A functional variant at miRNA-122 binding site in IL-1α 3' UTR predicts risk and HPV-positive tumours of oropharyngeal cancer

Eur J Cancer. 2015 Jul;51(11):1415-23. doi: 10.1016/j.ejca.2015.04.016. Epub 2015 May 14.

Abstract

Background: Genetic polymorphisms in the 3' untranslated regions (3' UTRs) targeted by miRNAs alter the strength of miRNA binding in a manner that affects the behaviour of individual miRNAs. An insertion (Ins)/deletion (Del) polymorphism (rs3783553) in the 3' UTR of IL-1α may disrupt a binding site for miRNA-122. IL-1α plays an important role in inflammation, immunity and defense against infection. Thus, we hypothesised that the rs3783553 polymorphism affects individual susceptibility to human papillomavirus (HPV)-associated oral squamous cell carcinoma (OSCC).

Methods: We genotyped the rs3783553 polymorphism; and determined HPV16 L1 serology, tumour HPV16 DNA and serum IL-1α expression. Univariate/multivariable logistic regression models were used to calculate associations.

Results: We found that HPV16 L1 seropositivity alone was associated with an increased risk of OSCC (Odds ratio (OR), 3.1; 95% confidence interval (CI), 2.1-4.6), and the risk of HPV16-associated OSCC was modified by the rs3783553 polymorphism. Patients with both HPV16 L1 seropositivity and Del/Del genotype for the rs3783553 had the highest risk of OSCC when using patients with HPV16 L1 seronegativity and Ins/Del+Ins/Ins genotypes as a comparison group. Notably, that effect modification was particularly pronounced in several subgroups (e.g. SCCOP, never-smokers and never-drinkers). The patients with Del/Del genotype were approximately 3.0 times more likely to have HPV16-positive squamous cell carcinoma of the oropharynx (SCCOP) tumours compared to those patients with Ins/Del+Ins/Ins genotypes. Additionally, functional relevance of this variant was characterised to explore the genotype-phenotype correlation.

Conclusion: These results suggest that IL-1α 3' UTR rs3783553 polymorphism may be functional and influence susceptibility to HPV16-associated OSCC, particularly for SCCOP. Validation of our findings is warranted.

Keywords: Biomarker; Cancer risk; HPV; IL-1α variant; Oral cancer; SCCOP; miRNA.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions*
  • Adult
  • Aged
  • Binding Sites
  • Carcinoma, Squamous Cell / genetics*
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Head and Neck Neoplasms / genetics*
  • Human papillomavirus 16 / genetics*
  • Humans
  • Interleukin-1alpha / genetics*
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • Oropharyngeal Neoplasms / genetics*
  • Oropharyngeal Neoplasms / virology
  • Papillomavirus Infections / genetics*
  • Papillomavirus Infections / virology
  • Polymorphism, Genetic
  • Risk Factors
  • Squamous Cell Carcinoma of Head and Neck

Substances

  • 3' Untranslated Regions
  • Interleukin-1alpha
  • MIRN122 microRNA, human
  • MicroRNAs