Unraveling the Genetic Architecture of Hepatoblastoma Risk: Birth Defects and Increased Burden of Germline Damaging Variants in Gastrointestinal/Renal Cancer Predisposition and DNA Repair Genes

Abstract

The ultrarare hepatoblastoma (HB) is the most common pediatric liver cancer. HB risk is related to a few rare syndromes, and the molecular bases remain elusive for most cases. We investigated the burden of rare damaging germline variants in 30 Brazilian patients with HB and the presence of additional clinical signs. A high frequency of prematurity (20%) and birth defects (37%), especially craniofacial (17%, including craniosynostosis) and kidney (7%) anomalies, was observed. Putative pathogenic or likely pathogenic monoallelic germline variants mapped to 10 cancer predisposition genes (CPGs: APC, CHEK2, DROSHA, ERCC5, FAH, MSH2, MUTYH, RPS19, TGFBR2 and VHL) were detected in 33% of the patients, only 40% of them with a family history of cancer. These findings showed a predominance of CPGs with a known link to gastrointestinal/colorectal and renal cancer risk. A remarkable feature was an enrichment of rare damaging variants affecting different classes of DNA repair genes, particularly those known as Fanconi anemia genes. Moreover, several potentially deleterious variants mapped to genes impacting liver functions were disclosed. To our knowledge, this is the largest assessment of rare germline variants in HB patients to date, contributing to elucidate the genetic architecture of HB risk.

Dual Molecular Diagnoses of Recessive Disorders in a Child from Consanguineous Parents: Case Report and Literature Review

“…On the other hand, clinical reevaluation, biochemical analysis of 7-DHC, and finding the same homozygous variant in the DHCR7 gene in her healthy mother do not support that this variant is contributing to the patient’s phenotype. These findings support that the c.988G>A variant in exon 9 of the DHCR7 gene is not deleterious and is in line with more recent findings by Saskin et al (2017) [ 51 ], Kars et al (2021) [ 52 ], and Aguiar et al (2022) [ 53 ], in which this variant was classified as class 3.…”

A rare case of hepatoblastoma in a syndromic child with a de novo germline JAG1 mutation

“…[1][2][3] A few genetic syndromes increase the risk for hepatoblastoma development, although the full mutational spectrum remains poorly elucidated. [4][5][6][7] Herein, we describe a male child presenting with global developmental delay, facial dysmorphisms, and a complex congenital heart defect (scimitar syndrome with total anomalous pulmonary venous return) who developed hepatoblastoma, evolving to a fatal outcome (detailed clinical data available in the Supporting Information). Physical examination at age 2 revealed craniofacial dysmorphisms (Figure 1A), holosystolic heart murmur, abdominal distention, umbilical hernia, and prominent calcanei.…”

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

“…HB occurs with an approximate incidence of two cases per million children per year in the United States 1 . Only a minority of patients carry a germline predisposition associated with an increased incidence of HB 7–10 . Low birth weight confers the highest relative risk of developing HB, particularly for premature infants born at less than 1000 g, although the etiology of this risk remains unclear 11 .…”

“…1 Only a minority of patients carry a germline predisposition associated with an increased incidence of HB. [7][8][9][10] Low birth weight confers the highest relative risk of developing HB, particularly for premature infants born at less than 1000 g, although the etiology of this risk remains unclear. 11 The incidence of HB has increased globally over the last decade potentially secondary to the improved survival of premature infants.…”