Occurrence of Hepatoblastomas in Patients with Beckwith–Wiedemann Spectrum (BWSp)

SIMPLE SUMMARY: Beckwith–Wiedemann syndrome (BWS) is an overgrowth and cancer predisposition disorder that is associated with increased risk of hepatoblastoma (HB), a liver tumor, and Wilms tumors (WTs), a kidney tumor. Patients with BWS are screened for these tumors during their childhood. In this study, we present 16 cases of BWS with HB, focusing on their molecular diagnosis and clinical phenotype. We obtained liver and matched HB samples from 8 of the 16 cases and tumor-only samples from 2 additional cases. By analyzing the molecular subtypes of these liver samples, we were able to stratify BWS-HB into three distinct groups, providing insight into the oncogenesis of HB. Based on our data, we suggest that organ-specific mosaicism is a major hurdle for genotype–phenotype correlation within BWS. ABSTRACT: Patients with Beckwith–Wiedemann syndrome (BWS), an epigenetic imprinting disorder involving alterations in genes at the 11p15 chromosomal location, are predisposed to develop hepatoblastomas (HBs), which are rare embryonal liver tumors. Tumors can develop after a BWS diagnosis or, conversely, can be the presenting feature leading to a subsequent diagnosis. While HBs are the cardinal tumors of BWS, not all patients with the BWS spectrum will develop HBs. This observation has led to many hypotheses, including genotype-associated risk, tissue mosaicism, and tumor-specific second hits. To explore these hypotheses, we present the largest cohort of patients with BWS and HBs to date. Our cohort comprised 16 cases, and we broadened our sample size by searching the literature for all cases of BWS with HBs. From these isolated case studies, we amassed another 34 cases, bringing the total number to 50 cases of BWS-HB. We observed that paternal uniparental isodisomy (upd(11)pat) was the most common genotype, representing 38% of cases. The next most common genotype was IC2 LOM, representing 14% of cases. Five patients had clinical BWS without a molecular diagnosis. To investigate the potential mechanism of HBs in BWS, we analyzed normal liver and HB samples from eight cases and isolated tumor samples from another two cases. These samples underwent methylation testing, and 90% of our tumor samples underwent targeted cancer next-generation sequencing (NGS) panels. These matched samples provided novel insights into the oncogenesis of HBs in BWS. We found that 100% of the HBs that underwent NGS panel testing had variants in the CTNNB1 gene. We further identified three distinct groups of BWS-HB patients based on epigenotype. We also demonstrated epigenotype mosaicism, where 11p15 alterations can differ between the blood, HB, and normal liver. In light of this epigenotype mosaicism, tumor risk assessment based on blood profiling may not be accurate. Therefore, universal screening is recommended for all patients with BWS.