The genomic landscape of cholangiocarcinoma reveals the disruption of post-transcriptional modifiers
Yaodong Zhang, Zijian Ma, Changxian Li, Cheng Wang, Wangjie Jiang, Jiang Chang, Sheng Han, Zefa Lu, Zicheng Shao, Yirui Wang, Hongwei Wang, Chenyu Jiao, Dong Wang, Xiaofeng Wu, Hongbing Shen, Xuehao Wang, Zhibin Hu, Xiangcheng Li
Abstract
Molecular variation between geographical populations and subtypes indicate potential genomic heterogeneity and novel genomic features within CCA. Here, we analyze exome-sequencing data of 87 perihilar cholangiocarcinoma (pCCA) and 261 intrahepatic cholangiocarcinoma (iCCA) cases from 3 Asian centers (including 43 pCCAs and 24 iCCAs from our center). iCCA tumours demonstrate a higher tumor mutation burden and copy number alteration burden (CNAB) than pCCA tumours, and high CNAB indicates a poorer pCCA prognosis. We identify 12 significantly mutated genes and 5 focal CNA regions, and demonstrate common mutations in post-transcriptional modification-related potential driver genes METTL14 and RBM10 in pCCA tumours. Finally we demonstrate the tumour-suppressive role of METTL14, a major RNA N6-adenosine methyltransferase (m6A), and illustrate that its loss-of-function mutation R298H may act through m6A modification on potential driver gene MACF1. Our results may be valuable for better understanding of how post-transcriptional modification can affect CCA development, and highlight both similarities and differences between pCCA and iCCA.