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

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.

Identification of Gene-Tyrosine Kinase 2 (TYK2) in Head and Neck Squamous Cell Carcinoma Patients—An Integrated Bioinformatics Approach

“…Accordingly, the role of immunomodulation and potentially related biomarkers in therapy and diagnosis of HNSC has become an emerging field ([ 2 , 3 , 9 , 10 ]). Alongside with this aspect, the genetic and epigenetic mechanisms and related pathways have been highlighted ([ 11 – 13 ]).…”

Unveiling the role of MGMT and DAPK hypermethylation in response to anti‐EGFR agents: Molecular insights for advancing HNSCC treatment

“…This repair process safeguards genetic material from mutations and DNA damage caused by alkylating agents. The increased methylation of MGMT is linked to established risk factors in the progression of HNSCC 59 . Our research has revealed a correlation between the methylation status of this tumor suppressor gene and resistance to EGFR inhibitors, particularly Afatinib ( p = 0.001) and Allitinib ( p = 0.011).…”

“…The increased methylation of MGMT is linked to established risk factors in the progression of HNSCC. 59 Our research has revealed a correlation between the methylation status of this tumor suppressor gene and resistance to EGFR inhibitors, particularly Afatinib (p = 0.001) and Allitinib ( p = 0.011). Notably, prior literature did not yield support for such a connection, yet numerous studies [60][61][62] showing the association between high methylation levels and poor overall survival, have underscored the prognostic importance of MGMT.…”

Epigenetic editing and tumor‑dependent immunosuppressive signaling in head and neck malignancies (Review)

“…Methylation usually occurs in CpG islands (Fig. 1) and characteristically acts to repress gene transcription in HNSCC (36)(37)(38)(39)(40). Aberrant methylation in the promoter region of tumor suppressor genes could induce their abnormal expression in order to influence carcinogenesis.…”