Integrated Genomic Analysis Identifies Driver Genes and Cisplatin-Resistant Progenitor Phenotype in Pediatric Liver Cancer

Hirsch, Théo Z.; Pilet, Jill; Morcrette, Guillaume; Roehrig, Amélie; Monteiro, Benedict J.E.; Molina, Laura; Bayard, Quentin; Trépo, Eric; Meunier, Léa; Caruso, Stefano; Renault, Victor; Deleuze, Jean‐François; Fresneau, Brice; Chardot, Christophe; Gonzalès, Emmanuel; Jacquemin, Emmanuel; Guérin, Florent; Fabrè, Monique; Aerts, Isabelle; Taque, Sophie; Laithier, Véronique; Branchereau, Sophie; Guettier, Catherine; Brugières, Laurence; Rebouissou, Sandra; Letouzé, Éric; Zucman–Rossi, Jessica

doi:10.1158/2159-8290.cd-20-1809

Cited by 46 publications

(106 citation statements)

References 76 publications

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“…The most recurrent mutation is found in the CTNNB1 gene, the key effector of the Wnt/β -catenin signaling pathway, mainly harboring exon 3 mutations or deletions [11,12] . Besides CTNNB1, additional mutations in other genes have been reported in different studies [Table 1] [4,12,[14][15][16][17][18][19][20] .…”

Section: Molecular Mechanisms Of Carcinogenesis In Hbmentioning

confidence: 99%

“…1%-7% [14,15] APC 7%-14% [14,19,20] ARID1A 2.9%-3.1% [16,17] NFE2L2/KEAP1, HGF/c-Met, PI3K/AKT/mTOR, SP/NK-1R, and IGF pathways. The role of these pathways in the development and progression of HB was recently reviewed by Zhang et al [21] .…”

Section: Axin1mentioning

confidence: 99%

“…As aforementioned, Wnt/β-catenin is the most important pathway dysregulated in HB due to the high rate of mutations of CTNNB1 and APC genes [12,16,78] . APC constitutes part of the repressive complex in charge of the degradation of β-catenin in normal conditions [79] .…”

Section: Dna Methylation In Hepatoblastomamentioning

confidence: 99%

“…Indeed, a study analyzing the methylation status of 25 genes in HB reported that APC is hypermethylated in 30% of HB tissues [77] . Therefore, it is possible that APC mutation or methylation-dependent downregulation might be associated with the activation of the Wnt/βcatenin pathway in β-catenin wild-type HBs [16] . Therefore, experimental studies are needed to assess the importance of APC gene methylation in HB development.…”

Section: Dna Methylation In Hepatoblastomamentioning

confidence: 99%

“…Most of the studies on HB have focused their attention on overexpressed proteins such as glypican 3 (GPC3) [16,102] , delta-like 1 homolog (DLK-1) [16] , NFE2L2 [12] , and LIN28B [103] . As mentioned above, the increased expression of certain proteins may be associated with a reduced methylation of their respective genes.…”

Section: Dna Methylation In Hepatoblastomamentioning

confidence: 99%

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Epigenetics in hepatoblastoma

Clavería-Cabello¹,

Arechederra²,

Berasain³

et al. 2021

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Hepatoblastoma (HB) is the most frequent pediatric primary liver tumor. When the tumoral lesions can be resected, prognosis is generally favorable. However, there is a significant number of cases in which resection is not possible at diagnosis, and patients usually receive neo-adjuvant cisplatin-based chemotherapy prior to surgery. Unfortunately, some HBs develop resistance to initial chemotherapy or after recurrence, progressing to metastatic disease. Moreover, long-term side effects of chemotherapy remain a serious concern. Understanding the molecular bases of HB development and progression is thus essential for the identification of more efficacious therapies. HBs have a very low mutational burden, and the most frequent mutations occur in the CTNN1B gene (> 80% of cases) and to a lesser extent in NFE2L2 (~10% of cases). These observations suggest that other pathogenic processes besides genetic mutations may play a role in HB tumorigenesis. Epigenetic mechanisms encompass a variety of molecular processes with a tremendous potential to regulate gene expression. They include the covalent modifications of DNA and histones, the activity of enzymatic chromatin remodelers, and the expression of noncoding RNAs. Dysregulation of epigenetic processes has clearly become a hallmark of cancer. Regarding HB, recent studies have explored its epigenetic landscape, the expression of specific epigenetic effectors, and the tumorigenic consequences of epigenetic alterations. The reversible nature of most epigenetic modifications and the possibility to target non-coding RNAs may pave the way for new therapeutic avenues in HB. Here, we summarize and discuss the most relevant findings in this less explored aspect of HB.

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Section: Molecular Mechanisms Of Carcinogenesis In Hbmentioning

confidence: 99%

Section: Axin1mentioning

confidence: 99%

Section: Dna Methylation In Hepatoblastomamentioning

confidence: 99%

Section: Dna Methylation In Hepatoblastomamentioning

confidence: 99%

Section: Dna Methylation In Hepatoblastomamentioning

confidence: 99%

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Epigenetics in hepatoblastoma

Clavería-Cabello¹,

Arechederra²,

Berasain³

et al. 2021

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Single‐cell transcriptomics uncovers cellular architecture and developmental trajectories in hepatoblastoma

Huang

Lü

et al. 2023

Hepatology

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Background and Aims: Hepatoblastoma (HB) is the predominant type of childhood liver cancer. Treatment options for the clinically advanced HB remain limited. We aimed to dissect the cellular and molecular basis underlying HB oncogenesis and heterogeneity at the single‐cell level, which could facilitate a better understanding of HB at both the biological and clinical levels. Approach and Results: Single‐cell transcriptome profiling of tumor and paired distal liver tissue samples from five patients with HB was performed. Deconvolution analysis was used for integrating the single‐cell transcriptomic profiles with the bulk transcriptomes of our HB cohort of post–neoadjuvant chemotherapy tumor samples. A single‐cell transcriptomic landscape of early human liver parenchymal development was established for exploring the cellular root and hierarchy of HB oncogenesis. As a result, seven distinct tumor cell subpopulations were annotated, and an effective HB subtyping method was established based on their compositions. A HB tumor cell hierarchy was further revealed to not only fit with the classical cancer stem cell (CSC) model but also mirror the early human liver parenchymal development. Moreover, FACT inhibition, which could disrupt the oncogenic positive feedback loop between MYC and SSRP1 in HB, was identified as a promising epigenetic‐targeted therapeutic strategy against the CSC‐like HB1–Pro‐like1 subpopulation and its related high‐risk “Pro‐like1” subtype of HB. Conclusions: Our findings illustrate the cellular architecture and developmental trajectories of HB via integrative bulk and single‐cell transcriptome analyses, thus establishing a resourceful framework for the development of targeted diagnostics and therapeutics in the future.

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Children's Oncology Group's 2023 blueprint for research: Liver tumors

O’Neill

Meyers

Katzenstein³

et al. 2023

Pediatric Blood & Cancer

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Liver tumors account for approximately 1%–2% of all pediatric malignancies, with the two most common tumors being hepatoblastoma (HB) and hepatocellular carcinoma (HCC). Previous Children's Oncology Group studies have meaningfully contributed to the current understanding of disease pathophysiology and treatment, laying groundwork for the ongoing prospective international study of both HB and HCC. Future work is focused on elucidating the biologic underpinnings of disease to support an evolution in risk categorization, advancements in the multidimensional care required to treat these patients, and the discovery of novel therapies.

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Integrated Genomic Analysis Identifies Driver Genes and Cisplatin-Resistant Progenitor Phenotype in Pediatric Liver Cancer

Cited by 46 publications

References 76 publications

Epigenetics in hepatoblastoma

Epigenetics in hepatoblastoma

Single‐cell transcriptomics uncovers cellular architecture and developmental trajectories in hepatoblastoma

Children's Oncology Group's 2023 blueprint for research: Liver tumors

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