Christopher P Wardell1, Masashi Fujita1, Toru Yamada2, Michele Simbolo3, Matteo Fassan3, Rosa Karlic4, Paz Polak5, Jaegil Kim5, Yutaka Hatanaka6, Kazuhiro Maejima1, Rita T Lawlor3, Yoshitsugu Nakanishi2, Tomoko Mitsuhashi7, Akihiro Fujimoto1, Mayuko Furuta1, Andrea Ruzzenente8, Simone Conci8, Ayako Oosawa1, Aya Sasaki-Oku1, Kaoru Nakano1, Hiroko Tanaka9, Yujiro Yamamoto10, Kubo Michiaki11, Yoshiiku Kawakami12, Hiroshi Aikata12, Masaki Ueno13, Shinya Hayami13, Kunihito Gotoh14, Shun-Ichi Ariizumi15, Masakazu Yamamoto15, Hiroki Yamaue13, Kazuaki Chayama12, Satoru Miyano9, Gad Getz5, Aldo Scarpa3, Satoshi Hirano2, Toru Nakamura2, Hidewaki Nakagawa16. 1. Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan. 2. Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan. 3. Department of Pathology and Diagnostics, University of Verona, Verona, Italy. 4. Bioinformatics Group, Department of Molecular Biology, Division of Biology, Faculty of Science, University of Zagreb, Croatia. 5. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. 6. Research Division of Companion Diagnostics, Hokkaido University Hospital, Sapporo 060-8648, Japan. 7. Department of Surgical Pathology, Hokkaido University Hospital, Sapporo 060-8648, Japan. 8. Department of Surgery, General and Hepatobiliary Surgery, University Hospital G.B. Rossi, University and Hospital Trust of Verona, Verona, Italy. 9. Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. 10. Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan; Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan. 11. Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan. 12. Department of Gastroenterology and Metabolism, Institute of Biomedical and Health Sciences, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan. 13. Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan. 14. Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan. 15. Department of Gastroenterological Surgery, Tokyo Women's Medical University, Tokyo 162-8666, Japan. 16. Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan. Electronic address: hidewaki@ims.u-tokyo.ac.jp.
Abstract
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.
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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