Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma

Abstract

Pancreatoblastoma is a rare pediatric pancreatic malignancy for which the molecular pathogenesis is not understood. In this study, we report the findings of an integrated multiomics study of whole-exome and RNA sequencing as well as genome-wide copy number and methylation analyses of ten pancreatoblastoma cases. The pancreatoblastoma genome was characterized by a high frequency of aberrant activation of the Wnt signaling pathway, either via somatic mutations of (90%) and copy-neutral loss of heterozygosity (CN-LOH) of (10%). In addition, imprinting dysregulation of as a consequence of CN-LOH (80%), gain of paternal allele (10%), and gain of methylation (10%) was universally detected. At the transcriptome level, pancreatoblastoma exhibited an expression profile characteristic of early pancreas progenitor-like cells along with upregulation of the R-spondin/LGR5/RNF43 module. Our results offer a comprehensive description of the molecular basis for pancreatoblastoma and highlight rational therapeutic targets for its treatment. Molecular genetic analysis of a rare untreatable pediatric tumor reveals Wnt/IGF2 aberrations and features of early pancreas progenitor-like cells, suggesting cellular origins and rational strategies for therapeutic targeting. .

Pancreatic Neoplasms With Acinar Differentiation: A Review of Pathologic and Molecular Features

“…27 Metastatic pancreatoblastomas have been described with a higher number of somatic mutations, perhaps suggesting that additional mutations drive or are selected in metastasis. 57 Multiple studies have shown frequent alterations in the WNT signaling pathway in pancreatoblastomas, most commonly activating mutations in CTNNB1 but also loss of APC. 27,48,57 CTNNB1 is the most frequently altered gene in this tumor type and one of the only genes to date reported with somatic mutation in multiple pancreatoblastoma samples.…”

NOTCH1 pathway activating mutations and clonal evolution in pediatric T‐cell acute lymphoblastic leukemia

“…Intrasample subpopulations were estimated using a hierarchical Beta Binomial emission model implemented in PyClone 30 and the variational Bayesian beta mixture model in SciClone 31 as described previously. 32,33 Mutations in indels, for which VAFs were poorly estimated, were not used for the analysis. We constructed branchbased phylogenetic trees using a bootstrap resampling technique implemented in ClonEvol.…”

Pancreatoblastoma: Cytologic and histologic analysis of 12 adult cases reveals helpful criteria in their diagnosis and distinction from common mimics

“…This interesting angle warrants further investigation. Aberrant Wnt pathway activation manifests as somatic CTNNB1 mutations (in 90% of cases) and loss of heterozygosity (LOH) of APC (in 10%) . Other abnormalities include upregulation of the R‐spondin/LGR5/RNF43 module, a progenitor‐like pancreatic cell expression profile, and LOH of chromosome 11p .…”

“…Aberrant Wnt pathway activation manifests as somatic CTNNB1 mutations (in 90% of cases) and loss of heterozygosity (LOH) of APC (in 10%) . Other abnormalities include upregulation of the R‐spondin/LGR5/RNF43 module, a progenitor‐like pancreatic cell expression profile, and LOH of chromosome 11p . APC /β‐catenin pathway alterations are seen in patients with and without FAP, which has led some to propose that PBLs may represent an extracolonic manifestation of FAP .…”

“…These tumors were first defined by Becker in 1957, but the term pancreatoblastoma was not proposed until 1975 by Kissane and again by Horie et al in 1977 because of the tumor's morphologic resemblance to 7‐week‐old fetal pancreatic tissue . Since then, there have been several reports describing its clinicopathologic and molecular characteristics . In 1995, Klimstra et al established the histomorphologic features in an analysis of 14 cases—the largest series in the English literature.…”