Molecular Biomarkers of Malignant Transformation in Head and Neck Dysplasia

Abstract

Head and neck squamous cell carcinoma (HNSCC) and its treatments are associated with substantial morbidity, often resulting in cosmetic deformity and loss of physiologic functions including speech and swallowing. Despite advancements in treatment, 5-year survival rates for mucosal malignancies remain below 70%. Effective prevention of HNSCC demands an understanding of the molecular pathways of carcinogenesis. Specifically, defining features of pre-cancerous dysplastic lesions that indicate a better or worse prognosis is necessary to help identify patients who are likely to develop a carcinoma and allow a more aggressive approach to management. There remains a need for identification of biomarkers that can provide both early prognostic and predictive value in clinical decision-making by serving as both therapeutic targets as well as predictors of therapy response. Here, we comprehensively review the most frequently altered molecular biomarkers of malignant transformation in head and neck dysplasia. These markers are involved in a wide range of cellular processes in head and neck carcinogenesis, including extracellular matrix degradation, cell motility and invasion, cell-cell adhesion, solute transport, immortalization, metabolism, the cell cycle and apoptosis, transcription, and cell signaling.

Keywords: biomarker; dysplasia; head and neck cancer; head and neck squamous cell carcinoma; molecular marker; tumor microenvironment.

Figure 1

Molecular biomarkers in head and neck dysplasia. Biomarkers include matrix metalloproteinases, cell surface receptors, cancer stem cell markers, cell adhesion molecules, transcriptional regulators, DNA replication and repair proteins, and cell cycle regulators. Created with BioRender.

Figure 2

Genetic progression model of head and neck squamous cell carcinoma. Accumulation of loss of heterozygosity or amplification at various genetic loci occurs as lesions proceed from normal mucosa to hyperplasia to dysplasia to carcinoma in situ to invasive carcinoma. Created with BioRender.

Figure 3

p53 tumor suppressor pathway. p53 acts on the G1/S checkpoint of the cell cycle to mediate cell cycle arrest via activation of CDK inhibitors. Arrows represent alterations in head and neck dysplasia. Adapted from “G1/S Checkpoint” and “The p53-Mediated Response,” by BioRender.com (2022) (https://app.biorender.com/biorender-templates (accessed on 10 August 2022)).

Figure 4

Transcriptional regulators in head and neck dysplasia: (A) p53, p63, and p73; (B) SOX-2 and OCT-4; (C) AP-1 and C-Jun; (D) BRD-4, YAP, TAZ, and TEAD. Created with BioRender.

Figure 5

Hippo pathway with Human Papilloma Virus E6/E7 Oncoproteins. Adapted from “The Hippo Tumor Suppressor Pathway” and “Hippo Pathway in Mammals”, by BioRender.com (2022) (https://app.biorender.com/biorender-templates (accessed on 10 August 2022)).