Multiomics and machine learning-based analysis of pancancer pseudouridine modifications

Pseudouridine widely affects the stability and function of RNA. However, our knowledge of pseudouridine properties in tumors is incomplete. We systematically analyzed pseudouridine synthases (PUSs) expression, genomic aberrations, and prognostic features in 10907 samples from 33 tumors. We found that the pseudouridine-associated pathway was abnormal in tumors and affected patient prognosis. Dysregulation of the PUSs expression pattern may arise from copy number variation (CNV) mutations and aberrant DNA methylation. Functional enrichment analyses determined that the PUSs expression was closely associated with the MYC, E2F, and MTORC1 signaling pathways. In addition, PUSs are involved in the remodeling of the tumor microenvironment (TME) in solid tumors, such as kidney and lung cancers. Particularly in lung cancer, increased expression of PUSs is accompanied by increased immune checkpoint expression and Treg infiltration. The best signature model based on more than 112 machine learning combinations had good prognostic ability in ACC, DLBC, GBM, KICH, MESO, THYM, TGCT, and PRAD tumors, and is expected to guide immunotherapy for 19 tumor types. The model was also effective in identifying patients with tumors amenable to etoposide, camptothecin, cisplatin, or bexarotene treatment. In conclusion, our work highlights the dysregulated features of PUSs and their role in the TME and patient prognosis, providing an initial molecular basis for future exploration of pseudouridine. Studies targeting pseudouridine are expected to lead to the development of potential diagnostic strategies and the evaluation and improvement of antitumor therapies.