tRNA modification genes are associated with genomic instability, proliferative programs, and poor prognosis in breast cancer.

The modifications of transfer RNA (tRNA) add an extra layer of post-transcriptional gene regulation in cancer biology. While translation initiation and termination have been extensively studied, the role of tRNA modifications in elongation remains largely unexplored. These chemical changes, particularly in the anticodon loop, enhance codon–anticodon pairing and translation fidelity, but their impact on cancer, especially breast cancer, is not well defined. We analyzed 73 tRNA modification–related genes across 33 TCGA cancer types and breast cancer subtypes by integrating transcriptomic and proteogenomic data. These genes were enriched among poor-prognosis markers in many cancers, with strong associations in HER2-positive and Luminal A breast cancers. tRNA modification activity was positively correlated with genomic instability metrics and proliferative pathways, and negatively with immune-related pathways, patterns most evident in ER-positive and Luminal breast cancers. Proteogenomic analysis confirmed RNA–protein concordance for most genes, and higher protein-based modification scores were linked to increased stemness and chromosomal instability. Three genes, FTSJ1, TRMT2B, and ELP1, showed strong prognostic relevance, influencing chromatin regulator ZNF518A and immune-related factor PPARGC1A. Our findings indicate that modifications of tRNA during the elongation phase of protein synthesis are not merely passive but actively contribute to cancer biology. These changes may promote tumor growth, destabilize the genome, and help malignant cells evade immune detection. Together, these insights emphasize tRNA modifications as promising targets for new therapeutic strategies, especially for aggressive breast cancer subtypes where treatment options are still limited.