ABCB1/MDR1 gene polymorphisms as a prognostic factor in colorectal cancer

Abstract

Objective: To 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 methods: Tumour 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.

Results: A 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).

Conclusions: These 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.

Fig. 1

Adjusted survival probability of colorectal cancer patients according to T₁₂₃₆ allele (CC₁₂₃₆ vs. TT₁₂₃₆ or CT₁₂₃₆ genotype) F Cox test: T1 = 33.16845, T2 = 9.831555, F(60.24) = 1.349469, p = 0.05

Fig. 2

Adjusted survival probability of colorectal cancer patients according to histological type (adenocarcinoma vs. mucinous adenocarcinoma and medullary adenocarcinoma) F Cox test: T1 = 30.52871, T2 = 12.47129, F(50. 34) = 1.664585, p = 0.05