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.
authors: 1] Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan [2] Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors: Akihiro
authors: A
authors: Fujimoto
authors: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
authors: Mayuko
authors: M
authors: Furuta
authors: Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors: Yuichi
authors: Y
authors: Shiraishi
authors: Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
authors: Kunihito
authors: K
authors: Gotoh
authors: Department of Medicine &Molecular Science, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.
authors: Yoshiiku
authors: Y
authors: Kawakami
authors: Department of Anatomical Pathology, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.
authors: Koji
authors: K
authors: Arihiro
authors: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors: Toru
authors: T
authors: Nakamura
authors: Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan.
authors: Masaki
authors: M
authors: Ueno
authors: Department of Gastroenterological Surgery, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors: Shun-ichi
authors: S
authors: Ariizumi
authors: 1] Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan [2] Genome Analysis Laboratory, Institute of Genome Research, Vietnam Academy of Science and Technology, Hanoi Vietnam.
authors: Ha Hai
authors: HH
authors: Nguyen
authors: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors: Daichi
authors: D
authors: Shigemizu
authors: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors: Tetsuo
authors: T
authors: Abe
authors: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors: Keith A
authors: KA
authors: Boroevich
authors: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
authors: Kaoru
authors: K
authors: Nakano
authors: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
authors: Aya
authors: A
authors: Sasaki
authors: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
authors: Rina
authors: R
authors: Kitada
authors: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
authors: Kazihiro
authors: K
authors: Maejima
authors: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
authors: Yujiro
authors: Y
authors: Yamamoto
authors: Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors: Hiroko
authors: H
authors: Tanaka
authors: Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors: Tetsuo
authors: T
authors: Shibuya
authors: Division of Cancer Genomics, National Cancer Center, Chuo-ku, Tokyo 104-0045, Japan.
authors: Tatsuhiro
authors: T
authors: Shibata
authors: Division of Molecular Pathology, National Cancer Center, Chuo-ku, Tokyo 104-0045, Japan.
authors: Hidenori
authors: H
authors: Ojima
authors: Hepatobiliary and Pancreatic Surgery Division, National Cancer Center, Chuo-ku, Tokyo 104-0045, Japan.
authors: Kazuaki
authors: K
authors: Shimada
authors: Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan.
authors: Shinya
authors: S
authors: Hayami
authors: Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan.
authors: Yoshinobu
authors: Y
authors: Shigekawa
authors: Department of Medicine &Molecular Science, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.
authors: Hiroshi
authors: H
authors: Aikata
authors: Department of Gastroenterological Surgery, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.
authors: Hideki
authors: H
authors: Ohdan
authors: Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
authors: Shigeru
authors: S
authors: Marubashi
authors: Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
authors: Terumasa
authors: T
authors: Yamada
authors: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors: Michiaki
authors: M
authors: Kubo
authors: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors: Satoshi
authors: S
authors: Hirano
authors: Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
authors: Osamu
authors: O
authors: Ishikawa
authors: Department of Gastroenterological Surgery, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors: Masakazu
authors: M
authors: Yamamoto
authors: Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan.
authors: Hiroki
authors: H
authors: Yamaue
authors: 1] Department of Medicine &Molecular Science, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan [2] Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima 734-8551, Japan.
authors: Kazuaki
authors: K
authors: Chayama
authors: 1] Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan [2] Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors: Satoru
authors: S
authors: Miyano
authors: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors: Tatsuhiko
authors: T
authors: Tsunoda
authors: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
authors: Hidewaki
authors: H
authors: Nakagawa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000235:genetics; D001653:Bile Ducts, Intrahepatic; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D018281:Cholangiocarcinoma / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D006505:Hepatitis / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D019098:Telomerase / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C512511:ARID2 protein, human; C400134:BAP1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D009479:Neuropeptides; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; C498630:PCLO protein, human; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C509186:TERT protein, human; D019098:Telomerase; D043222:Ubiquitin Thiolesterase; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins