作为 mRNA 中最丰富的信使 RNA (mRNA) 修饰，N 6-甲基腺苷 (m6A) 在 RNA 命运中发挥着至关重要的作用，影响各种肿瘤类型的细胞和生理过程。然而，我们对 m6A 甲基化组在肿瘤异质性中的功能和作用的理解仍然有限。在此，我们从 97 个 m6A 测序 (m6A-seq) 和 RNA 测序样本中收集并分析了 9 个人体组织的 m6A 甲基化组。我们的研究结果表明，与正常组织相比，m6A 在大多数肿瘤组织中表现出不同的异质性，这导致不同癌症类型的临床结果不同。我们还发现，癌症类型特异性 m6A 水平调节不同癌症类型中不同癌症相关基因的表达。利用一种名为“m6A-express”的新颖可靠的方法，我们预测了 m6A 调节基因，并揭示了癌症类型特异性 m6A 调节基因有助于不同患者群体的预后、肿瘤起源和免疫细胞浸润水平。此外，我们还鉴定了调节癌症特异性 m6A 的细胞特异性 m6A 调节因子，并构建了调节网络。进行了实验验证，确认细胞特异性 m6A 调节因子 CAPRIN1 控制 TP53 的 m6A 水平。总的来说，我们的工作揭示了 m6A 在各种肿瘤组织中的临床相关性，并解释了这种异质性是如何建立的。这些结果进一步表明 m6A 在针对不同癌症类型患者的癌症精准医疗方面的潜力。© 作者 2024。由牛津大学出版社和科学出版社代表中国科学院北京基因组研究所出版/中国中国生物信息与遗传学会国家中心。

As the most abundant messenger RNA (mRNA) modification in mRNA, N  6-methyladenosine (m6A) plays a crucial role in RNA fate, impacting cellular and physiological processes in various tumor types. However, our understanding of the function and role of the m6A methylome in tumor heterogeneity remains limited. Herein, we collected and analyzed m6A methylomes across nine human tissues from 97 m6A sequencing (m6A-seq) and RNA sequencing samples. Our findings demonstrate that m6A exhibits different heterogeneity in most tumor tissues compared to normal tissues, which contributes to the diverse clinical outcomes in different cancer types. We also found that the cancer type-specific m6A level regulated the expression of different cancer-related genes in distinct cancer types. Utilizing a novel and reliable method called "m6A-express", we predicted m6A-regulated genes and revealed that cancer type-specific m6A-regulated genes contributed to the prognosis, tumor origin, and infiltration level of immune cells in diverse patient populations. Furthermore, we identified cell-specific m6A regulators that regulate cancer-specific m6A and constructed a regulatory network. Experimental validation was performed, confirming that the cell-specific m6A regulator CAPRIN1 controls the m6A level of TP53. Overall, our work reveals the clinical relevance of m6A in various tumor tissues and explains how such heterogeneity is established. These results further suggest the potential of m6A for cancer precision medicine for patients with different cancer types.© The Author(s) 2024. Published by Oxford University Press and Science Press on behalf of the Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China.