-G(2677)-C(3435) haplotype and less advanced CRC, so these genetic markers may play a role as potentially good prognostic factors. Differences in haplotype distributions and degree of clinical staging may suggest that some other potential SNPs, especially in regulatory region of ABCB1/MDR1 gene, may influence P-glycoprotein function and CRC progression.

Project description:IntroductionHyperprolactinaemia, a common adverse effect of antipsychotic drugs, is primarily linked to blockade of dopamine D2 receptors in the pituitary gland. Certain antipsychotic drugs, such as, for example risperidone and paliperidone, are more likely to induce hyperprolactinaemia compared to others. This effect is probably caused by a relatively high blood/brain concentration ratio, a consequence of being a substrate of P-glycoprotein. Genetic variants of P-glycoprotein with changed functional activity might influence the potential of risperidone and paliperidone to cause hyperprolactinaemia as the altered blood/brain concentration ratio would lead to a reduced therapeutic drug level within essential brain areas making dose adaptations necessary. This increases exposure of dopamine D2 receptors within the pituitary gland.AimsTo investigate possible associations between MDR1/ABCB1 gene polymorphisms and antipsychotic drug-induced hyperprolactinaemia in Russian patients with schizophrenia and to determine possible differences between risperidone/paliperidone and other antipsychotics.MethodsIn total, 446 patients with schizophrenia were included from 3 psychiatric hospitals in Siberia. Blood samples were obtained in a cross-sectional study design for DNA extraction and prolactin measurement. Associations between hyperprolactinaemia and 8 MDR1/ABCB1 gene-polymorphisms were assessed using logistic regression analysis accounting for covariates. The analysis was repeated in a patient subgroup using risperidone or paliperidone.ResultsWe did not observe an association between any of the 8 single nucleotide polymorphisms and the prevalence of antipsychotic-induced hyperprolactinaemia in the total patient population. However, in the risperidone/paliperidone subgroup, the single nucleotide polymorphism rs2032582 (G2677T) was found to be negatively associated with risperidone/paliperidone-induced hyperprolactinaemia.ConclusionThis study revealed a significant association between the ABCB1 gene polymorphism rs2032582 (G2677T) and risperidone/paliperidone-induced hyperprolactinaemia.

Dataset Information

The MDR1/ABCB1 gene rs 1045642 polymorphism in colorectal cancer.

Publications

The MDR1/ABCB1 gene rs 1045642 polymorphism in colorectal cancer.

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