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

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 NakanoHiroko Tanaka, Yujiro Yamamoto, Michiaki Kubo, 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, Hidewaki Nakagawa

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)959-969
Number of pages11
JournalJournal of Hepatology
Volume68
Issue number5
DOIs
Publication statusPublished - 01-05-2018

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Biliary Tract Neoplasms
Mutation
Genes
Cholangiocarcinoma
Neoplasm Genes
Epigenomics
Genome
Germ-Line Mutation
Hepatitis
Hepatocytes
Klatskin Tumor
Exome
Cystic Duct
p53 Genes
Gallbladder
Population
Carcinogenesis
Therapeutics

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Wardell, C. P., Fujita, M., Yamada, T., Simbolo, M., Fassan, M., Karlic, R., ... Nakagawa, H. (2018). Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. Journal of Hepatology, 68(5), 959-969. https://doi.org/10.1016/j.jhep.2018.01.009
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 ; Kubo, Michiaki ; 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. / Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. In: Journal of Hepatology. 2018 ; Vol. 68, No. 5. pp. 959-969.
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title = "Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations",
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.",
author = "Wardell, {Christopher P.} and Masashi Fujita and Toru Yamada and Michele Simbolo and Matteo Fassan and Rosa Karlic and Paz Polak and Jaegil Kim and Yutaka Hatanaka and Kazuhiro Maejima and Lawlor, {Rita T.} and Yoshitsugu Nakanishi and Tomoko Mitsuhashi and Akihiro Fujimoto and Mayuko Furuta and Andrea Ruzzenente and Simone Conci and Ayako Oosawa and Aya Sasaki-Oku and Kaoru Nakano and Hiroko Tanaka and Yujiro Yamamoto and Michiaki Kubo and Yoshiiku Kawakami and Hiroshi Aikata and Masaki Ueno and Shinya Hayami and Kunihito Gotoh and Ariizumi, {Shun ichi} and Masakazu Yamamoto and Hiroki Yamaue and Kazuaki Chayama and Satoru Miyano and Gad Getz and Aldo Scarpa and Satoshi Hirano and Toru Nakamura and Hidewaki Nakagawa",
year = "2018",
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language = "English",
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pages = "959--969",
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Wardell, CP, Fujita, M, Yamada, T, Simbolo, M, Fassan, M, Karlic, R, Polak, P, Kim, J, Hatanaka, Y, Maejima, K, Lawlor, RT, Nakanishi, Y, Mitsuhashi, T, Fujimoto, A, Furuta, M, Ruzzenente, A, Conci, S, Oosawa, A, Sasaki-Oku, A, Nakano, K, Tanaka, H, Yamamoto, Y, Kubo, M, Kawakami, Y, Aikata, H, Ueno, M, Hayami, S, Gotoh, K, Ariizumi, SI, Yamamoto, M, Yamaue, H, Chayama, K, Miyano, S, Getz, G, Scarpa, A, Hirano, S, Nakamura, T & Nakagawa, H 2018, 'Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations', Journal of Hepatology, vol. 68, no. 5, pp. 959-969. https://doi.org/10.1016/j.jhep.2018.01.009

Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. / 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; Kubo, Michiaki; 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.

In: Journal of Hepatology, Vol. 68, No. 5, 01.05.2018, p. 959-969.

Research output: Contribution to journalArticle

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 - Kubo, Michiaki

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

PY - 2018/5/1

Y1 - 2018/5/1

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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DO - 10.1016/j.jhep.2018.01.009

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