High-resolution characterization of a hepatocellular carcinoma genome

Totoki, Yasushi; Tatsuno, Kenji; Yamamoto, Shozo; Arai, Yasuhito; Hosoda, Fumie; Ishikawa, Shumpei; Tsutsumi, Sadami; Sonoda, Kotaro; Totsuka, Hirohiko; Shirakihara, Takuya; Sanada, Hiromi; Wang, Linghua; Ojima, Hidenori; Shimada, Kazuaki; Kosuge, Tomoo; Okusaka, Takuji; Kato, Kazuto; Kusuda, Jun; Yoshida, Teruhiko; Aburatani, Hiroyuki; Shibata, Tatsuhiro

doi:10.1038/ng.804

Cited by 258 publications

(203 citation statements)

References 25 publications

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“…TSC2 mutations were not reported in recent next-generation sequencing studies of HCC (39)(40)(41)(42) and there is only one report finding a TSC1 mutation in HCC (35). The different patient ethnicity (Caucasian HCC) and HCC etiology (HCV þ for Japan HCC) in those studies may account for the differences between those and our results.…”

Section: Discussioncontrasting

confidence: 87%

“…It is also noteworthy to point out that TSC1 inactivation can lead to TSC2 protein degradation. Although no TSC1 mutations were identified in any of our HCC samples, a TSC1 mutation has been identified by high-resolution characterization of one hepatocellular carcinoma genome (35). The exact mechanisms of nongenetic loss of TSC2 in HCC remain to be determined.…”

Section: Discussionmentioning

confidence: 84%

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Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Huynh

Hao²,

Chan

et al. 2015

Molecular Cancer Therapeutics

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV þ HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients. Mol Cancer Ther; 14(5); 1224-35. Ó2015 AACR.

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Section: Discussioncontrasting

confidence: 87%

Section: Discussionmentioning

confidence: 84%

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Huynh

Hao²,

Chan

et al. 2015

Molecular Cancer Therapeutics

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“…Many large-scale genome sequencing projects have been executed to identify how somatic mutations [11][12][13][14][15][16][17][18] and hepatitis B virus (HBV) integration [19][20][21] affect HCC patients. In contrast, large-scale genome sequencing projects targeting the ICC cancer genomes just started to catch up.…”

mentioning

confidence: 99%

Mutational landscape of intrahepatic cholangiocarcinoma

et al. 2014

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“…This in-frame BCORL1-ELF4 fusion combined exons 1 to 11 of BCORL1 with exon 8 of ELF4 (Fig. 2C) and was generated by an intrachromosomal inversion (27). ELF4/ myeloid elf-1 like factor (MEF) is a transcriptional activator that regulates hematopoietic and glioma stem cell functions as well as several lymphocytes and myelocytes (28,29).…”

Section: Bcorl1-e74-like Factor 4 Fusion In Hepatocellular Carcinomamentioning

confidence: 99%

“…ELF4/ myeloid elf-1 like factor (MEF) is a transcriptional activator that regulates hematopoietic and glioma stem cell functions as well as several lymphocytes and myelocytes (28,29). As a consequence of the chimeric fusion protein, BCORL1-ELF4 exhibited decreased repression activity compared with BCORL1 (27). BCOR and BCORL1 Are Putative TumorSuppressor Genes We overviewed the genetic mutations that have been found in the BCOR family in a broad range of human cancers.…”

Section: Bcorl1-e74-like Factor 4 Fusion In Hepatocellular Carcinomamentioning

confidence: 99%

Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

Yamamoto

Abe

Emi

2014

Molecular Cancer Research

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The dysregulation of proper transcriptional control is a major cause of developmental diseases and cancers. Polycomb proteins form chromatin-modifying complexes that transcriptionally silence genome regions in higher eukaryotes. The BCL6 corepressor (BCOR) complex comprises ring finger protein 1B (RNF2/RING1B), polycomb group ring finger 1 (PCGF1), and lysine-specific demethylase 2B (KDM2B) and is uniquely recruited to nonmethylated CpG islands, where it removes histone H3K36me2 and induces repressive histone H2A monoubiquitylation. Germline BCOR mutations have been detected in patients with oculofaciocardiodental and Lenz microphthalmia syndromes, which are inherited conditions. Recently, several variants of BCOR and BCORlike 1 (BCORL1) chimeric fusion transcripts were reported in human cancers, including acute promyelocytic leukemia, bone sarcoma, and hepatocellular carcinoma. In addition, massively parallel sequencing has identified inactivating somatic BCOR and BCORL1 mutations in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, medulloblastoma, and retinoblastoma. More importantly, patients with AML and MDS with BCOR mutations exhibit poor prognosis. This perspective highlights the detection of BCOR mutations and fusion transcripts of BCOR and BCORL1 and discusses their importance for diagnosing cancer subtypes and estimating the treatment responses of patients. Furthermore, this perspective proposes the need for additional functional studies to clarify the oncogenic mechanism by which BCOR and BCORL1 are disrupted in cancers, and how this may lead to the development of novel therapeutics. Mol Cancer Res; 12(4); 479-84. Ó2014 AACR. IntroductionA major cause of developmental diseases and cancers is the dysregulation of proper transcriptional control, a process that is directly regulated by transcription factors, coactivators, and corepressors. Till date, several hundred transcriptional coregulators have been reported in the literature. Recently, the increased use of massively parallel sequencing techniques has expanded our knowledge on the induction of congenital diseases and cancers caused by specific gene mutations.

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High-resolution characterization of a hepatocellular carcinoma genome

Cited by 258 publications

References 25 publications

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Mutational landscape of intrahepatic cholangiocarcinoma

Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

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