Pan-cancer analysis reveals m(6)A modification is functionally important in cancer

N 6 -Methyladenosine (m 6 A) 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 m 6 A in cancer is still lacking. We conducted a systematic analysis of the m 6 A-associated somatic mutations and expression of m 6 A 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 m 6 A machinery in cancer development. We revealed 1,973 genes with recurrent m 6 A-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 m 6 A-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 m 6 A “writers” and m 6 A 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 m 6 A modification sites to identify “driver” genes, thereby uncovering additional potential cancer “drivers” with rare mutations. Our study highlights m 6 A 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 m 6 A 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.