High-resolution characterization of a hepatocellular carcinoma genome.

TitleHigh-resolution characterization of a hepatocellular carcinoma genome.
Publication TypeJournal Article
Year of Publication2011
AuthorsTotoki, Y, Tatsuno, K, Yamamoto, S, Arai, Y, Hosoda, F, Ishikawa, S, Tsutsumi, S, Sonoda, K, Totsuka, H, Shirakihara, T, Sakamoto, H, Wang, L, Ojima, H, Shimada, K, Kosuge, T, Okusaka, T, Kato, K, Kusuda, J, Yoshida, T, Aburatani, H, Shibata, T
JournalNat Genet
Date Published2011 May
KeywordsCarcinoma, Hepatocellular, Exons, Gene Rearrangement, Genes, Tumor Suppressor, Genetic Variation, Genomic Library, Genomics, Hepacivirus, Humans, INDEL Mutation, Liver Neoplasms, Mutation, Oncogenes, Polymorphism, Single Nucleotide, Selection, Genetic

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.

Alternate JournalNat Genet
PubMed ID21499249

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