Genetic Variation in microRNA-binding Site and Prognosis of Patients With Colorectal Cancer

J Cancer Res Clin Oncol. 2015 Jan;141(1):35-41. doi: 10.1007/s00432-014-1780-6. Epub 2014 Jul 31.

Abstract

Background: 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.

Results: 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).

Conclusion: The current study provides evidence that the TPST1 rs3757417T>G and PAUF rs12373A>C polymorphisms are possible prognostic biomarkers for patients with colorectal cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Binding Sites
  • Biomarkers, Tumor / genetics
  • Cohort Studies
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Combined Modality Therapy
  • Female
  • Follow-Up Studies
  • Genotype
  • Humans
  • Lectins / genetics*
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / mortality
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Staging
  • Polymorphism, Genetic / genetics*
  • Prognosis
  • Sulfotransferases / genetics*
  • Survival Rate
  • Validation Studies as Topic
  • Young Adult

Substances

  • 3' Untranslated Regions
  • Biomarkers, Tumor
  • Lectins
  • MicroRNAs
  • PAUF protein, human
  • Sulfotransferases
  • protein-tyrosine sulfotransferase