Abstract
RNA methylation, catalysed by a set of RNA methyltransferases (RNMTs), modulates RNA structures, properties, and biological functions. RNMTs are increasingly documented to be dysregulated in various human diseases, particularly developmental disorders and cancer. However, the genomic and transcriptomic alterations of RNMTs, as well as their functional roles in human cancer, are limited. In this study, we utilized an unbiased approach to examine copy number alterations and mutation rates of 58 RNMTs in more than 10,000 clinical samples across 32 human cancer types. We also investigated these alterations and RNMT expression level as they related to clinical features such as tumour subtype, grade, and survival in a large cohort of tumour samples, focusing on breast cancer. Loss-of-function analysis was performed to examine RNMT candidates with important roles in growth and viability of breast cancer cells. We identified a subset of RNMTs, notably TRMT12, NSUN2, TARBP1, and FTSJ3, that were amplified or mutated in a subset of human cancers. Several RNMTs were significantly associated with breast cancer aggressiveness and poor prognosis. Loss-of-function analysis indicated FTSJ3, a 2'-O-Me methyltransferase, as a candidate RNMT with functional roles in promoting cancer growth and survival. A subset of RNMTs, like FTSJ3, represents promising novel targets for anticancer drug discovery. Our findings provide a framework for further study of the functional consequences of RNMT alterations in human cancer and for developing therapies that target cancer-promoting RNMTs in the future.