title: High-resolution characterization of a hepatocellular carcinoma genome.
abstract: Hepatocellular carcinoma, one of the most common virus-associated cancers, is the third most frequent cause of cancer-related death worldwide. By massively parallel sequencing of a primary hepatitis C virus-positive hepatocellular carcinoma (36× coverage) and matched lymphocytes (>28× coverage) from the same individual, we identified more than 11,000 somatic substitutions of the tumor genome that showed predominance of T>C/A>G transition and a decrease of the T>C substitution on the transcribed strand, suggesting preferential DNA repair. Gene annotation enrichment analysis of 63 validated non-synonymous substitutions revealed enrichment of phosphoproteins. We further validated 22 chromosomal rearrangements, generating four fusion transcripts that had altered transcriptional regulation (BCORL1-ELF4) or promoter activity. Whole-exome sequencing at a higher sequence depth (>76× coverage) revealed a TSC1 nonsense substitution in a subpopulation of the tumor cells. This first high-resolution characterization of a virus-associated cancer genome identified previously uncharacterized mutation patterns, intra-chromosomal rearrangements and fusion genes, as well as genetic heterogeneity within the tumor.
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Totoki
authors.forename: Kenji
authors.initials: K
authors.lastname: Tatsuno
authors.forename: Shogo
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Arai
authors.forename: Fumie
authors.initials: F
authors.lastname: Hosoda
authors.forename: Shumpei
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Sonoda
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Totsuka
authors.forename: Takuya
authors.initials: T
authors.lastname: Shirakihara
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Linghua
authors.initials: L
authors.lastname: Wang
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ojima
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimada
authors.forename: Tomoo
authors.initials: T
authors.lastname: Kosuge
authors.forename: Takuji
authors.initials: T
authors.lastname: Okusaka
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kato
authors.forename: Jun
authors.initials: J
authors.lastname: Kusuda
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000821:virology; D005091:Exons; D015321:Gene Rearrangement; D016147:Genes, Tumor Suppressor; D014644:Genetic Variation; D015698:Genomic Library; D023281:Genomics; D016174:Hepacivirus / Q000472:pathogenicity; D006801:Humans; D054643:INDEL Mutation; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology; D009154:Mutation; D009857:Oncogenes; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic