Interpretable deep cross networks unveiled common signatures of dysregulated epitranscriptomes across 12 cancer types

Cancer is a complex and multifaceted group of diseases characterized by uncontrolled cell growth that leads to the formation of malignant tumors. Recent studies suggest that N6-methyladenosine (m⁶A) RNA methylation plays pivotal roles in cancer pathology by influencing various cellular processes. However, the degree to which these mechanisms are shared across different cancer types remains unclear. In this study, we analyze an expansive array of 167 m⁶A epitranscriptome profiles covering 12 distinct cancer types and their originating normal tissues. We trained 12 distinct, cancer type-specific interpretable deep cross network models, which successfully distinguish between specific pairs of normal and cancer m⁶A contexts using integrated information from both the sequences and curated genomic knowledge. Interestingly, cross-cancer type testing indicated the existence of shared genomic patterns across various cancers at the epitranscriptome level. A pan-cancer model was subsequently developed to identify these shared patterns that could not be observed in a single cancer type. Our analysis uncovered, for the first time, a common epitranscriptome signature shared across multiple cancer types, particularly associated with RNA hybridization process and aberrant splicing. This highlights the importance of a comprehensive understanding of the pan-cancer epitranscriptome and holding potential implications in the development of RNA methylation-based therapeutics for various cancers.