Portrait of DNA methylated genes predictive of poor prognosis in head and neck cancer and the implication for targeted therapy

Jessica Hier,Mariana Maschietto,Olivia Vachon,Iman Ibrahim,Moulay A Alaoui-Jamali,Allison Bernstein,Michael Hier,Alex Mlynarek,Sabrina Daniela Da Silva

doi:10.1038/s41598-021-89476-x

Abstract

In addition to chronic infection with human papilloma virus (HPV) and exposure to environmental carcinogens, genetic and epigenetic factors act as major risk factors for head and neck cancer (HNC) development and progression. Here, we conducted a systematic review in order to assess whether DNA hypermethylated genes are predictive of high risk of developing HNC and/or impact on survival and outcomes in non-HPV/non-tobacco/non-alcohol associated HNC. We identified 85 studies covering 32,187 subjects where the relationship between DNA methylation, risk factors and survival outcomes were addressed. Changes in DNA hypermethylation were identified for 120 genes. Interactome analysis revealed enrichment in complex regulatory pathways that coordinate cell cycle progression (CCNA1, SFN, ATM, GADD45A, CDK2NA, TP53, RB1 and RASSF1). However, not all these genes showed significant statistical association with alcohol consumption, tobacco and/or HPV infection in the multivariate analysis. Genes with the most robust HNC risk association included TIMP3, DCC, DAPK, CDH1, CCNA1, MGMT, P16, MINT31, CD44, RARβ. From these candidates, we further validated CD44 at translational level in an independent cohort of 100 patients with tongue cancer followed-up beyond 10 years. CD44 expression was associated with high-risk of tumor recurrence and metastasis (P = 0.01) in HPV-cases. In summary, genes regulated by methylation play a modulatory function in HNC susceptibility and it represent a critical therapeutic target to manage patients with advanced disease.

Highlights

In addition to chronic infection with human papilloma virus (HPV) and exposure to environmental carcinogens, genetic and epigenetic factors act as major risk factors for head and neck cancer (HNC) development and progression
The search strategy focused on key words including their abbreviation, truncations, synonyms, and subsets for search, such as: “head and neck neoplasms” or “facial neoplasms” or “head and neck cancer” or “oral cancer” or “tongue cancer” or “mouth cancer” or the codes described in the International Classification of Diseases for Oncology (ICD-O) for Head and Neck Tumors; and “epigenetics” or “epigenomics” or “methylation” or “histone modification” or “non-coding RNA” or “ncRNA” and “risk factors” or “smoke” or "tobacco" or “alcohol” or “HPV”
In this systematic review we discussed and validated common genes regulated by DNA hypermethylation with fundamental role in HNC progression and metastatic competence, considering independent investigations with different HNC cohorts around the world

Summary

Introduction

In addition to chronic infection with human papilloma virus (HPV) and exposure to environmental carcinogens, genetic and epigenetic factors act as major risk factors for head and neck cancer (HNC) development and progression. We conducted a systematic review in order to assess whether DNA hypermethylated genes are predictive of high risk of developing HNC and/or impact on survival and outcomes in non-HPV/non-tobacco/non-alcohol associated HNC. Interactome analysis revealed enrichment in complex regulatory pathways that coordinate cell cycle progression (CCNA1, SFN, ATM, GADD45A, CDK2NA, TP53, RB1 and RASSF1) Not all these genes showed significant statistical association with alcohol consumption, tobacco and/or HPV infection in the multivariate analysis. Genes with the most robust HNC risk association included TIMP3, DCC, DAPK, CDH1, CCNA1, MGMT, P16, MINT31, CD44, RARβ From these candidates, we further validated CD44 at translational level in an independent cohort of 100 patients with tongue cancer followed-up beyond 10 years. Additional factors have been identified to enhance individual susceptibility to HNC, in particular, genetic abnormalities impacting on cell proliferation, differentiation features, cell cycle checkpoints, angiogenesis and tumor metabolism. We discussed the potential of relevant FDA-approved drugs as alternative therapeutics for invasive HNC

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Results

Conclusion