Genetic and epigenetic basis of hepatoblastoma diversity

Nagae, Genta; Yamamoto, Shozo; Fujita, Masashi; Fujita, Takanori; Nonaka, Aya; Umeda, Tomohiro; Fukuda, Shiro; Tatsuno, Kenji; Maejima, Kazuhiro; Hayashi, Akimasa; Kurihara, Sho; Kojima, Masato; Hishiki, Tomoro; Watanabe, Kenichiro; Ida, Kohmei; Yano, Michihiro; Hiyama, Yoko; Tanaka, Yukichi; Inoue, Takeshi; Ueda, Hiroki; Nakagawa, Hidewaki; Aburatani, Hiroyuki; Hiyama, Eiso

doi:10.1038/s41467-021-25430-9

Cited by 56 publications

(89 citation statements)

References 65 publications

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“…After quality control, we obtained 21,450 single-cell transcriptomes from PT and AT samples of HB. Based on the canonical marker gene expression, 3,085 cells were annotated as tumor cells ( GPC3, EPCAM, AFP, ALB, DLK1 ), while 18,365 cells were designed as non-tumor cells ( Figures 4D, E ) ( 44 , 45 ). We further confirmed the identity of tumor cells by evaluation of inferred segmental chromosomal alterations.…”

Section: Resultsmentioning

confidence: 99%

The Cellular and Molecular Landscape of Synchronous Pediatric Sialoblastoma and Hepatoblastoma

Yang

Zhan

et al. 2022

Front. Oncol.

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Sialoblastoma (SBL) is an infrequent embryonal malignant tumor originating from the salivary gland, resembling primitive salivary gland anlage, whereas hepatoblastoma (HB) is the most common pediatric liver malignancy. The simultaneous occurrence of both tumors is extremely rare. Here we reported a case of a 6-month-old infant diagnosed with synchronous SBL and HB. The patient received neoadjuvant chemotherapy followed by surgical resection. Fresh tissues of both tumors were collected before and after chemotherapy, which were further profiled by whole exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq). WES analysis revealed potential somatic driver mutation PIK3CA p.Glu454Lys for SBL and canonical mutation CTNNB1 p.Ser45Pro for HB. No shared somatic variants or common copy number alterations were found between SBL and HB primary tumor samples. Though scRNA-seq, single-cell atlases were constructed for both tumors. SBL may recapitulate a pre-acinar stage in the development of salivary gland, including basaloid, duct-like, myoepithelial-like, and cycling phenotypes. In the meantime, HB was composed of tumor cells resembling different stages of the liver, including hepatocyte-like, hepatic progenitor-like, and hepatoblast-like cells. After chemotherapy, both tumors were induced into a more mature phenotype. In terms of transcriptional signatures, SBL and HB showed enhanced expression of epithelial markers KRT8, KRT18, and essential embryo development genes SDC1, MDK, indicating the disruption of normal embryo epithelium development. Finally, heterozygous deleterious germline mutation BLM and FANCI were identified which could predispose the patient to higher cancer risk. It partially explained the reason for the co-occurrence of SBL and HB. Taken together, we provided valuable resources for deciphering cellular heterogeneity and adaptive change of tumor cells after chemotherapy for synchronous SBL and HB, providing insights into the mechanisms leading to synchronous pediatric tumors.

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Section: Resultsmentioning

confidence: 99%

The Cellular and Molecular Landscape of Synchronous Pediatric Sialoblastoma and Hepatoblastoma

Yang

Zhan

et al. 2022

Front. Oncol.

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“…22 Conversely, the genomic landscape of pediatric cHCC is heterogeneous and includes molecular alterations in genes that are frequently mutated in adult HCC, including CTNNB1 and TERT, although TP53 mutations appear to be less common in pediatric versus adult cHCCs. 23,24 Analyzing differences in outcomes between these types of hepatocellular neoplasms is complex, because both resection rates and transplantation rates differ between cell types. Early studies suggested improved (1.43, 61.16) .02…”

Section: Discussionmentioning

confidence: 99%

“…The DNAJB1 ‐ PRKACA fusion changes PKA activity and phosphorylation targets, 21 in addition to subsequent downstream transcriptomic changes 22 . Conversely, the genomic landscape of pediatric cHCC is heterogeneous and includes molecular alterations in genes that are frequently mutated in adult HCC, including CTNNB1 and TERT , although TP53 mutations appear to be less common in pediatric versus adult cHCCs 23,24 …”

Section: Discussionmentioning

confidence: 99%

Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study

Short

Kastenberg

Guo

et al. 2022

Cancer

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Background Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis. Methods A multi‐institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB‐HCC). Univariate and multivariate analyses identified predictors of mortality and relapse. RESULTS In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB‐HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio [HR], 1.63; P = .038), elevated α‐fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease‐free status at any point predicted survival. Conclusions This multi‐institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk‐stratified algorithms for children with HCC. Lay Summary This is the largest reported granular data set on children with hepatocellular carcinoma. The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes. This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.

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“…It is well known that beta-catenin mutation is a hallmark of HB, although results from recent whole-exome sequencing analyses have shown that other mutations are rarely seen in HB (Jia et al, 2014;Sumazin et al, 2016;Nagae et al, 2020;Carrillo-Reixach et al, 2021). This paucity of mutations has been reported in many pediatric tumors and may be correlated with their early age of onset (Vogelstein et al, 2013), indicating that epigenetic aberrations may be an important mechanism involved in the pathogenesis of HB.…”

Section: Introductionmentioning

confidence: 99%

Research Article Functional analysis of <i>OCIAD2</i> in hepatoblastoma

Matsushima¹,

Honda²,

Miyagi³

et al. 2022

Genet. Mol. Res.

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Hepatoblastoma (HB) is the most common malignant liver tumor in children; however, the molecular mechanisms responsible for its progression remain unclear. We previously identified hypermethylation of the ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2) as a poor prognostic factor for HB in a genome-wide methylation analysis of HB excision specimens. As it has been already reported that such hypermethylation of OCIAD2 dysregulates the expression of OCIAD2, to elucidate the function of OCIAD2 in HB, we evaluated altered cellular functions such as cell growth, invasion, and migration abilities using OCIAD2 overexpression cell lines of HB. In the in vitro analysis with OCIAD2 overexpression, no significant difference was observed in cell proliferation between the groups. However, migration and invasion abilities were significantly lower in OCIAD2 overexpressed cell lines. Second, overexpression of OCIAD2 reduced matrix metalloproteinase 2 (MMP2) levels in each cell line. These results suggest that OCIAD2 suppresses HB invasion and migration in relation to MMP2.

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Genetic and epigenetic basis of hepatoblastoma diversity

Cited by 56 publications

References 65 publications

The Cellular and Molecular Landscape of Synchronous Pediatric Sialoblastoma and Hepatoblastoma

The Cellular and Molecular Landscape of Synchronous Pediatric Sialoblastoma and Hepatoblastoma

Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study

Research Article Functional analysis of <i>OCIAD2</i> in hepatoblastoma

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