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 () and Hidewaki Nakagawa ()
Additional contact information
Akihiro Fujimoto: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences
Mayuko Furuta: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences
Yuichi Shiraishi: Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo
Kunihito Gotoh: Osaka Medical Center for Cancer and Cardiovascular Diseases
Yoshiiku Kawakami: Hiroshima University School of Medicine
Koji Arihiro: Hiroshima University School of Medicine
Toru Nakamura: Hokkaido University Graduate School of Medicine
Masaki Ueno: Wakayama Medical University
Shun-ichi Ariizumi: Tokyo Women’s Medical University
Ha Hai Nguyen: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences
Daichi Shigemizu: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences
Tetsuo Abe: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences
Keith A. Boroevich: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences
Kaoru Nakano: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences
Aya Sasaki: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences
Rina Kitada: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences
Kazihiro Maejima: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences
Yujiro Yamamoto: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences
Hiroko Tanaka: Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo
Tetsuo Shibuya: Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo
Tatsuhiro Shibata: National Cancer Center
Hidenori Ojima: National Cancer Center
Kazuaki Shimada: National Cancer Center
Shinya Hayami: Wakayama Medical University
Yoshinobu Shigekawa: Wakayama Medical University
Hiroshi Aikata: Hiroshima University School of Medicine
Hideki Ohdan: Hiroshima University School of Medicine
Shigeru Marubashi: Osaka Medical Center for Cancer and Cardiovascular Diseases
Terumasa Yamada: Osaka Medical Center for Cancer and Cardiovascular Diseases
Michiaki Kubo: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences
Satoshi Hirano: Hokkaido University Graduate School of Medicine
Osamu Ishikawa: Osaka Medical Center for Cancer and Cardiovascular Diseases
Masakazu Yamamoto: Tokyo Women’s Medical University
Hiroki Yamaue: Wakayama Medical University
Kazuaki Chayama: Hiroshima University School of Medicine
Satoru Miyano: Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo
Tatsuhiko Tsunoda: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences
Hidewaki Nakagawa: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7120

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