Pediatric epithelial liver tumors
2024-10-04 Paola Dal Cin, PhD , Rita Alaggio, MD Affiliation1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
2.IRCCS Ospedale Bambino Gesu', Roma (Italy)
Keywords
Hepatoblastoma, hepatocellular carcinoma, fibrolamellar HCCClassification
Definition
Hepatoblastoma (HB) is the most common malignant liver tumor in children, follow by hepatocellular carcinoma (HCC). 1,2 HBs have the lowest somatic mutation rate with CTNNB1 mutations being the typical genetic alteration. 3 Recent genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups. 4,5 HCCs in children are still poorly characterized, and include two groups: those arising in the context of a cirrhosis from a pre-existing disease (metabolic disorders, more rarely previous B hepatitis.) or de novo. HCC show multiple molecular alterations in WNT pathway genes. 6 The genetic of fibrolamellar HCC is distinct from conventional HCC, with a DNAJB1::PRKACA fusion been the mainly genetic finding with consequent PRKACA expression, or rarely PRKAR1A mutations. 7
| Pediatric digestive system tumors | ||
|---|---|---|
| Pediatic epithelial liver tumors | Genetic marker(s) | |
| Hepatoblastoma (HB) | It is is the most common primary liver malignancy in children. Several genetic syndromes are associated with hepatoblastoma, 8 as well as, an increased incidence of hepatoblastoma have been reported in children with congenital anomalies e,g, trisomy 18. 3 | |
| HB has the lowest mutational burden among the pediatric tumors. CTNNB1 mutations are present in 90% of cases. Other genetic alterations have been identified, with prognostic significance: NFE2L mutations are associated to resistance to cisplatin; TERT mutations are associated with so-called hepatoblastoma with HCC-like features, 4 mostly in older children and IGF2 at 11p15.5 alterations, either through copy-neutral loss of heterozygosity or loss or gain of methylation. Several chromsosmal gains and losses were observed in HBs, with gains of 8q and 20 been associated in patient with poorer outcome and LOH of 11p15.5 with frequent relapse. 3 | ||
| Transcriptome profiling studies have demonstrated different molecular subtypes in HB related to histology (fetal versus embryonal) and predictive of prognosis. A recent study based on a 16 genes signature identified three molecular subgroups: HB1 (low risk), HB2 (high risk), and HB3 (intermediate risk) with different expression of hepatic progenitor markers e.g. LIN28B, SALL4, AFP, hepatobiliary e.g. HNF1A, NOTCH1, metabolic e.g.NFE2L2 and other cancer pathways e.g.TP53 and TERT.4 Further transcriptomic studies using 16 genes signature+vimentin have demontrated 3 HB groups: C1 and C2A and C2B related to two patterns of DNA methylation: Epi-CA, enriched with C1 and C2B tumors, and Epi-CB, enriched with C2 subtype tumors.5 Besides methylation, the overexpression of the 14q23 locus containing DLK1-DIO3 has been found in some hepatoblastomas. Integration of epigenetic classification and expression level of 14q23 led to a molecular risk stratification into: low risk (MRS-1), intermediate risk (MRS-2), high risk (MRS-3) tumors related with 3 year event free survivals of 91%, 82%, and 52%, respectively.5 | ||
| Fibrolamellar variant of hepatocellular carcinoma (FL-HCC) | It is a rare pediatric liver cancer with different features from conventional hepatocellular carcinoma (HCC). Genetically, it is characterized by DNAJB1::PRKACA fusion, resulting by a 400-kb intrachromosomal deletion in chromosome 19 p-arm. 9 Cytogenetic studies also demonstrated relatively chromosomally stable ploidy abnormalities with few large changes, compared to typical HCC. 10,11 | |
| However, DNAJB1::PRKACA fusion is neither exclusive nor diagnostic for fibrolamellar hepatocellular carcinoma, since has been reported in adult pancreatobiliary neoplasms 12 | ||
| Pediatric hepatocellular carcinoma (HCC) | Multiple molecular alterations in WNT pathway genes e.g. intragenic deletions of CTNNB1, APC inversions and AMER1 somatic mutations; and telomerase pathway genes (TERT} activation or ATRX mutation, with much less frequent TP53 mutations. 6 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 33183723 | 2020 | Pediatric Liver Tumors: Updates in Classification. | Cho SJ et al |
| 2 | 37536892 | 2023 | Mesenchymal Neoplasms of the Liver. | Papke DJ Jr et al |
| 3 | 35438389 | 2022 | Current Approaches in Hepatoblastoma-New Biological Insights to Inform Therapy. | Wu PV et al |
| 4 | 27775819 | 2017 | Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups. | Sumazin P et al |
| 5 | 32240714 | 2020 | Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications. | Carrillo-Reixach J et al |
| 6 | 30977242 | 2019 | Characterization of pediatric hepatocellular carcinoma reveals genomic heterogeneity and diverse signaling pathway activation. | Haines K et al |
| 7 | 36302754 | 2022 | The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma. | Bauer J et al |
| 8 | 32469081 | 2020 | Cancer diagnostic profile in children with structural birth defects: An assessment in 15,000 childhood cancer cases. | Schraw JM et al |
| 9 | 24578576 | 2014 | Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. | Honeyman JN et al |
| 10 | 25605237 | 2015 | The genomic landscape of fibrolamellar hepatocellular carcinoma: whole genome sequencing of ten patients. | Darcy DG et al |
| 11 | 37429175 | 2023 | Exploring the molecular pathogenesis, diagnosis and treatment of fibrolamellar hepatocellular carcinoma: A state of art review of the current literature. | Alshareefy Y et al |
| 12 | 31676785 | 2020 | DNAJB1-PRKACA fusions occur in oncocytic pancreatic and biliary neoplasms and are not specific for fibrolamellar hepatocellular carcinoma. | Vyas M et al |
Citation
Paola Dal Cin, PhD ; Rita Alaggio, MD
Pediatric epithelial liver tumors
Atlas Genet Cytogenet Oncol Haematol. 2024-10-04
Online version: http://atlasgeneticsoncology.org/solid-tumor/209268/pediatric-epithelial-liver-tumors
