High-resolution characterization of a hepatocellular carcinoma genome

Yasushi Totoki, Kenji Tatsuno, Shogo Yamamoto, Yasuhito Arai, Fumie Hosoda, Shumpei Ishikawa, Shuichi Tsutsumi, Kohtaro Sonoda, Hirohiko Totsuka, Takuya Shirakihara, Hiromi Sakamoto, Linghua Wang, Hidenori Ojima, Kazuaki Shimada, Tomoo Kosuge, Takuji Okusaka, Kazuto Kato, Jun Kusuda, Teruhiko Yoshida, Hiroyuki AburataniTatsuhiro Shibata

Research output: Contribution to journalArticlepeer-review

242 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)464-471
Number of pages8
JournalNature genetics
Issue number5
Publication statusPublished - 2011 May
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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