Genetic variation in microRNA-binding site and prognosis of patients with colorectal cancer
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Single nucleotide polymorphisms (SNPs) located in the 3′-UTR of miRNA target genes could affect miRNA-mediated gene regulation, thereby contributing to the susceptibility or prognosis of cancer. Accordingly, the present study analyzed SNPs located at putative miRNA-binding sites of the 3′-UTR of various genes and investigated their impact on the prognosis for patients with colorectal cancer.
Materials and methods
In total, 831 consecutive patients (discovery cohort, n = 309; validation cohort, n = 522) with curatively resected colorectal adenocarcinoma were enrolled. Plus, 157 SNPs were selected from an in silico analysis based on several miRNA and HapMap databases. The SNP genotyping was performed using a Sequenom MassARRAY. A luciferase assay was used to investigate whether miR-571 modulated PAUF gene expression when rs12373 was included in the PAUF 3′UTR region.
In the discovery cohort, 18 SNPs were identified as possible prognostic biomarkers in a survival analysis. In the validation cohort, two SNPs (TPST1 rs3757417T>G and PAUF rs12373A>C) were significantly associated with prognosis in the same direction as the discovery cohort when adjusted for age, preoperative carcinoembryonic antigen level, and pathologic stage (discovery + validation cohort; TPST1 rs3757417T>G, disease-free survival (DFS), p value = 0.0004, overall survival (OS), p value = 0.01 in recessive model; PAUF rs12373A>C, DFS, p value = <0.0001, OS, p value = 0.0008 in dominant model). A significantly lower Renilla activity was observed in the rs12373 CC construct when compared with the rs12373 AA construct (p = 0.002).
The current study provides evidence that the TPST1 rs3757417T>G and PAUF rs12373A>C polymorphisms are possible prognostic biomarkers for patients with colorectal cancer.
KeywordsColorectal cancer MiRNA target gene Polymorphism Prognosis
This work was supported in part by National Research Foundation (NRF) of Korea Grant funded by the Korean Government (NRF-2011-0015862) and in part by NRF funded by the Ministry of Education (2013R1A1A4A01008144).
Conflict of interest
The authors declare no conflict of interest.
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