Abstract
Simple SummarySquamous cell carcinomas affect different head and neck subsites and, although these tumors arise from the same epithelial lining and share risk factors, they differ in terms of clinical behavior and molecular carcinogenesis mechanisms. Differences between HPV-negative and HPV-positive tumors are those most frequently explored, but further data suggest that the molecular heterogeneity observed among head and neck subsites may go beyond HPV infection. In this review, we explore how alterations of DNA methylation and microRNA expression contribute to head and neck squamous cell carcinoma (HNSCC) development and progression. The association of these epigenetic alterations with risk factor exposure, early carcinogenesis steps, transformation risk, and prognosis are described. Finally, we discuss the potential application of the use of epigenetic biomarkers in HNSCC.Head and neck squamous cell carcinomas (HNSCC) are among the ten most frequent types of cancer worldwide and, despite all efforts, are still diagnosed at late stages and show poor overall survival. Furthermore, HNSCC patients often experience relapses and the development of second primary tumors, as a consequence of the field cancerization process. Therefore, a better comprehension of the molecular mechanisms involved in HNSCC development and progression may enable diagnosis anticipation and provide valuable tools for prediction of prognosis and response to therapy. However, the different biological behavior of these tumors depending on the affected anatomical site and risk factor exposure, as well as the high genetic heterogeneity observed in HNSCC are major obstacles in this pursue. In this context, epigenetic alterations have been shown to be common in HNSCC, to discriminate the tumor anatomical subsites, to be responsive to risk factor exposure, and show promising results in biomarker development. Based on this, this review brings together the current knowledge on alterations of DNA methylation and microRNA expression in HNSCC natural history, focusing on how they contribute to each step of the process and on their applicability as biomarkers of exposure, HNSCC development, progression, and response to therapy.
Highlights
Head and neck squamous cell carcinomas (HNSCC) are among the ten most frequent and lethal cancers among men worldwide, affecting both developed and developing countries [1]. It is usually associated with lifelong exposure to tobacco and alcohol [2,3,4], but more recently, human papillomavirus (HPV) infection has emerged as a third risk factor [4]
Considering that tobacco smoke contains more than 60 different carcinogens [196], alcohol may contribute to carcinogenesis by different mechanisms [197], HPV oncoproteins regulate key epigenetic enzymes [169,170,172,173], and that how all these factors interact is largely unknown, much is yet to be learned considering the effects of risk factor exposure on epigenetic mechanisms in head and neck tissues
As highlighted in this review, epigenetic alterations are a common feature of HNSCC, and affect all steps in their natural history
Summary
Head and neck squamous cell carcinomas (HNSCC) are among the ten most frequent and lethal cancers among men worldwide, affecting both developed and developing countries [1]. In the 1950s, Slaughter and colleagues evaluated the origin and spreading of tobacco- and alcohol-associated oral squamous cell carcinoma (OSCC), the most frequent and most accessible HNSCC [7] In this groundbreaking work, they showed that (i) horizontal is more common than vertical spread; (ii) the surrounding benign epithelium was usually microscopically abnormal; (iii) when tumors were ≤1 cm, other in situ cancer foci or isolated islands of invasive carcinoma were found; and (iv) 11% of the cases presented synchronous macroscopic SPT in the mucosa of the upper alimentary and respiratory tracts. White (leukoplakias) and red (erythroplakias) patches in head and neck linings have been studied, and up to now, it is still difficult to estimate how often they will progress to malignant tumors and the associated factors These lesions were evaluated exclusively according to microscopic morphological aspects. We bring together the current knowledge on alterations of DNA methylation and microRNA expression in HNSCC natural history, focusing on how they contribute to each step of the process and on their applicability as biomarkers of exposure, HNSCC development, progression, and response to therapy
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