%0 Journal Article %J Nat Genet %D 2014 %T Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. %A Totoki, Yasushi %A Tatsuno, Kenji %A Covington, Kyle R %A Ueda, Hiroki %A Creighton, Chad J %A Kato, Mamoru %A Tsuji, Shingo %A Donehower, Lawrence A %A Slagle, Betty L %A Nakamura, Hiromi %A Yamamoto, Shogo %A Shinbrot, Eve %A Hama, Natsuko %A Lehmkuhl, Megan %A Hosoda, Fumie %A Arai, Yasuhito %A Kimberly Walker %A Dahdouli, Mahmoud %A Gotoh, Kengo %A Nagae, Genta %A Marie-Claude Gingras %A Donna M Muzny %A Ojima, Hidenori %A Shimada, Kazuaki %A Midorikawa, Yutaka %A Goss, John A %A Cotton, Ronald %A Hayashi, Akimasa %A Shibahara, Junji %A Ishikawa, Shumpei %A Guiteau, Jacfranz %A Tanaka, Mariko %A Urushidate, Tomoko %A Ohashi, Shoko %A Okada, Naoko %A Harshavardhan Doddapaneni %A Wang, Min %A Zhu, Yiming %A Dinh, Huyen %A Okusaka, Takuji %A Kokudo, Norihiro %A Kosuge, Tomoo %A Takayama, Tadatoshi %A Fukayama, Masashi %A Richard A Gibbs %A Wheeler, David A %A Aburatani, Hiroyuki %A Shibata, Tatsuhiro %K Algorithms %K Asian People %K Carcinoma, Hepatocellular %K CpG Islands %K DNA Mutational Analysis %K Exome %K Gene Expression Regulation, Neoplastic %K Genome, Human %K Genome, Viral %K Hepacivirus %K Hepatitis B virus %K Humans %K Japan %K Liver Neoplasms %K Models, Statistical %K Mutation %K Principal Component Analysis %K Telomerase %K TOR Serine-Threonine Kinases %K United States %K White People %X

Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities.

%B Nat Genet %V 46 %P 1267-73 %8 2014 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/25362482?dopt=Abstract %R 10.1038/ng.3126 %0 Journal Article %J Genome Res %D 2012 %T Whole-exome sequencing of human pancreatic cancers and characterization of genomic instability caused by MLH1 haploinsufficiency and complete deficiency. %A Wang, Linghua %A Tsutsumi, Shuichi %A Kawaguchi, Tokuichi %A Nagasaki, Koichi %A Tatsuno, Kenji %A Yamamoto, Shogo %A Sang, Fei %A Sonoda, Kohtaro %A Sugawara, Minoru %A Saiura, Akio %A Hirono, Seiko %A Yamaue, Hiroki %A Miki, Yoshio %A Isomura, Minoru %A Totoki, Yasushi %A Nagae, Genta %A Isagawa, Takayuki %A Ueda, Hiroki %A Murayama-Hosokawa, Satsuki %A Shibata, Tatsuhiro %A Sakamoto, Hiromi %A Kanai, Yae %A Kaneda, Atsushi %A Noda, Tetsuo %A Aburatani, Hiroyuki %K Adaptor Proteins, Signal Transducing %K Alleles %K Cell Line, Tumor %K Exome %K Genomic Instability %K Haploinsufficiency %K High-Throughput Nucleotide Sequencing %K Humans %K Loss of Heterozygosity %K Mutation %K Mutation Rate %K MutL Protein Homolog 1 %K Nuclear Proteins %K Pancreatic Neoplasms %K Reproducibility of Results %X

Whole-exome sequencing (Exome-seq) has been successfully applied in several recent studies. We here sequenced the exomes of 15 pancreatic tumor cell lines and their matched normal samples. We captured 162,073 exons of 16,954 genes and sequenced the targeted regions to a mean coverage of 56-fold. This study identified a total of 1517 somatic mutations and validated 934 mutations by transcriptome sequencing. We detected recurrent mutations in 56 genes. Among them, 41 have not been described. The mutation rates varied widely among cell lines. The diversity of the mutation rates was significantly correlated with the distinct MLH1 copy-number status. Exome-seq revealed intensive genomic instability in a cell line with MLH1 homozygous deletion, indicated by a dramatically elevated rate of somatic substitutions, small insertions/deletions (indels), as well as indels in microsatellites. Notably, we found that MLH1 expression was decreased by nearly half in cell lines with an allelic loss of MLH1. While these cell lines were negative in conventional microsatellite instability assay, they showed a 10.5-fold increase in the rate of somatic indels, e.g., truncating indels in TP53 and TGFBR2, indicating MLH1 haploinsufficiency in the correction of DNA indel errors. We further analyzed the exomes of 15 renal cell carcinomas and confirmed MLH1 haploinsufficiency. We observed a much higher rate of indel mutations in the affected cases and identified recurrent truncating indels in several cancer genes such as VHL, PBRM1, and JARID1C. Together, our data suggest that MLH1 hemizygous deletion, through increasing the rate of indel mutations, could drive the development and progression of sporadic cancers.

%B Genome Res %V 22 %P 208-19 %8 2012 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/22156295?dopt=Abstract %R 10.1101/gr.123109.111 %0 Journal Article %J Nat Genet %D 2011 %T High-resolution characterization of a hepatocellular carcinoma genome. %A Totoki, Yasushi %A Tatsuno, Kenji %A Yamamoto, Shogo %A Arai, Yasuhito %A Hosoda, Fumie %A Ishikawa, Shumpei %A Tsutsumi, Shuichi %A Sonoda, Kohtaro %A Totsuka, Hirohiko %A Shirakihara, Takuya %A Sakamoto, Hiromi %A Wang, Linghua %A Ojima, Hidenori %A Shimada, Kazuaki %A Kosuge, Tomoo %A Okusaka, Takuji %A Kato, Kazuto %A Kusuda, Jun %A Yoshida, Teruhiko %A Aburatani, Hiroyuki %A Shibata, Tatsuhiro %K Carcinoma, Hepatocellular %K Exons %K Gene Rearrangement %K Genes, Tumor Suppressor %K Genetic Variation %K Genomic Library %K Genomics %K Hepacivirus %K Humans %K INDEL Mutation %K Liver Neoplasms %K Mutation %K Oncogenes %K Polymorphism, Single Nucleotide %K Selection, Genetic %X

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.

%B Nat Genet %V 43 %P 464-9 %8 2011 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/21499249?dopt=Abstract %R 10.1038/ng.804