Proteogenomic Analysis on RNA m6A Modification-Associated Genes Identifies a Distinct Subgroup with High IGF2BPs Expression Across Cancer Types

<b>Background</b>: RNA N6-methyladenosine (m6A) modification is a key epitranscriptomic mechanism that regulates post-transcriptional gene expression. Although m6A-associated regulators have been implicated in cancer, their context-dependent roles and impacts on tumor heterogeneity remain incompletely defined. <b>Methods</b>: We conducted a pan-cancer proteogenomic analysis of m6A-dependent mechanisms using multi-omics datasets from the Clinical Proteomic Tumor Analysis Consortium, utilizing genomic, transcriptomic, proteomic, and phosphoproteomic data. Unsupervised clustering based on expression of m6A regulatory genes identified distinct subgroups. We integrated m6A-seq and RIP-seq data from cancer cell lines and analyzed the immune deconvolution results to define m6A-driven regulatory programs and assess tumor immune infiltration across subgroups. <b>Results</b>: Three molecular subgroups (IGF2BP-H, -M, and-L) were defined based on the expression patterns of m6A readers, with IGF2BP1/2/3 acting as the primary markers distinguishing the subgroups. Their upregulation has been attributed to either copy number amplification or transcription factor activation, depending on the tumor context. The IGF2BP-H subgroup exhibited enhanced cell cycle activity, which was supported by concordant transcriptomic, proteomic, and phosphoproteomic signatures. Mechanistic analyses revealed that IGF2BPs directly bind to and stabilize m6A-modified transcripts, including TOP2A, ANLN, and TFRC, thereby promoting their translation and contributing to cell cycle progression. IGF2BPs also enhanced VEGFA expression in head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma, potentially promoting immunosuppressive signaling. Immune deconvolution revealed reduced CD8⁺ T cell infiltration in IGF2BP-H tumors, suggesting a less inflamed microenvironment and potentially diminished responsiveness to immunotherapy. <b>Conclusion</b>: Our results highlight the pivotal role of IGF2BP in governing m6A-dependent regulatory mechanisms in cancer cells, highlighting their potential link with aggressive tumor behavior and immune evasion. This study provides important insights into the heterogeneity of m6A-related processes across different malignancies and reveals potential avenues for therapeutic interventions.