Rita Alaggio | PubMed Health

PubMed2026

Asynchronous transitions from high-risk hepatoblastoma to carcinoma.

BACKGROUND & AIMS: Most pediatric hepatocellular tumors are classified as hepatoblastoma (HB) or hepatocellular carcinoma (HCC), yet a subset exhibits mixed histological and molecular features. These hepatoblastomas with carcinoma features (HBCs) include cases provisionally designated as hepatocellular neoplasm-not otherwise specified (HCN-NOS). Their biology remains poorly understood, with unresolved questions about their cellular composition and outcomes. It is unclear whether HBCs comprise hybrid cells with combined HB and HCC characteristics (HBC cells) or admixtures of distinct HB and HCC cells. We characterized the biology, etiology, cellular composition, and evolutionary dynamics of HBCs. METHODS: We performed multi-omics profiling - including single-nucleus RNA sequencing, single-nucleus DNA sequencing, and multi-region longitudinal bulk RNA and DNA sequencing - to characterize HBC composition, evolution, and treatment response. Two-thirds of our samples were post-chemotherapy resections. RESULTS: HBCs comprise heterogeneous mixtures of HB-like, HBC-like, and HCC-like molecular cell types. Outcomes in HBC are significantly worse than in HB, and HBC cells are more chemoresistant than HB cells, with resistance shaped by their cell identity, genetic alterations, and embryonic differentiation stage. HBC cells originate from HB cells that were arrested at early hepatic stem cell development stages because of aberrant WNT signaling activation. Inhibition of WNT signaling promoted differentiation and enhanced sensitivity to chemotherapy. Furthermore, each analyzed HBC reflected a dynamic process of multiple HB-to-HBC and HBC-to-HCC transitions, underscoring their evolutionary complexity. A limitation of our study is our inability to pinpoint the role of chemotherapy-induced genome modifications. CONCLUSIONS: Multi-omics profiling of HBCs revealed key insights into their biology and composition, demonstrating that they originate from HB precursors at early hepatic stem cell development stages and that their differentiation arrest depends on sustained aberrant WNT signaling activity. IMPACT AND IMPLICATIONS: Hepatoblastomas with carcinoma features (HBCs) represent a poorly understood subset of pediatric liver tumors with mixed characteristics of hepatoblastoma (HB) and hepatocellular carcinoma (HCC). Using multi-omics profiling, we show that HBCs comprise heterogeneous mixtures of HB-like, intermediate HBC-like, and HCC-like cell populations that arise from HB precursors arrested at early hepatic stem cell developmental stages due to aberrant WNT signaling. This differentiation arrest contributes to chemoresistance and poorer clinical outcomes compared with HB. Importantly, pharmacologic inhibition of WNT signaling promoted differentiation and increased chemotherapy sensitivity, suggesting a potential therapeutic strategy. These findings refine the biological classification of HBCs and highlight differentiation-based treatment approaches for this aggressive tumor subtype.

Multiomics↗

PubMed2025

Recurrent FGFR2 and PIK3CA Mutations in Sialoblastoma.

PURPOSE: Sialoblastoma is an extremely rare low-grade malignant salivary gland neoplasm that presents at birth or early infancy and has heterogeneous clinical behavior. Due to its rarity, the molecular landscape remains incompletely characterized. We aimed to expand the current understanding of the genetic alterations in sialoblastoma through comprehensive molecular analysis. METHODS: Five sialoblastoma cases were retrieved from four institutional archives. Clinical and pathologic review was performed, and targeted next-generation sequencing was conducted using clinically validated panels. Copy number analysis was performed on four cases. RESULTS: The cohort included five patients with tumors located in parotid gland (n = 2), minor salivary glands (n = 2), and submandibular gland (n = 1). Four patients were diagnosed before 6 months of age. Histologically, all tumors showed solid organoid nests with primitive basaloid cells, dense fibrous stroma, and mitotic activity ranging from 8 to 25 per 10 high-power fields. Recurrent FGFR2 p.C382R variants were identified in 80% (4/5) of cases. Additional alterations were seen in FGFR2 p.C382R mutated tumors, including PIK3CA hotspot mutations in two cases (p.R88Q, p.R38H) and a truncating FGFR2 variant (p.L776Rfs) in one. The single tumor that lacked FGFR2 mutations harbored a CTNNB1 p.I35T variant and showed more favorable histologic features. Copy number analysis revealed recurrent whole-chromosome gains of chromosomes 8, 10, and 11. CONCLUSION: A distinct subset of sialoblastoma has FGFR2 p.C382R hotspot mutation as the predominant driver mutation. Tumors with this mutation tend to have solid growth pattern, aggressive histologic features, and clinical behavior. The identification of concurrent genomic alterations expands the molecular landscape of this rare tumor. The detection of alternative drivers, such as CTNNB1 hotspot mutations typical of basal cell adenoma, also suggests that a subset of sialoblastoma may represent other salivary gland tumors presenting in infancy.

Humans↗