Hypermethylation status of DAPK, MGMT and RUNX3 in HPV negative oral and oropharyngeal squamous cell carcinoma

Abstract

Squamous cell carcinoma of the oral cavity and oropharynx is the sixth most common type of cancer in the world. During tumorigenesis, gene promoter hypermethylation is considered an important mechanism of transcription silencing of tumor suppressor genes, such as DAPK, MGMT and RUNX3. These genes participate in signaling pathways related to apoptosis, DNA repair and proliferation whose loss of expression is possibly associated with cancer development and progression. In order to investigate associations between hypermethylation and clinicopathological and prognostic parameters, promoter methylation was evaluated in 72 HPV negative oral and oropharyngeal tumors using methylation-specific PCR. Hypermethylation frequencies found for DAPK, MGMT and RUNX3 were 38.88%, 19.44% and 1.38% respectively. Patients with MGMT hypermethylation had a better 2-year overall survival compared to patients without methylation. Being MGMT a repair gene for alkylating agents, it could be a biomarker of treatment response for patients who are candidates for cisplatin chemotherapy, predicting drug resistance. In view of the considerable levels of hypermethylation in cancer cells and, for MGMT, its prognostic relevance, DAPK and MGMT show potential as epigenetic markers, in a way that additional studies may test its viability and efficacy in clinical management.

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

“…Dysfunction of this gene due to methylation processes has been associated with HNSCC. 60,63 Our analysis unveiled a significant association between the methylation status of the DAPK gene and resistance to the EGFR inhibitor Allitinib (p = 0.041), which corroborates with Takenori Ogawa and colleagues. 64 Their findings provided evidence of DAPK methylation in the drug-resistant derivatives.…”

“…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. Our analytical approach offers promising prospects for the discovery of a potential biomarker for treatment resistance, emphasizing the significance of elucidating the associated resistance mechanisms.…”

Epigenetic methylation changes: implication as biomarkers in oral and maxillofacial area cancers

“…A more significant number of patients and confounding factors analysis are needed to confirm our results, not only from tissue but also from serum or saliva [41]. Additional studies should be considered based on HPV status [11].…”

“…A meta-analysis study revealed that the DNA hypermethylation of the Dapk1 gene promoter was a promising prognostic and diagnostic biomarker [21,40]. Dapk and MGMT show potential as epigenetic markers in HPV-negative oral and oropharyngeal squamous cell carcinoma [11].…”

“…These mechanisms may take place in varying order [4], but their complementarity is involved in every step of cancer evolution, from responses to environmental exposures to progression into malignancy [6][7][8][9][10]. The increased methylation pattern has essential effects on cellular mechanisms, altering the transcriptional control that leads to inappropriate inhibition of suppressor genes or activation of oncogenes [6,11,12].…”