Head and Neck Cancers Are Not Alike When Tarred with the Same Brush: An Epigenetic Perspective from the Cancerization Field to Prognosis

Abstract

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.

Tracking the Molecular Fingerprint of Head and Neck Cancer for Recurrence Detection in Liquid Biopsies

“…EBV ctDNA is another promising biomarker with low cost and high sensitivity for predicting disease recurrence [ 46 ]. For non-viral-driven subtypes of HNSCC, specific mutations, methylation markers, or RNA expression have been explored as biomarkers [ 24 , 26 , 50 , 51 , 52 , 53 , 56 , 57 , 64 , 67 , 68 , 69 , 79 , 80 , 81 , 82 ].…”

“…DNA methylation is an epigenetic mechanism of gene expression control, and its dysregulation has been reported in various cancers, including HNSCC. Methylation signatures of circulating DNA have proven useful in the detection and classification of different cancer types at diagnosis [ 29 , 62 ], and methylation signatures of diagnostic tissue samples provide prognostic value for HPV-positive head and neck cancers [ 63 , 64 ]. For example, the transposable element LINE-1 has been shown to be hypermethylated in HPV-positive HNSCC tumors [ 64 ], depending on its location in the genome (with intergenic regions being hypermethylated).…”

“…Methylation signatures of circulating DNA have proven useful in the detection and classification of different cancer types at diagnosis [ 29 , 62 ], and methylation signatures of diagnostic tissue samples provide prognostic value for HPV-positive head and neck cancers [ 63 , 64 ]. For example, the transposable element LINE-1 has been shown to be hypermethylated in HPV-positive HNSCC tumors [ 64 ], depending on its location in the genome (with intergenic regions being hypermethylated). Because it would be present in multiple cell-free copies in blood, LINE-1 methylation would likely outperform single-copy genes in ctDNA liquid biopsy [ 64 ].…”

“…For example, the transposable element LINE-1 has been shown to be hypermethylated in HPV-positive HNSCC tumors [ 64 ], depending on its location in the genome (with intergenic regions being hypermethylated). Because it would be present in multiple cell-free copies in blood, LINE-1 methylation would likely outperform single-copy genes in ctDNA liquid biopsy [ 64 ]. However, direct evidence that LINE-1 activation can be used as a cancer biomarker is still limited.…”

It Takes Two to Tango: A Review of Oncogenic Virus and Host Microbiome Associated Inflammation in Head and Neck Cancer

“…First, E7 blocks retinoblastoma protein (RB1), increasing production of transcription factors [69]. It also stimulates s-phase cyclins and acts on centrioles to rapidly progress cells through the DNA-amplification step of the cell cycle; oncoprotein (E6 and E7) expression has been associated with patterns of hypermethylation which promote E7 expressing genes, often via DNMT1s and maintained via miRNA dysregulation [70]. Inhibition of MAPK by E7 can also impede epithelial differentiation, contributing to mutagenesis.…”