Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations

• Published in: Journal of hepatology Vol. 68; no. 5; pp. 959 - 969
• Main Authors: Wardell, Christopher P., Fujita, Masashi, Yamada, Toru, Simbolo, Michele, Fassan, Matteo, Karlic, Rosa, Polak, Paz, Kim, Jaegil, Hatanaka, Yutaka, Maejima, Kazuhiro, Lawlor, Rita T., Nakanishi, Yoshitsugu, Mitsuhashi, Tomoko, Fujimoto, Akihiro, Furuta, Mayuko, Ruzzenente, Andrea, Conci, Simone, Oosawa, Ayako, Sasaki-Oku, Aya, Nakano, Kaoru, Tanaka, Hiroko, Yamamoto, Yujiro, Michiaki, Kubo, Kawakami, Yoshiiku, Aikata, Hiroshi, Ueno, Masaki, Hayami, Shinya, Gotoh, Kunihito, Ariizumi, Shun-ichi, Yamamoto, Masakazu, Yamaue, Hiroki, Chayama, Kazuaki, Miyano, Satoru, Getz, Gad, Scarpa, Aldo, Hirano, Satoshi, Nakamura, Toru, Nakagawa, Hidewaki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2018; Elsevier Science Ltd
• Subjects: Biliary tract; Biliary tract cancer; BRCA1 protein; BRCA2 protein; Cancer; Carcinogenesis; Cell origin; Cholangiocarcinoma; Clonal deletion; Driver gene; Gallbladder; Gallbladder diseases; Genome sequencing; Genomes; Genomics; Hepatitis; Medical prognosis; MLH1 protein; MSH2 protein; Mutation; p53 Protein; Patients; Predisposing mutation; Prognosis; Smad4 protein; Genome sequencing; Driver gene; Biliary tract cancer; Cholangiocarcinoma; Cell origin; Predisposing mutation
• ISSN: 0168-8278; 1600-0641; 1600-0641
• DOI: 10.1016/j.jhep.2018.01.009

[Display omitted] •Biliary tract cancers are clinically and genetically heterogeneous.•32 significantly mutated genes were identified, some negatively affecting prognosis.•A novel deletion of MUC17 at 7q22.1 was detected.•Cell-of-origin predictions suggest hepatocyte-origin of hepatitis-related ICCs.•Deleterious germline mutations of cancer-predisposing genes were detected in 11% of patients with BTC. Biliary 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. We 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. We 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. BTCs 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. We 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.