title: Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors.
abstract: Patients with hepatocellular carcinoma (HCC) have a high-risk of multi-centric (MC) tumor occurrence due to a strong carcinogenic background in the liver. In addition, they have a high risk of intrahepatic metastasis (IM). Liver tumors withIM or MC are profoundly different in their development and clinical outcome. However, clinically or pathologically discriminating between IM and MC can be challenging. This study investigated whether IM or MC could be diagnosed at the molecular level.
  
  
  
  We performed whole genome and RNA sequencing analyses of 49 tumors including two extra-hepatic metastases, and one nodule-in-nodule tumor from 23 HCC patients.
  
  
  
  Sequencing-based molecular diagnosis using somatic single nucleotide variation information showed higher sensitivity compared to previous techniques due to the inclusion of a larger number of mutation events. This proved useful in cases, which showed inconsistent clinical diagnoses. In addition, whole genome sequencing offered advantages in profiling of other genetic alterations, such as structural variations, copy number alterations, and variant allele frequencies, and helped to confirm the IM/MCdiagnosis. Divergent alterations between IM tumors with sorafenib treatment, long time-intervals, or tumor-in-tumor nodules indicated high intra-tumor heterogeneity, evolution, and clonal switching of liver cancers.
  
  
  
  It is important to analyze the differences between IM tumors, in addition to IM/MC diagnosis, before selecting a therapeutic strategy for multiple tumors in the liver.
  
  
  
  Whole genome sequencing of multiple liver tumors enabled the accuratediagnosis ofmulti-centric occurrence and intrahepatic metastasis using somatic single nucleotide variation information. In addition, genetic discrepancies between tumors help us to understand the physical changes during recurrence and cancer spread.
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Furuta
authors.affiliation: Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ueno
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fujimoto
authors.affiliation: Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Hayami
authors.affiliation: Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kyoto 602-8565, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Yasukawa
authors.affiliation: Department of Pathology, Wakayama Medical University, Wakayama 641-8510, Japan.
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Kojima
authors.affiliation: Department of Anatomical Pathology, Hiroshima University, Hiroshima 734-8551, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Arihiro
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima 734-8551, Japan.
authors.forename: Yoshiiku
authors.initials: Y
authors.lastname: Kawakami
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Wardell
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Maejima
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Sasaki-Oku
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tokunaga
authors.affiliation: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Boroevich
authors.affiliation: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Abe
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima 734-8551, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aikata
authors.affiliation: Department of Gastroenterological Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohdan
authors.affiliation: Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
authors.forename: Kunihito
authors.initials: K
authors.lastname: Gotoh
authors.affiliation: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima 734-8551, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.affiliation: Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan. Electronic address: yamaue-h@wakayama-med.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamaue
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan. Electronic address: hidewaki@ims.u-tookoyo.ac.jp.
authors.forename: Hidewaki
authors.initials: H
authors.lastname: Nakagawa
mesh_terms: D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000628:therapy; D056915:DNA Copy Number Variations; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007564:Japan; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009378:Neoplasms, Multiple Primary / Q000235:genetics / Q000473:pathology / Q000628:therapy; D018579:Patient Selection; D000073336:Whole Genome Sequencing / Q000379:methods
keywords: Hepatocellular Carcinoma; Intrahepatic metastasis; Liver cancer; Multi-centric occurrence; Somatic SNVs; Whole genome sequencing