Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity

Akihiro Fujimoto; Mayuko Furuta; Yuichi Shiraishi; Kunihito Gotoh; Yoshiiku Kawakami; Koji Arihiro; Toru Nakamura; Masaki Ueno; Shun Ichi Ariizumi; Ha Hai Nguyen; Daichi Shigemizu; Tetsuo Abe; Keith A. Boroevich; Kaoru Nakano; Aya Sasaki; Rina Kitada; Kazihiro Maejima; Yujiro Yamamoto; Hiroko Tanaka; Tetsuo Shibuya; Tatsuhiro Shibata; Hidenori Ojima; Kazuaki Shimada; Shinya Hayami; Yoshinobu Shigekawa; Hiroshi Aikata; Hideki Ohdan; Shigeru Marubashi; Terumasa Yamada; Michiaki Kubo; Satoshi Hirano; Osamu Ishikawa; Masakazu Yamamoto; Hiroki Yamaue; Kazuaki Chayama; Satoru Miyano; Tatsuhiko Tsunoda; Hidewaki Nakagawa

doi:10.1038/ncomms7120

Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity

Akihiro Fujimoto, Mayuko Furuta, Yuichi Shiraishi, Kunihito Gotoh, Yoshiiku Kawakami, Koji Arihiro, Toru Nakamura, Masaki Ueno, Shun Ichi Ariizumi, Ha Hai Nguyen, Daichi Shigemizu, Tetsuo Abe, Keith A. Boroevich, Kaoru Nakano, Aya Sasaki, Rina Kitada, Kazihiro Maejima, Yujiro Yamamoto, Hiroko Tanaka, Tetsuo ShibuyaTatsuhiro Shibata, Hidenori Ojima, Kazuaki Shimada, Shinya Hayami, Yoshinobu Shigekawa, Hiroshi Aikata, Hideki Ohdan, Shigeru Marubashi, Terumasa Yamada, Michiaki Kubo, Satoshi Hirano, Osamu Ishikawa, Masakazu Yamamoto, Hiroki Yamaue, Kazuaki Chayama, Satoru Miyano, Tatsuhiko Tsunoda, Hidewaki Nakagawa

Research output: Contribution to journal › Article › peer-review

185 Citations (Scopus)

Abstract

Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma show varying degrees of biliary epithelial differentiation, which can be defined as liver cancer displaying biliary phenotype (LCB). LCB is second in the incidence for liver cancers with and without chronic hepatitis background and more aggressive than hepatocellular carcinoma (HCC). To gain insight into its molecular alterations, we performed whole-genome sequencing analysis on 30 LCBs. Here we show, the genome-wide substitution patterns of LCBs developed in chronic hepatitis livers overlapped with those of 60 HCCs, whereas those of hepatitis-negative LCBs diverged. The subsequent validation study on 68 LCBs identified recurrent mutations in TERT promoter, chromatin regulators (BAP1, PBRM1 and ARID2), a synapse organization gene (PCLO), IDH genes and KRAS. The frequencies of KRAS and IDHs mutations, which are associated with poor disease-free survival, were significantly higher in hepatitis-negative LCBs. This study reveals the strong impact of chronic hepatitis on the mutational landscape in liver cancer and the genetic diversity among LCBs.

Original language	English
Article number	6120
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7120
Publication status	Published - 2015
Externally published	Yes

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms7120

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Fujimoto, A., Furuta, M., Shiraishi, Y., Gotoh, K., Kawakami, Y., Arihiro, K., Nakamura, T., Ueno, M., Ariizumi, S. I., Nguyen, H. H., Shigemizu, D., Abe, T., Boroevich, K. A., Nakano, K., Sasaki, A., Kitada, R., Maejima, K., Yamamoto, Y., Tanaka, H., ... Nakagawa, H. (2015). Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity. Nature communications, 6, Article 6120. https://doi.org/10.1038/ncomms7120

@article{ffc527ca8a17461b9d7f76389864dd23,

title = "Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity",

abstract = "Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma show varying degrees of biliary epithelial differentiation, which can be defined as liver cancer displaying biliary phenotype (LCB). LCB is second in the incidence for liver cancers with and without chronic hepatitis background and more aggressive than hepatocellular carcinoma (HCC). To gain insight into its molecular alterations, we performed whole-genome sequencing analysis on 30 LCBs. Here we show, the genome-wide substitution patterns of LCBs developed in chronic hepatitis livers overlapped with those of 60 HCCs, whereas those of hepatitis-negative LCBs diverged. The subsequent validation study on 68 LCBs identified recurrent mutations in TERT promoter, chromatin regulators (BAP1, PBRM1 and ARID2), a synapse organization gene (PCLO), IDH genes and KRAS. The frequencies of KRAS and IDHs mutations, which are associated with poor disease-free survival, were significantly higher in hepatitis-negative LCBs. This study reveals the strong impact of chronic hepatitis on the mutational landscape in liver cancer and the genetic diversity among LCBs.",

author = "Akihiro Fujimoto and Mayuko Furuta and Yuichi Shiraishi and Kunihito Gotoh and Yoshiiku Kawakami and Koji Arihiro and Toru Nakamura and Masaki Ueno and Ariizumi, {Shun Ichi} and Nguyen, {Ha Hai} and Daichi Shigemizu and Tetsuo Abe and Boroevich, {Keith A.} and Kaoru Nakano and Aya Sasaki and Rina Kitada and Kazihiro Maejima and Yujiro Yamamoto and Hiroko Tanaka and Tetsuo Shibuya and Tatsuhiro Shibata and Hidenori Ojima and Kazuaki Shimada and Shinya Hayami and Yoshinobu Shigekawa and Hiroshi Aikata and Hideki Ohdan and Shigeru Marubashi and Terumasa Yamada and Michiaki Kubo and Satoshi Hirano and Osamu Ishikawa and Masakazu Yamamoto and Hiroki Yamaue and Kazuaki Chayama and Satoru Miyano and Tatsuhiko Tsunoda and Hidewaki Nakagawa",

year = "2015",

doi = "10.1038/ncomms7120",

language = "English",

volume = "6",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Fujimoto, A, Furuta, M, Shiraishi, Y, Gotoh, K, Kawakami, Y, Arihiro, K, Nakamura, T, Ueno, M, Ariizumi, SI, Nguyen, HH, Shigemizu, D, Abe, T, Boroevich, KA, Nakano, K, Sasaki, A, Kitada, R, Maejima, K, Yamamoto, Y, Tanaka, H, Shibuya, T, Shibata, T, Ojima, H, Shimada, K, Hayami, S, Shigekawa, Y, Aikata, H, Ohdan, H, Marubashi, S, Yamada, T, Kubo, M, Hirano, S, Ishikawa, O, Yamamoto, M, Yamaue, H, Chayama, K, Miyano, S, Tsunoda, T & Nakagawa, H 2015, 'Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity', Nature communications, vol. 6, 6120. https://doi.org/10.1038/ncomms7120

TY - JOUR

T1 - Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity

AU - Fujimoto, Akihiro

AU - Furuta, Mayuko

AU - Shiraishi, Yuichi

AU - Gotoh, Kunihito

AU - Kawakami, Yoshiiku

AU - Arihiro, Koji

AU - Nakamura, Toru

AU - Ueno, Masaki

AU - Ariizumi, Shun Ichi

AU - Nguyen, Ha Hai

AU - Shigemizu, Daichi

AU - Abe, Tetsuo

AU - Boroevich, Keith A.

AU - Nakano, Kaoru

AU - Sasaki, Aya

AU - Kitada, Rina

AU - Maejima, Kazihiro

AU - Yamamoto, Yujiro

AU - Tanaka, Hiroko

AU - Shibuya, Tetsuo

AU - Shibata, Tatsuhiro

AU - Ojima, Hidenori

AU - Shimada, Kazuaki

AU - Hayami, Shinya

AU - Shigekawa, Yoshinobu

AU - Aikata, Hiroshi

AU - Ohdan, Hideki

AU - Marubashi, Shigeru

AU - Yamada, Terumasa

AU - Kubo, Michiaki

AU - Hirano, Satoshi

AU - Ishikawa, Osamu

AU - Yamamoto, Masakazu

AU - Yamaue, Hiroki

AU - Chayama, Kazuaki

AU - Miyano, Satoru

AU - Tsunoda, Tatsuhiko

AU - Nakagawa, Hidewaki

PY - 2015

Y1 - 2015

N2 - Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma show varying degrees of biliary epithelial differentiation, which can be defined as liver cancer displaying biliary phenotype (LCB). LCB is second in the incidence for liver cancers with and without chronic hepatitis background and more aggressive than hepatocellular carcinoma (HCC). To gain insight into its molecular alterations, we performed whole-genome sequencing analysis on 30 LCBs. Here we show, the genome-wide substitution patterns of LCBs developed in chronic hepatitis livers overlapped with those of 60 HCCs, whereas those of hepatitis-negative LCBs diverged. The subsequent validation study on 68 LCBs identified recurrent mutations in TERT promoter, chromatin regulators (BAP1, PBRM1 and ARID2), a synapse organization gene (PCLO), IDH genes and KRAS. The frequencies of KRAS and IDHs mutations, which are associated with poor disease-free survival, were significantly higher in hepatitis-negative LCBs. This study reveals the strong impact of chronic hepatitis on the mutational landscape in liver cancer and the genetic diversity among LCBs.

AB - Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma show varying degrees of biliary epithelial differentiation, which can be defined as liver cancer displaying biliary phenotype (LCB). LCB is second in the incidence for liver cancers with and without chronic hepatitis background and more aggressive than hepatocellular carcinoma (HCC). To gain insight into its molecular alterations, we performed whole-genome sequencing analysis on 30 LCBs. Here we show, the genome-wide substitution patterns of LCBs developed in chronic hepatitis livers overlapped with those of 60 HCCs, whereas those of hepatitis-negative LCBs diverged. The subsequent validation study on 68 LCBs identified recurrent mutations in TERT promoter, chromatin regulators (BAP1, PBRM1 and ARID2), a synapse organization gene (PCLO), IDH genes and KRAS. The frequencies of KRAS and IDHs mutations, which are associated with poor disease-free survival, were significantly higher in hepatitis-negative LCBs. This study reveals the strong impact of chronic hepatitis on the mutational landscape in liver cancer and the genetic diversity among LCBs.

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U2 - 10.1038/ncomms7120

DO - 10.1038/ncomms7120

M3 - Article

C2 - 25636086

AN - SCOPUS:84943272498

SN - 2041-1723

VL - 6

JO - Nature communications

JF - Nature communications

M1 - 6120

ER -

Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity

Abstract

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