Abstract
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'-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. We tested 12 SNPs in the 3'-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). 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 = 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 = 5.6 × 10(-5)). 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. We provide the first evidence that variations in miRNA-binding sites in BER genes 3'-UTR may modulate colorectal cancer prognosis and therapy response.
Highlights
Colorectal cancer is the second most common cancer in Western countries [1]
single-nucleotide polymorphisms (SNP) in the SMUG1 and NEIL2 genes were associated with overall survival
None of the genotyped Base excision repair (BER) polymorphisms were associated with colorectal cancer risk
Summary
Colorectal cancer is the second most common cancer in Western countries [1]. it is a preventable and potentially curable malignancy, it still represents the second leading cause of cancer-related death among men and women [2].Authors' Affiliations: 1Human Genetics Foundation Torino; 2Department of Medical Sciences, University of Turin, Turin; 3Department of Biology, University of Pisa, Pisa; 4Laboratory of Computational Oncology, Center for Integrated Biology (CIBIO), University of Trento, Trento, Italy; 5Department of Molecular Biology of Cancer, Institute of Experimental Medicine; Departments of 6Surgery and 7Oncology, Thomayer Hospital; 8Institute of Biology and Department of Medical Genetics; and 9Department of Oncology, First Faculty of Medicine, Charles University, Prague, Czech RepublicNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).Ó2013 American Association for Cancer Research.Impaired DNA repair capacity and DNA damage accumulation may lead to cancer development. Colorectal cancer is the second most common cancer in Western countries [1] It is a preventable and potentially curable malignancy, it still represents the second leading cause of cancer-related death among men and women [2]. Subjects homozygous for the variant alleles of two exon-localized polymorphisms of BER genes, APE1 and hOGG1, were at an increased risk of colorectal cancer [6]. Such variant alleles were associated with significantly lower BER rates in healthy subjects, suggesting the importance of DNA repair in cancer susceptibility, as well as gene–gene and gene–environment interactions [7]
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