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

Author

Listed:
  • Akihiro Fujimoto

    (Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences
    Laboratory for Medical Science Mathematics, 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
    Genome Analysis Laboratory, Institute of Genome Research, Vietnam Academy of Science and Technology)

  • 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
    Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences)

  • Satoru Miyano

    (Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo
    Laboratory of Sequence 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)

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.

Suggested Citation

  • 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 A, 2015. "Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity," Nature Communications, Nature, vol. 6(1), pages 1-8, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7120
    DOI: 10.1038/ncomms7120
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