Methylation-Driven downregulation of GABRB2 in oral carcinoma's subtype: implications for early diagnosis and...

Oral squamous cell carcinoma (OSCC) remains a major global health burden, often diagnosed at advanced stages, with limited survival improvement. Epigenetic dysregulation, particularly promoter hypermethylation, plays a significant role in OSCC pathogenesis. Previous study by Demokan et al. identified Gamma-Aminobutyric Acid Receptor Beta-2 (GABRB2) as a candidate gene subject to methylation-dependent transcriptional silencing. This study aimed to evaluate the methylation and expression profiles of GABRB2 in OSCC and to explore its potential as a diagnostic biomarker.

Tissue and serum samples from 48 OSCC patients and 15 healthy controls were analyzed for GABRB2 promoter methylation via quantitative methylation-specific PCR and for gene expression levels via quantitative real-time PCR. Relationships between methylation, expression levels, clinicopathological parameters, and patient outcomes were statistically assessed.

GABRB2 promoter hypermethylation was detected in 14.6% of tumor samples, predominantly in floor of the mouth and buccal tumors. Decreased GABRB2 expression was observed in 52.1% of tumor tissues compared to matched-normal tissues, while 22.9% of tumors exhibited increased expression. Methylation-dependent expression loss was confirmed in 71.4% of methylated tumors. Notably, decreased expression and hypermethylation of GABRB2 were correlated with poor prognosis parameters (p < 0.05). ROC analysis showed moderate discrimination for GABRB2 expression in distinguishing tumor from normal tissues (AUC = 0.635, p = 0.022), while serum-based analysis demonstrated poor diagnostic performance. Survival analysis revealed no statistically significant prognostic impact of GABRB2 expression levels (p > 0.05). However, alcohol consumption (p = 0.006) and recurrence developed (p = 0.030) as independent predictors of poor prognosis in multivariate analysis.

Our study suggests that there was association between methylation-based expression loss of GABRB2 with OSCC' subgroups. To our knowledge, this is the first study to investigate GABRB2 gene methylation and expression profiling in both invasive/non-invasive samples from OSCC patients. Hypermethylation in the newly identified candidate GABRB2 gene may play a role in the development of tumors originating from the mouth floor and buccal anatomical regions of the oral cavity. However, since the loss of expression seen in the majority of our patients, we thought that only methylation may not the inhibition mechanism for GABRB2 gene decreased expression. The new identified candidate gene may be specific for the OSCC's subgroups.