Abstract
BackgroundHPV-associated HNSCCs have a distinct etiologic mechanism and better prognosis than those with non-HPV associated HNSCCs. However, even within the each group, there is heterogeneity in survival time. Here, we test the hypothesis that specific candidate gene methylation markers (CCNA1, NDN, CD1A, DCC, p16, GADD45A) are associated with tumor recurrence and survival, in a well-characterized, prospective, cohort of 346 HNSCC patients.MethodsKaplan-Meier curves were used to estimate survival time distributions. Multivariable Cox Proportional Hazards models were used to test associations between each methylation marker and OST/RPFT after adjusting for known or identified prognostic factors. Stratified Cox models included an interaction term between HPV and methylation marker to test for differences in the associations of the biomarker with OST or RPFT across HPV status.ResultsMethylation markers were differentially associated with patient characteristics. DNA hypermethylation of NDN and CD1A was found to be significantly associated with overall survival time (OST) in all HNSCC patients (NDN hazard ratio (HR): 2.35, 95 % CI: 1.40-3.94; CD1A HR: 1.31, 95 % CI: 1.01-1.71). Stratification by HPV status revealed hypermethylation of CD1A was associated with better OST and recurrence/persistence-free time (RPFT) (OST HR: 3.34, 95 % CI: 1.88-5.93; RPFT HR: 2.06, 95 % CI: 1.21-3.49), while hypomethylation of CCNA1 was associated with increased RPFT in HPV (+) patients only (HR: 0.31, 95 % CI: 0.13-0.74).ConclusionsThis study is the first to describe novel epigenetic alterations associated with survival in an unselected, prospectively collected, consecutive cohort of patients with HNSCC. DNA hypermethylation of NDN and CD1A was found to be significantly associated with increased overall survival time in all HNSCC patients. However, stratification by the important prognostic factor of HPV status revealed the immune marker, CD1A, and the cell cycle regulator, CCNA1 to be associated with prognosis in HPV (+) patients, specifically. Here, we identified novel methylation markers and specific, epigenetic molecular differences associated with HPV status, which warrant further investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1806-8) contains supplementary material, which is available to authorized users.
Highlights
human papillomavirus (HPV)-associated Head and neck squamous cell carcinoma (HNSCC) have a distinct etiologic mechanism and better prognosis than those with non-HPV associated head and neck squamous cell carcinomas (HNSCCs)
This study is the first to describe novel epigenetic alterations associated with survival in an unselected, prospectively collected, consecutive cohort of patients with HNSCC
These unique discoveries raise new questions about why these specific epigenetic changes differ among biologically distinct subsets of HNSCC patients (HPV + versus HPV -) and if these differences are linked to HPV status or other factors
Summary
HPV-associated HNSCCs have a distinct etiologic mechanism and better prognosis than those with non-HPV associated HNSCCs. even within the each group, there is heterogeneity in survival time. Heavy tobacco and alcohol use are well established risk factors, but high-risk human papillomavirus (HPV) infection has recently been identified as an independent etiologic factor for a subset of head and neck squamous cell carcinomas (HNSCCs) [3]. The incidence of HPV-associated HNSCC has steadily increased, especially in younger patients, while incidence of non-HPV associated HNSCC has declined in recent years [8,9,10]. HPV-associated HNSCCs have a unique risk profile, a distinct etiologic mechanism, and better prognosis than non-HPV associated HNSCCs [11,12,13,14]. There is strong interest in identifying prognostic markers for both HPV (+) and HPV (-) patients with HNSCC
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