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Novel insights into epigenetic drivers of oropharyngeal squamous cell carcinoma: role of HPV and lifestyle factors.

ABSTRACT: In the last years, the explosion of high throughput sequencing technologies has enabled epigenome-wide analyses, allowing a more comprehensive overview of the oropharyngeal squamous cell carcinoma (OPSCC) epigenetic landscape. In this setting, the cellular pathways contributing to the neoplastic phenotype, including cell cycle regulation, cell signaling, DNA repair, and apoptosis have been demonstrated to be potential targets of epigenetic alterations in OPSCC. Of note, it has becoming increasingly clear that HPV infection and OPSCC lifestyle risk factors differently drive the epigenetic machinery in cancer cells. Epigenetic changes, including DNA methylation, histone modifications, and non-coding RNA expression, can be used as powerful and reliable tools for early diagnosis of OPSCC patients and improve prognostication. Since epigenetic changes are dynamic and reversible, epigenetic enzymes may also represent suitable targets for the development of more effective OPSCC therapeutic strategies. Thus, this review will focus on the main known epigenetic modifications that can occur in OPSCC and their exploitation as potential biomarkers and therapeutic targets. Furthermore, we will address epigenetic alterations to OPSCC risk factors, with a particular focus on HPV infection, tobacco exposure, and heavy alcohol consumption.

SUBMITTER: Boscolo-Rizzo P

PROVIDER: S-EPMC5704592 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Novel insights into epigenetic drivers of oropharyngeal squamous cell carcinoma: role of HPV and lifestyle factors.

Boscolo-Rizzo Paolo P Furlan Carlo C Lupato Valentina V Polesel Jerry J Fratta Elisabetta E

Clinical epigenetics 20171128

In the last years, the explosion of high throughput sequencing technologies has enabled epigenome-wide analyses, allowing a more comprehensive overview of the oropharyngeal squamous cell carcinoma (OPSCC) epigenetic landscape. In this setting, the cellular pathways contributing to the neoplastic phenotype, including cell cycle regulation, cell signaling, DNA repair, and apoptosis have been demonstrated to be potential targets of epigenetic alterations in OPSCC. Of note, it has becoming increasin ...[more]

PMID: 29209433

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Project description:The global rise of HPV(+) oropharyngeal squamous cell carcinoma (OPSCC) has generated considerable interest underlying its etiology and management. Despite an overall decline in head and neck malignancies, the incidence in OPSCC has by contrast sharply risen, with HPV(+) subtypes now comprising 80% of all OPSCC.1,2 Relative to HPV(-) OPSCC, HPV(+) patients are more responsive to chemoradiation and harbor a 52% risk-of-death reduction.3 Despite this distinct outcome, treatment regimens remain the same for all OPSCC subtypes (smoking-driven and virus-driven), rather than an adaptive approach to what most consider distinct diseases. The short-term effects (e.g., mucositis, odynophagia) and long-term toxicities (e.g., xerostomia, dysphagia, ototoxicity) from treatment substantially affect quality of life, and rival the impact of the cancer itself. Recently published as well as ongoing trials are actively examining deintensification approaches2,4-9, with the goal of diminishing treatment sequelae for HPV(+) subtypes. While deintensification may decrease chemoradiation-related toxicities, it nonetheless may also undertreat a meaningful percentage of HPV(+) patients who may then recur. In examining national trials, 19% of HPV(+) patients had disease progression after therapy, with a two-year survival rate of 60%.10 Current methods to ascertain HPV status involve p16 staining. However, on comparison with gold standard E6/E7 expression by qPCR, p16 harbored a 15% false positivity rate11, suggesting limited utility as a sole biomarker for deintensification. Improved molecular stratification would greatly enhance the clinician’s ability to precisely tailor treatment while minimizing the risk of jeopardizing outcomes. One approach encompasses in-depth proteomic profiling of HPV(+) OPSCC to reveal distinct protein expression profiles and delineate clinically relevant upstream pathways. In turn, these proteomic differences may distinguish higher-risk disease (cases predisposed to recurrence that may benefit from treatment intensification) from lower-risk phenotypes (cases whose treatment response is sufficiently robust to warrant deintensification). Here, two HPV(+) OPSCC cohorts stratified by treatment response are compared via a hybrid data dependent acquisition/data independent acquisition (DDA/DIA) approach via mass spectrometry. We focused on detection of low-abundance proteins to highlight proteomic signatures that can be potentially exploited for treatment stratification.

Project description:BACKGROUND:A subset of patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (HPV-OSCC) experience poor clinical outcomes. The authors of this report explored prognostic risk factors for overall survival (OS) and recurrence-free survival (RFS). METHODS:Patients with incident HPV-OSCC who received treatment at the Johns Hopkins Hospital between 1997 and 2008 and who had tissue available for HPV testing as well as demographic and clinicopathologic information (N?=?176) were included. Tissue was tested for HPV by in situ hybridization (ISH) and/or p16 immunohistochemistry. Demographic and clinicopathologic information was extracted from medical records. RESULTS:In total, 157 of 176 patients (90%) with OSCC had HPV-associated disease (HPV-OSCC). In the patients with HPV-OSCC, the 3-year and 5-year OS rates were 93% (95% confidence interval [CI], 88%-98%) and 89% (95% CI, 81%-97%), respectively. Shorter survival was observed among older patients (hazard ratio [HR], 2.33 per 10-year increase; 95% CI, 1.05-5.16 per 10-year increase; P?=?.038), patients with advanced clinical T classification (HR, 5.78; 95% CI, 1.60-20.8; P?= .007), and patients who were currently using tobacco (HR, 4.38; 95% CI, 1.07-18.0; P?= .04). Disease recurrence was associated with advanced clinical T-classification (HR, 8.32; 95% CI, 3.06-23; P?<?.0001), current/former alcohol use (HR, 13; 95% CI, 1.33-120; P?= .03), and unmarried status (HR, 3.28; 95% CI, 1.20-9.00; P?= .02). Patients who remained recurrence free for 5 years had an 8.6% chance of recurrence by 10 years (1-sided 95% CI upper bound, 19%; P?= .088). CONCLUSIONS:In this study, prognostic risk factors were identified for patients with HPV-OSCC. The observed recurrence rates between 5 years and 10 years after definitive therapy need to be validated in additional studies to determine whether extended cancer surveillance is warranted in this cancer population. Cancer 2013;119:3462-3471.. © 2013 American Cancer Society.

Dataset Information

Novel insights into epigenetic drivers of oropharyngeal squamous cell carcinoma: role of HPV and lifestyle factors.

Publications

Novel insights into epigenetic drivers of oropharyngeal squamous cell carcinoma: role of HPV and lifestyle factors.

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