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.

HPV RNA CISH score identifies two prognostic groups in a p16 positive oropharyngeal squamous cell carcinoma population

“…Micro-RNAs (mir-9, miR181, and miR-375) were also shown to modulate E6 and E7 expression in HPV positive oropharyngeal squamous cell carcinomas. Additionally, HPV genome methylation has been described in HPV-related oropharyngeal squamous cell carcinomas [33][34][35][36] and histone modifications due to tobacco could modulate HPV carcinogenesis [37]. HPV integration into the host DNA enhances levels of E6 and E7 transcripts in cervical cancers [38].…”

Oncogenic drivers in 11q13 associated with prognosis and response to therapy in advanced oropharyngeal carcinomas

“…The molecular mechanisms underlying oropharyngeal carcinogenesis have been investigated and potential biomarkers were reported, however the data are still unclear and controversial [15][16][17][18][19]. The integration of genomic and transcriptomic analysis can be used to identify cancer-driver genes and disrupted pathways, which can be drug targetable [20].…”

Stratification of HPV‐associated and HPV‐negative oropharyngeal squamous cell carcinomas based on DNA methylation epigenotypes

“…Although genetic mutation could stratify OPSCC samples into two types, HPV(+) OPSCC and HPV(−) OPSCC, it could not further divide HPV(+) or HPV(−) OPSCC into subtypes, indicating that, besides genetic alterations, the accumulation of aberrant epigenetic alterations might deeply influence OPSCC biology and contribute to additional subclassification of both HPV-associated and HPVnegative OPSCC. 16,41 Whereas HPV-associated OPSCC shows generally better prognosis than HPV-negative OPSCC, a fraction of HPVassociated OPSCC cases has reportedly exhibited therapeutic resistance or worse prognosis. Ang et al reported the importance of smoking status combined with tumor stage, in stratifying HPV-associated OPSCC, 11 which was subsequently validated by Granata et al 42 However, the molecular aberrations underlying this intermediate risk is yet to be clarified despite previous genome-wide and epigenome-wide studies in HNSCC.…”