Variation within 3′-UTRs of Base Excision Repair Genes and Response to Therapy in Colorectal Cancer Patients: A Potential Modulation of microRNAs Binding

Abstract

Purpose: Colorectal cancer is routinely treated with a 5-fluorouracil (5-FU)-based chemotherapy. 5-FU incorporates into DNA, and the base excision repair (BER) pathway specifically recognizes such damage. We investigated the association of single-nucleotide polymorphisms (SNP) in the 3 0 -untranslated regions (UTR) of BER genes, and potentially affecting the microRNA (miRNA) binding, on the risk of colorectal cancer, its progression, and prognosis. SNPs in miRNA-binding sites may modulate the posttranscriptional regulation of gene expression operated by miRNAs and explain interindividual variability in BER capacity and response to 5-FU. Experimental Design: We tested 12 SNPs in the 3 0 -UTRs of five BER genes for colorectal cancer susceptibility in a case-control study (1,098 cases and 1,459 healthy controls). Subsequently, we analyzed the role of these SNPs on clinical outcomes of patients (866 in the Training set and 232 in the Replication set).Results: SNPs in the SMUG1 and NEIL2 genes were associated with overall survival. In particular, SMUG1 rs2233921 TT carriers showed increased survival compared with those with GT/GG genotypes [HR, 0.54; 95% confidence interval (CI), 0.36-0.81; P ¼ 0.003] in the Training set and after pooling results from the Replication set. The association was more significant following stratification for 5-FU-based chemotherapy (P ¼ 5.6 Â 10 À5 ). A reduced expression of the reporter gene for the T allele of rs2233921 was observed when compared with the common G allele by in vitro assay. None of the genotyped BER polymorphisms were associated with colorectal cancer risk. Conclusions:We provide the first evidence that variations in miRNA-binding sites in BER genes 3 0 -UTR may modulate colorectal cancer prognosis and therapy response.

Predictive Value of MiR-219-1, MiR-938, MiR-34b/c, and MiR-218 Polymorphisms for Gastric Cancer Susceptibility and Prognosis

“…Yoon, K. A et al found that no significant association emerged between this polymorphism and survival of nonsmall cell lung cancer. Further, Pardini et al thought that rs231210 could be a predictor of clinical outcomes in colorectal cancer patients [8]. However, our results suggested that rs231210 was associated with GC susceptibility but not associated with GC prognosis.…”

“…Aberrant expression of miRNA may characterize many diseases, including cancer, and these patterns could be used as predictors of susceptibility and prognosis in cancer patients [6, 7]. Various studies have indicated that single nucleotide polymorphisms (SNPs) in the 3′-untranslated region affected the expression levels or the mature sequence of miRNAs and further impacted mRNA and protein expressions [8–10]. …”

Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer

“…In vitro experiments using cell lines revealed potential functions of some biomarkers, including XRCC3 [50], XRCC2 [58], FGFR4 [66], and NF-κB [75], in chemoradiation sensitivity. Interestingly, two nCRT-responsive SNPs located in miRNA target sites of the MRE11A gene (rs2155209) [140] and the SMUG1 gene (rs2233921) [141] affected gene transcription. Although miRNAs that target these SNPs were not identified, the results suggested potential biological links of these SNPs to nCRT response.…”

“…Vymetalkova et al examined 13 SNPs in predicted miRNA target sites in mucin genes in 310 rectal cancer patients and the patients with CC genotype of rs4729655 in mucin 17 ( MUC17 ) gene exhibited a longer overall survival (hazard ratio = 0.27, 95% CI = 0.14–0.54, p < 0.001) than those without CC genotype [139]. The same research group also identified significant association of overall survival in CRC with SNPs located in miRNA target sites of DNA repair protein RAD52 homolog ( RAD52 ) (rs11226), X-ray repair cross-complementing protein 5 ( XRCC5 ) (rs1051685) and single-strand-selective monofunctional uracil-DNA glycosylase 1 ( SMUG1 ) (rs2233921) [140,141]. …”

MicroRNA binding site polymorphisms as biomarkers in cancer management and research

“…Concerning the most commonly used therapies based on 5-fluorouracil (5-FU), miRSNPs in BER genes were evaluated, and interesting results were found for miRSNPs rs1534862 within NEIL2 and rs223392 within SMUG1 57. Both miRSNPs were found to be associated with OS, with the stronger association for TT homozygotes of rs223392 after stratification for 5-FU-based chemotherapy.…”