Genomic profiles of a hepatoblastoma from a patient with Beckwith-Wiedemann syndrome with uniparental disomy on chromosome 11p15 and germline mutation of APC and PALB2

Abstract

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth disorder mainly associated with altered genomic imprinting at chromosome 11p15.5. Children with BWS, especially uniparental disomy (UPD) at 11p15.5, are at increased risk of embryonal tumors including hepatoblastoma. Although genetic alterations of sporadic hepatoblastomas have been identified, integrated germline and somatic alterations of BWS-related hepatoblastoma have not been reported. For this, we performed whole-exome sequencing and genome-wide loss of heterozygosity/copy number analyses using a single nucleotide polymorphism (SNP) array for a hepatoblastoma in a BWS infant with paternal UPD at chromosome 11p15.5. We found germline 11p15.5 UPD as well as germline mutations of APC and PALB2 in the patient. At the somatic level, we found a CTNNB1 hotspot mutation and chromosome 1q gain in the tumor. The development of hepatoblastoma in this case might be explained by predisposition of the germline events (11p15.5 UPD, mutations of APC and PALB2) and later by somatic events with CTNNB1 somatic mutation and 1q gain. To our knowledge, this is the first report of germline and somatic genomic alteration profiles in hepatoblastoma arising from BWS. Clinically, our results provide a rationale for performing a more strict and intense protocol for hepatoblastoma surveillance in a high-risk BWS infant, such as the UPD-carrying case, for early detection and treatment.

Defining an optimal time window to screen for hepatoblastoma in children with Beckwith‐Wiedemann syndrome

“…A total of 76 patients with BWSp and HB were identified (64 from the literature and 12 unpublished patients from the authors’ cohorts; 10 Kalish/Duffy, 2 Musso/Ferrero).…”

NRAS and KRAS polymorphisms are not associated with hepatoblastoma susceptibility in Chinese children

“…Hepatoblastoma is a rare pediatric embryonic tumor with incidence of about 1/1,000,000 [33], and is often associated with chromosomal abnormalities, especially at chromosome 2, 11, 18, and 20 [34]. However, the relative risk of hepatoblastoma is 2280 times higher in children with Beckwith–Wiedemann syndrome, indicating that aberrations in chromosome 11 play an important role in pathogenesis [35]. Similarly, the risk is 1220-fold higher in children with familial adenomatous polyposis, implying that lesions in chromosome 5 are also involved [36].…”

Computational tools to detect signatures of mutational processes in DNA from tumours: A review and empirical comparison of performance

“…distinct defective DNA repair processes). In order to estimate E and P , it has been proposed to consider E as latent data and P as a matrix of unknown parameters and to apply an expectation-maximization algorithm [9] or use Bayesian approaches [10–12]. One important advantage of statistical approaches is the availability of model selection techniques for the choice of N .…”