• Christopher P Wardell, Masashi Fujita, Toru Yamada, Michele Simbolo, Matteo Fassan, Rosa Karlic, Paz Polak, Jaegil Kim, Yutaka Hatanaka, Kazuhiro Maejima, Rita T Lawlor, Yoshitsugu Nakanishi, Tomoko Mitsuhashi, Akihiro Fujimoto, Mayuko Furuta, Andrea Ruzzenente, Simone Conci, Ayako Oosawa, Aya Sasaki-Oku, Kaoru Nakano, Hiroko Tanaka, Yujiro Yamamoto, Kubo Michiaki, Yoshiiku Kawakami, Hiroshi Aikata, Masaki Ueno, Shinya Hayami, Kunihito Gotoh, Shun-Ichi Ariizumi, Masakazu Yamamoto, Hiroki Yamaue, Kazuaki Chayama, Satoru Miyano, Gad Getz, Aldo Scarpa, Satoshi Hirano, Toru Nakamura, and Hidewaki Nakagawa.
• Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
• J. Hepatol. 2018 May 1; 68 (5): 959-969.

Background & AimsBiliary tract cancers (BTCs) are clinically and pathologically heterogeneous and respond poorly to treatment. Genomic profiling can offer a clearer understanding of their carcinogenesis, classification and treatment strategy. We performed large-scale genome sequencing analyses on BTCs to investigate their somatic and germline driver events and characterize their genomic landscape.MethodsWe analyzed 412 BTC samples from Japanese and Italian populations, 107 by whole-exome sequencing (WES), 39 by whole-genome sequencing (WGS), and a further 266 samples by targeted sequencing. The subtypes were 136 intrahepatic cholangiocarcinomas (ICCs), 101 distal cholangiocarcinomas (DCCs), 109 peri-hilar type cholangiocarcinomas (PHCs), and 66 gallbladder or cystic duct cancers (GBCs/CDCs). We identified somatic alterations and searched for driver genes in BTCs, finding pathogenic germline variants of cancer-predisposing genes. We predicted cell-of-origin for BTCs by combining somatic mutation patterns and epigenetic features.ResultsWe identified 32 significantly and commonly mutated genes including TP53, KRAS, SMAD4, NF1, ARID1A, PBRM1, and ATR, some of which negatively affected patient prognosis. A novel deletion of MUC17 at 7q22.1 affected patient prognosis. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes such as BRCA1, BRCA2, RAD51D, MLH1, or MSH2 were detected in 11% (16/146) of BTC patients.ConclusionsBTCs have distinct genetic features including somatic events and germline predisposition. These findings could be useful to establish treatment and diagnostic strategies for BTCs based on genetic information.Lay SummaryWe here analyzed genomic features of 412 BTC samples from Japanese and Italian populations. A total of 32 significantly and commonly mutated genes were identified, some of which negatively affected patient prognosis, including a novel deletion of MUC17 at 7q22.1. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes were detected in 11% of patients with BTC. BTCs have distinct genetic features including somatic events and germline predisposition.Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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