A let-7 microRNA Polymorphism in the KRAS 3'-UTR Is Prognostic in Oropharyngeal Cancer

Cancer Epidemiol. 2014 Oct;38(5):591-8. doi: 10.1016/j.canep.2014.07.008. Epub 2014 Aug 12.

Abstract

Introduction: This study aimed to investigate the effect of genetic polymorphisms in miRNA sequences, miRNA target genes and miRNA processing genes as additional biomarkers to HPV for prognosis in oropharyngeal squamous cell carcinoma (OPSCC) patients. Secondarily, the prevalence of HPV-associated OPSCC in a European cohort was mapped.

Methods: OPSCC patients (n=122) were genotyped for ten genetic polymorphisms in pre-miRNAs (pre-mir-146a, pre-mir-196a2), in miRNA biosynthesis genes (Drosha, XPO5) and in miRNA target genes (KRAS, SMC1B). HPV status was assessed by p16 immunohistochemistry (IHC) and high-risk HPV in situ hybridization (ISH) or by p16 IHC and PCR followed by enzyme-immunoassay (EIA). Overall and disease specific survival were analysed using Kaplan-Meier plots (log-rank test). Cox proportional hazard model was used to calculate hazard ratios (HR).

Results: The overall HPV prevalence rate in our Belgian/Dutch cohort was 27.9%. Patients with HPV(+) tumours had a better 5-years overall survival (78% vs. 46%, p=0.001) and a better 5-years disease specific survival (90% vs. 70%, p=0.016) compared to patients with HPV(-) tumours. In multivariate Cox analysis including clinical, treatment and genetic parameters, HPV negativity (HR=3.89, p=0.005), advanced T-stage (HR=1.81, p=0.050), advanced N-stage (HR=5.86, p=0.001) and >10 pack-years of smoking (HR=3.45, p=0.012) were significantly associated with reduced overall survival. The variant G-allele of the KRAS-LCS6 polymorphism was significantly associated with a better overall survival (HR=0.40, p=0.031).

Conclusions: Our results demonstrate that OPSCC patients with the KRAS-LCS6 variant have a better outcome and suggest that this variant may be used as a prognostic biomarker for OPSCC.

Keywords: Genetic polymorphisms; HPV; KRAS; Oropharyngeal cancer; Prevalence; Prognostic biomarker; miRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Adult
  • Aged
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / virology
  • Female
  • Follow-Up Studies
  • Genotype
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • Oropharyngeal Neoplasms / genetics
  • Oropharyngeal Neoplasms / pathology*
  • Oropharyngeal Neoplasms / virology
  • Papillomavirus Infections / complications
  • Papillomavirus Infections / epidemiology
  • Polymorphism, Genetic
  • Prevalence
  • Prognosis
  • Proportional Hazards Models
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • Survival Rate
  • ras Proteins / genetics*

Substances

  • 3' Untranslated Regions
  • KRAS protein, human
  • MicroRNAs
  • Proto-Oncogene Proteins
  • mirnlet7 microRNA, human
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins