Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets

Sekiguchi, Mutsuo; Seki, Masafumi; Kawai, Tomoko; Yoshida, Kenichi; Yoshida, Misa; Isobe, Tomoya; Hoshino, Naomi; Shirai, Ryota; Tanaka, Mio; Souzaki, Ryota; Watanabe, Kentaro; Arakawa, Yuki; Nannya, Yasuhito; Suzuki, Hiromichi; Fujii, Yoichi; Kataoka, Keisuke; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Shimamura, Teppei; Sato, Yusuke; Sato‐Otsubo, Aiko; Kimura, Shunsuke; Kubota, Yasuo; Hiwatari, Mitsuteru; Koh, Katsuyoshi; Hayashi, Yasuhide; Kanamori, Yutaka; Kasahara, Mureo; Kohashi, Kenichi; Kato, Motohiro; Yoshioka, Takako; Matsumoto, Kimikazu; Oka, Akira; Taguchi, Tomoaki; Sanada, Masashi; Tanaka, Yukichi; Miyano, Satoru; Hata, Kenichiro; Ogawa, Seishi; Takita, Junko

doi:10.1038/s41698-020-0125-y

Cited by 42 publications

(73 citation statements)

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“…We performed TCS for 381 pediatric cancer-related genes and regions (U-Tokyo Onco-panel ver.1) [ 24 ] ( S2 Table ) on 30 cases of INSS Stage 4 neuroblastoma ( S1 Table ). Each neuroblastoma sample harbored a mean of 4.2 variants (range = 1–10) ( S4 Table ).…”

Section: Resultsmentioning

confidence: 99%

“…Targeted capture was performed using a SureSelect custom kit (Agilent Technologies, Palo Alto, CA, USA) as previously described [24][25][26] The custom bait library (U-Tokyo Oncopanel ver.1) related to pediatric cancers (S2 Table) [24] was designed to include the following: (i) all coding exons of 367 genes; (ii) untranslated regions and introns of CD274, CTNNB1, ERG, ETV1, ETV4, EWSR1, FEV, FLI1, FOXO1, FUS, INO80D, NCOA1, NCOA2, NOTCH1, PAX3, and PAX7 for detecting breakpoints of structural variations; (iii) promoter and enhancer regions of FGFR3, MYC and TERT; (iv) microRNA genes MIR100, MIRLET7A1, MIRLET7A2, MIRLET7A3, MIRLET7B, MIRLET7C, MIRLET7D, MIRLET7E, MIRLET7F1, MIRLET7F2, and MIRLET7G; and (v) 3,527 positions of single nucleotide polymorphisms (SNP) for copy number analysis to generate genome-wide allele-specific copy number profiles. We selected 381 targeted genes and regions, not including the SNP positions, to include the following: (a) genes adopted in more than one of the following existing gene panels: MSK-IM-PACT27 CMS400 (Life Technologies, Carlsbad, CA, USA), FoundationOne (Foundation Medicine, Cambridge, MA, USA), or the Human Comprehensive Cancer Panel (QIAGEN, Hilden, Germany); (b) the most frequently mutated 20 genes in each type of malignancy according to the Catalogue of Somatic Mutations in Cancer (COSMIC) v78; and (c) genes that were recurrently affected in pediatric malignancies, including neuroblastoma, hepatoblastoma, pleuropulmonary blastoma, rhabdomyosarcoma, Ewing's sarcoma, and germ cell tumor.…”

Section: Targeted Capture Sequencing (Tcs)mentioning

confidence: 99%

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Association of high-risk neuroblastoma classification based on expression profiles with differentiation and metabolism

et al. 2021

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Neuroblastoma, the most common extracranial solid malignancy among children, originates from undifferentiated neural crest cells (NCC). Despite recent intensified treatment, high-risk patients still have a high mortality rate. To explore a new therapeutic strategy, we performed an integrated genomic and transcriptomic analysis of 30 high-risk neuroblastoma cases. Based on the expression profiling of RNA sequencing, neuroblastoma was classified into Mesenchymal (MES; n = 5) and Noradrenergic (ADRN; n = 25) clusters, as previously reported in the super-enhancer landscape. The expression patterns in MES-cluster cases were similar to normal adrenal glands, with enrichment in secretion-related pathways, suggesting chromaffin cell-like features built from NCC-derived Schwann cell precursors (SCPs). In contrast, neuron-related pathways were enriched in the ADRN-cluster, indicating sympathoblast features reported to originate from NCC but not via SCPs. Thus, MES- and ADRN-clusters were assumed to be corresponding to differentiation pathways through SCP and sympathoblast, respectively. ADRN-cluster cases were further classified into MYCN- and ATRX-clusters, characterized by genetic alterations, MYCN amplifications and ATRX alterations, respectively. MYCN-cluster cases showed high expression of ALDH18A1, encoding P5CS related to proline production. As reported in other cancers, this might cause reprogramming of proline metabolism leading to tumor specific proline vulnerability candidate for a target therapy of metabolic pathway. In ATRX-cluster, SLC18A2 (VMAT2), an enzyme known to prevent cell toxicity due to the oxidation of dopamine, was highly expressed and VMAT2 inhibitor (GZ-793A) represented significant attenuation of cell growth in NB-69 cell line (high SLC18A2 expression, no MYCN amplification) but not in IMR-32 cell line (MYCN amplification). In addition, the correlation of VMAT2 expression with metaiodobenzylguanidine (MIBG) avidity suggested a combination of VMAT2 inhibitor and MIBG radiation for a novel potential therapeutic strategy in ATRX-cluster cases. Thus, targeting the characteristics of unique neuroblastomas may prospectively improve prognosis.

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Section: Resultsmentioning

confidence: 99%

Section: Targeted Capture Sequencing (Tcs)mentioning

confidence: 99%

Association of high-risk neuroblastoma classification based on expression profiles with differentiation and metabolism

et al. 2021

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“…[ 20 , 136 ]. In addition to Nrf2 and AhR mediated induction of NQO1, the methylation status of the NQO1 promoter may also be an important factor controlling NQO1 expression [ [137] , [138] , [139] , [140] ]. Mechanisms have also been proposed for the transcriptional regulation of NQO1 by antiestrogen-liganded estrogen receptor [ 95 , 96 ].…”

Section: Inducibility Of Nqo1 – Nrf2 and Ah Receptor Mediated Inductimentioning

confidence: 99%

The diverse functionality of NQO1 and its roles in redox control

2021

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In this review, we summarize the multiple functions of NQO1, its established roles in redox processes and potential roles in redox control that are currently emerging. NQO1 has attracted interest due to its roles in cell defense and marked inducibility during cellular stress. Exogenous substrates for NQO1 include many xenobiotic quinones. Since NQO1 is highly expressed in many solid tumors, including via upregulation of Nrf2, the design of compounds activated by NQO1 and NQO1-targeted drug delivery have been active areas of research. Endogenous substrates have also been proposed and of relevance to redox stress are ubiquinone and vitamin E quinone, components of the plasma membrane redox system. Established roles for NQO1 include a superoxide reductase activity, NAD + generation, interaction with proteins and their stabilization against proteasomal degradation, binding and regulation of mRNA translation and binding to microtubules including the mitotic spindles. We also summarize potential roles for NQO1 in regulation of glucose and insulin metabolism with relevance to diabetes and the metabolic syndrome, in Alzheimer's disease and in aging. The conformation and molecular interactions of NQO1 can be modulated by changes in the pyridine nucleotide redox balance suggesting that NQO1 may function as a redox-dependent molecular switch.

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“…Sekiguchi et al recently employed a multi-omics approach to classify 59 HBs [ 63 ], and showed that epigenetic changes are not only widespread but may also contribute to heterogeneous HB appearances and clinical behaviors. 56 of the tumors contained β-catenin mutations and an additional four contained APC gene mutations (i.e., a 100% incidence of Wnt/β-catenin/APC pathway dysregulation).…”

Section: Remaining Questionsmentioning

confidence: 99%

Reconciling the Biological and Transcriptional Variability of Hepatoblastoma with Its Mutational Uniformity

Prochownik

2021

Cancers

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Hepatoblastoma (HB), the most common childhood liver cancer, is associated with seven distinct histologic subtypes and variable degrees of clinical aggressiveness and presentation. Yet it is among the least genomically altered tumors known, with about half of HBs showing mutation and/or dysregulation of the Wnt/β-catenin and Hippo pathways. This raises the question of how this mutational simplicity can generate such biological and histologic complexity. Recent work shows that the identity of the underlying β-catenin mutation is a major contributor. Mutation or over-expression of the NFE2L2/NRF2 transcription factor, previously thought only to promote anti-oxidant responses, has also recently been shown to accelerate the growth of HBs generated by mutations in the Wnt/β-catenin and Hippo pathways while imparting novel features such as the tumor-associated cysts and necrosis. Moreover, patient-associated NFE2L2 mutations are overtly transforming when co-expressed with either mutant β-catenin or a Hippo pathway effector. The finding that tumorigenesis can be driven by any two arms of the β-catenin/Hippo/NFE2L2 axis has permitted the identification of a small subset of coordinately regulated tumor-specific transcripts, some of whose levels correlate with inferior long-term outcomes in HB and other cancers. Collectively, these findings begin to provide for more refined and molecularly based classification, survival algorithms and design of chemotherapeutic regimens.

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Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets

Cited by 42 publications

References 47 publications

Association of high-risk neuroblastoma classification based on expression profiles with differentiation and metabolism

Association of high-risk neuroblastoma classification based on expression profiles with differentiation and metabolism

The diverse functionality of NQO1 and its roles in redox control

Reconciling the Biological and Transcriptional Variability of Hepatoblastoma with Its Mutational Uniformity

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