TY - JOUR
T1 - Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations
AU - Wardell, Christopher P.
AU - Fujita, Masashi
AU - Yamada, Toru
AU - Simbolo, Michele
AU - Fassan, Matteo
AU - Karlic, Rosa
AU - Polak, Paz
AU - Kim, Jaegil
AU - Hatanaka, Yutaka
AU - Maejima, Kazuhiro
AU - Lawlor, Rita T.
AU - Nakanishi, Yoshitsugu
AU - Mitsuhashi, Tomoko
AU - Fujimoto, Akihiro
AU - Furuta, Mayuko
AU - Ruzzenente, Andrea
AU - Conci, Simone
AU - Oosawa, Ayako
AU - Sasaki-Oku, Aya
AU - Nakano, Kaoru
AU - Tanaka, Hiroko
AU - Yamamoto, Yujiro
AU - Michiaki, Kubo
AU - Kawakami, Yoshiiku
AU - Aikata, Hiroshi
AU - Ueno, Masaki
AU - Hayami, Shinya
AU - Gotoh, Kunihito
AU - Ariizumi, Shun ichi
AU - Yamamoto, Masakazu
AU - Yamaue, Hiroki
AU - Chayama, Kazuaki
AU - Miyano, Satoru
AU - Getz, Gad
AU - Scarpa, Aldo
AU - Hirano, Satoshi
AU - Nakamura, Toru
AU - Nakagawa, Hidewaki
N1 - Funding Information:
This work was supported partially by RIKEN President’s Fund 2011, Grandin-aid for RIKEN CGM and IMS, JSPS Grants-in-Aid for Scientific Research (KAKENHI) for H.N. (15H04814) and S.M. (15H05912), the Princess Takamatsu Cancer Research Fund, Italian Ministry of Research (Cancer Genome Project FIRB RBAP10AHJB), Associazione Italiana Ricerca Cancro (AIRC n. 12182), and Fondazione Italiana Malattie Pancreas – Ministero Salute (CUP_J33G13000210001).
PY - 2018/5
Y1 - 2018/5
N2 - Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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. Lay summary: 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.
AB - Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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. Lay summary: 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.
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U2 - 10.1016/j.jhep.2018.01.009
DO - 10.1016/j.jhep.2018.01.009
M3 - Article
AN - SCOPUS:85042024087
VL - 68
SP - 959
EP - 969
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 5
ER -