Characterization of the m6A regulator-mediated methylation modification patterns in oral squamous cell carcinoma

Abstract

N⁶-methyladenosine (m⁶A) is a form of posttranscriptional modification that plays important roles in cancer including oral squamous cell carcinoma (OSCC). Most studies to date have focused on a limited number of regulators and oncogenic pathways, thus failing to provide comprehensive insight into the dynamic effects of m⁶A modification. In addition, the role of m⁶A modification in shaping immune cell infiltration in OSCC has yet to be clarified. This study was designed to assess m⁶A modification dynamics in OSCC and to understand how such modifications influence clinical immunotherapeutic treatment outcomes. m⁶A modification patterns linked with 23 m⁶A regulators were analyzed in 437 OSCC patients from TCGA and GEO cohorts. These patterns were then quantified through m⁶A score based on algorithms derived from a principal component analysis (PCA) approach. The m⁶A modification patterns of OSCC samples were grouped into two clusters based on the m⁶A regulators expression, and immune cell infiltration was linked with the 5-year survival outcomes of patients in these clusters. 1575 genes associated with OSCC patient prognosis were identified and used to re-cluster these samples into two groups. Patients in clusters exhibiting higher levels of m⁶A regulator expression exhibited poorer overall survival (OS), whereas patients with high m⁶A scores survived for longer (p < 0.001). The overall mortality rates in the groups of patients with low and high m⁶A scores were 55% and 40%, respectively, and the m⁶A score distributions in clusters of patients grouped by m⁶A modification patterns and gene expression further supported the link between a high m⁶A score and better prognostic outcomes. Immunophenoscore (IPS) values for patients in different m⁶A score groups suggested that the use of PD-1-specific antibodies or CTLA-4 inhibitors alone or in combination would yield superior treatment outcomes in patients in the high-m⁶A score group relative to the low-m⁶A score group. m⁶A modification patterns are relevant to heterogeneity in OSCC. Detailed analyses of m⁶A modification patterns may thus offer novel insight regarding immune cell infiltration within the OSCC tumor microenvironment, guiding novel efforts to provide patients with more effective immunotherapeutic interventions.