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.

中文翻译：

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RNA甲基转移酶的全癌分析确定FTSJ3是乳腺癌进展的潜在调节剂。

RNA甲基化由一组RNA甲基转移酶（RNMT）催化，可调节RNA的结构，性质和生物学功能。越来越多的文献证明RNMT在各种人类疾病（尤其是发育障碍和癌症）中失调。然而，RNMT的基因组和转录组改变及其在人类癌症中的功能作用是有限的。在这项研究中，我们采用无偏方法研究了32种人类癌症的10,000多个临床样品中58种RNMT的拷贝数变化和突变率。我们还研究了这些改变和RNMT表达水平，因为它们与临床特征相关，例如在一大批肿瘤样本中的肿瘤亚型，等级和生存率，重点是乳腺癌。进行功能丧失分析以检查在乳腺癌细胞的生长和存活中起重要作用的RNMT候选者。我们确定了RNMT的一个子集，特别是TRMT12，NSUN2，TARBP1和FTSJ3，它们在人类癌症的一个子集中被扩增或突变。几种RNMT与乳腺癌的侵袭性和不良预后显着相关。功能丧失分析表明，FTSJ3是一种2'-O-Me甲基转移酶，是候选RNMT，在促进癌症生长和存活中具有功能性作用。RNMT的子集（如FTSJ3）代表了抗癌药物发现的有希望的新型靶标。我们的发现为进一步研究RNMT改变在人类癌症中的功能后果以及将来开发针对促进癌症的RNMT的疗法提供了框架。