N6-Methyladenosine (m6A) is the most abundant post-transcriptional modification in mammalian RNA molecules and has a critical role in many diseases, including cancer. However, the systematic investigation of the role of m6A in cancer is still lacking. We conducted a systematic analysis of the m6A-associated somatic mutations and expression of m6A writers and erasers in 3,401 cancer genomes of 12 cancer types from The Cancer Genome Atlas (TCGA) to find a potential role of the m6A machinery in cancer development. We revealed 1,973 genes with recurrent m6A-associated somatic mutations across multiple cancer types. We identified many known cancer genes, such as TP53, CTNNB1 and CDKN2A, as well as many candidate genes whose cancer-specific roles are less understood. Strikingly, liver cancer had the highest frequency of m6A-associated somatic mutations among the 12 cancer types, and these mutations were significantly enriched in metabolic pathways, such as retinol metabolism. In liver cancer, the abnormalities in m6A “writers” and m6A modification sites were significantly correlated with worse overall survival, independent of other clinical characteristics (e.g., tumor stage and race).

Implications: We for the first time consider somatic mutations relevant to the m6A modification sites to identify “driver” genes, thereby uncovering additional potential cancer “drivers” with rare mutations. Our study highlights m6A modifications as an important epigenetic mechanism of cancer development.

Citation Format: Zhixiang Zuo, Yubin Xie, Yueyuan Zheng, Peng Nie, Shuai Jiang, QI Zhao, Yanyan Miao, Jian Ren. Pan-cancer analysis reveals m6A modification is functionally important in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4330.