A genetic variation in microRNA target site of KRT81 gene is associated with survival in early-stage non-small-cell lung cancer

Ann Oncol. 2015 Jun;26(6):1142-1148. doi: 10.1093/annonc/mdv100. Epub 2015 Feb 24.

Abstract

Background: MicroRNAs (miRNAs) have a key role in carcinogenesis through negative regulation of their target genes. Therefore, genetic variations in miRNAs or their target sites may affect miRNA-mRNA interactions, thereby result in altered expression of target genes. This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) located in the miRNA target sites (poly-miRTSs) and survival of patients with early-stage non-small-cell lung cancer (NSCLC).

Methods: Using public SNP database and miRNA target sites prediction program, 354 poly-miRTSs were selected for genotyping. Among these, 154 SNPs applicable to Sequenom's MassARRAY platform were investigated in 357 patients. A replication study was carried out on an independent patient population (n = 479). Renilla luciferase assay and reverse transcription-polymerase chain reaction were conducted to examine functional relevance of potentially functional poly-miRTSs.

Results: Of the 154 SNPs analyzed in a discovery set, 14 SNPs were significantly associated with survival outcomes. Among these, KRT81 rs3660G>C was found to be associated with survival outcomes in the validation cohort. In the combined analysis, patients with the rs3660 GC + CC genotype had a significantly better overall survival compared with those with GG genotype [adjusted hazard ratio (aHR) for OS, 0.65; 95% confidence interval (CI) 0.50-0.85; P = 0.001]. An increased expression of the reporter gene for the C allele of rs3660 compared with the G allele was observed by luciferase assay. Consistently, the C allele was associated with higher relative expression level of KRT81 in tumor tissues.

Conclusion: The rs3660G>C affects KRT81 expression and thus influences survival in early-stage NSCLC. The analysis of the rs3660G>C polymorphism may be useful to identify patients at high risk of a poor disease outcome.

Keywords: KRT81; miRNA target sites; non-small cell lung cancer; polymorphisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Aged
  • Binding Sites
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / therapy
  • Computational Biology
  • Databases, Genetic
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Frequency
  • Genetic Predisposition to Disease
  • HEK293 Cells
  • Humans
  • Kaplan-Meier Estimate
  • Keratins, Hair-Specific / genetics*
  • Keratins, Hair-Specific / metabolism
  • Keratins, Type II / genetics*
  • Keratins, Type II / metabolism
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy
  • Male
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Middle Aged
  • Neoplasm Staging
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Proportional Hazards Models
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Risk Factors
  • Time Factors
  • Transfection

Substances

  • 3' Untranslated Regions
  • KRT81 protein, human
  • Keratins, Hair-Specific
  • Keratins, Type II
  • MicroRNAs
  • RNA, Messenger