Destefanis Eliana, Sighel Denise, Dalfovo Davide, Gilmozzi Riccardo, Broso Francesca, Cappannini Andrea, Bujnicki Janusz M, Romanel Alessandro, Dassi Erik, Quattrone Alessandro
Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento 38123, Italy.
Laboratory of Bioinformatics and Computational Biology, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento 38123, Italy.
NAR Cancer. 2024 Oct 15;6(4):zcae040. doi: 10.1093/narcan/zcae040. eCollection 2024 Dec.
N-Methyladenosine (mA) is the most abundant internal modification in mRNAs. Despite accumulating evidence for the profound impact of mA on cancer biology, there are conflicting reports that alterations in genes encoding the mA machinery proteins can either promote or suppress cancer, even in the same tumor type. Using data from The Cancer Genome Atlas, we performed a pan-cancer investigation of 15 mA core factors in nearly 10000 samples from 31 tumor types to reveal underlying cross-tumor patterns. Altered expression, largely driven by copy number variations at the chromosome arm level, results in the most common mode of dysregulation of these factors. YTHDF1, YTHDF2, YTHDF3 and VIRMA are the most frequently altered factors and the only ones to be uniquely altered when tumors are grouped according to the expression pattern of the mA factors. These genes are also the only ones with coherent, pan-cancer predictive power for progression-free survival. On the contrary, METTL3, the most intensively studied mA factor as a cancer target, shows much lower levels of alteration and no predictive power for patient survival. Therefore, we propose the non-enzymatic YTHDF and VIRMA genes as preferred subjects to dissect the role of mA in cancer and as priority cancer targets.
N-甲基腺苷（mA）是mRNA中最丰富的内部修饰。尽管越来越多的证据表明mA对癌症生物学有深远影响，但关于编码mA机制蛋白的基因改变在癌症中究竟是促进还是抑制作用，却存在相互矛盾的报道，甚至在同一肿瘤类型中也是如此。利用癌症基因组图谱（The Cancer Genome Atlas）的数据，我们对来自31种肿瘤类型的近10000个样本中的15个mA核心因子进行了泛癌研究，以揭示潜在的跨肿瘤模式。表达改变主要由染色体臂水平的拷贝数变异驱动，这是这些因子失调最常见的模式。YTHDF1、YTHDF2、YTHDF3和VIRMA是最常发生改变的因子，也是根据mA因子的表达模式对肿瘤进行分组时唯一独特改变的因子。这些基因也是对无进展生存期具有连贯的泛癌预测能力的唯一基因。相反，作为癌症靶点研究最深入的mA因子METTL3，其改变水平要低得多，对患者生存也没有预测能力。因此，我们提出非酶促的YTHDF和VIRMA基因是剖析mA在癌症中的作用的首选对象，也是优先考虑的癌症靶点。
