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 journalArticle

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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 languageEnglish
Article number7120
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 01-01-2015

Fingerprint

hepatitis
phenotype
genome
Chronic Hepatitis
Liver Neoplasms
liver
Liver
Hepatitis
Cholangiocarcinoma
Genes
cancer
Genome
Phenotype
mutations
Mutation
Validation Studies
genes
Synapses
Disease-Free Survival
Chromatin

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Fujimoto, Akihiro ; Furuta, Mayuko ; Shiraishi, Yuichi ; Gotoh, Kunihito ; Kawakami, Yoshiiku ; Arihiro, Koji ; Nakamura, Toru ; Ueno, Masaki ; Ariizumi, Shun Ichi ; Nguyen, Ha Hai ; Shigemizu, Daichi ; Abe, Tetsuo ; Boroevich, Keith A. ; Nakano, Kaoru ; Sasaki, Aya ; Kitada, Rina ; Maejima, Kazihiro ; Yamamoto, Yujiro ; Tanaka, Hiroko ; Shibuya, Tetsuo ; Shibata, Tatsuhiro ; Ojima, Hidenori ; Shimada, Kazuaki ; Hayami, Shinya ; Shigekawa, Yoshinobu ; Aikata, Hiroshi ; Ohdan, Hideki ; Marubashi, Shigeru ; Yamada, Terumasa ; Kubo, Michiaki ; Hirano, Satoshi ; Ishikawa, Osamu ; Yamamoto, Masakazu ; Yamaue, Hiroki ; Chayama, Kazuaki ; Miyano, Satoru ; Tsunoda, Tatsuhiko ; Nakagawa, Hidewaki. / Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity. In: Nature Communications. 2015 ; Vol. 6.
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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",
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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, 7120. https://doi.org/10.1038/ncomms7120

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

In: Nature Communications, Vol. 6, 7120, 01.01.2015.

Research output: Contribution to journalArticle

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 - 2015/1/1

Y1 - 2015/1/1

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

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