MicroRNA Variants Increase the Risk of HPV-Associated Squamous Cell Carcinoma of the Oropharynx in Never Smokers

Xicheng Song,Lei Jin,Erich M Sturgis,Guojun Li,Caiyun Zhang,Jun Liu,Zhongqiu Wang,Qingyi Wei,Thomas F Schulz

doi:10.1371/journal.pone.0056622

Abstract

BackgroundBoth microRNAs and human papillomavirus (HPV) infection play an important role in the development and progression of oral squamous cell carcinoma (OSCC). In addition, microRNAs affect all facets of the immune/inflammation responses to infection, which may control HPV clearance. We thus hypothesized that microRNA polymorphisms modify the association between HPV16 seropositivity and OSCC risk.MethodsFour single-nucleotide polymorphisms in microRNAs were genotyped and HPV16 serology was determined in 325 cases and 335 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using univariate and multivariable logistic regression models.ResultsOverall, each polymorphism had no significant main effect on OSCC risk. Compared with the risk among individuals with both miR146 rs2910164 GG genotype and HPV16 seronegativity, risk of OSCC was increased among those with CG or CC genotype and HPV16 seronegativity (OR, 1.2; 95% CI, 0.9–1.8), GG genotype and HPV16 seropositivity (OR, 3.0; 95% CI, 1.8–5.0), and CG or CC genotype and HPV16 seropositivity (OR, 4.7; 95% CI, 2.3–9.4). Similar results were found for miR149 rs2292832, miR196 rs11614913, and miR499 rs3746444. Analyses stratified by tumor sites and smoking status showed that each polymorphism significantly increased the risk of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP), and such effect modification was particularly prominent in never smokers.ConclusionsOur results indicate that microRNA polymorphisms modify the risk of OSCC associated with HPV16 seropositivity, particularly in patients with SCCOP and never smokers. Larger studies are needed to verify our findings.

Highlights

Oral squamous cell carcinoma (OSCC; SCC of the oropharynx, squamous cell carcinoma of the oropharynx (SCCOP) and SCC of oral cavity) accounts for the majority of head and neck malignant tumors and is one of the most common malignancies worldwide
HPV type 16 (HPV16) seropositivity was associated with risk for oral squamous cell carcinoma (OSCC) (OR, 3.2, 95% confidence intervals (CIs), 2.1– 4.8), for SCCOP (OR, 5.4, 95% CI, 3.7-8/9), but not for oral cavity cancers (OR, 0.8, 95% CI, 0.38–1.48), after adjusting for age, sex, smoking status, and drinking status
Considering that the difference in the tumor human papillomavirus (HPV) status between patients with SCCOP and oral cavity cancers might be attributed to different etiologies at the two different anatomic sites, we further investigated the modifying effect of each single nucleotide polymorphisms (SNPs) on the association between HPV16 seropositivity and risk of SCCOP and oral cavity cancers (Table 4)

Summary

Introduction

Oral squamous cell carcinoma (OSCC; SCC of the oropharynx, SCCOP and SCC of oral cavity) accounts for the majority of head and neck malignant tumors and is one of the most common malignancies worldwide. Tobacco use and alcohol consumption are considered the most important risk factors for OSCC [4]. HPV may be another important etiologic factor for OSCC in addition to tobacco and alcohol use. HPV infection may be a major risk factor for OSCC, only a small fraction of individuals infected with HPV eventually develop the malignancy, implying that host genetic factors may modify the association between HPV infection and OSCC risk. Both microRNAs and human papillomavirus (HPV) infection play an important role in the development and progression of oral squamous cell carcinoma (OSCC). We hypothesized that microRNA polymorphisms modify the association between HPV16 seropositivity and OSCC risk

Methods

Results

Conclusion