Distinctive Molecular Genetic Alterations in Sporadic and Familial Adenomatous Polyposis-Associated Pancreatoblastomas

Abstract

Pancreatoblastomas are unusual malignant neoplasms of the pediatric pancreas that may also rarely affect adults. The molecular pathogenesis of pancreatoblastomas is unknown. They are clinicopathologically distinct from adult pancreatic ductal adenocarcinomas, but their occasional occurrence in patients with Beckwith-Wiedemann syndrome and the case presented here of a pancreatoblastoma in an adult patient with familial adenomatous polyposis (FAP) suggests that they might bear a genetic similarity to other infantile embryonal tumors such as hepatoblastomas. We analyzed a series of nine pancreatoblastomas for mutations common to other embryonal malignancies including somatic alterations in the adenomatous polyposis coli (APC)/beta-catenin pathway and chromosome 11p, using immunohistochemistry for beta-catenin, 5q and 11p allelic loss assays, and direct DNA sequencing of exon 3 of the beta-catenin gene and the mutation cluster region of the APC gene. In addition, we analyzed the pancreatoblastomas for alterations found in adult-type pancreatic ductal adenocarcinomas including mutations in the K-ras oncogene and the p53 and DPC4 tumor suppressor genes, using direct DNA sequencing of exon 1 of K-ras and immunohistochemistry for p53 and Dpc4. Allelic loss on chromosome 11p was the most common genetic alteration in pancreatoblastomas, present in 86% (six of seven informative cases). Molecular alterations in the APC/beta-catenin pathway were detected in 67% (six of nine), including five neoplasms with activating mutations of the beta-catenin oncogene and the one FAP-associated tumor with biallelic APC inactivation (germline truncating mutation combined with loss of the wild-type allele); seven neoplasms showed abnormal nuclear accumulation of beta-catenin protein. In contrast, loss of Dpc4 protein expression was present in only two cases (one diffuse and one focal), and no alterations in the K-ras gene or p53 expression were detected. Our findings indicate that pancreatoblastomas are genetically distinct from the more common pancreatic ductal adenocarcinomas, but bear a close molecular pathogenesis to hepatoblastomas. In addition, pancreatoblastoma may represent an extracolonic manifestation of FAP.

Aberrant Nuclear Localization and Gene Mutation of β-catenin in Low-Grade Adenocarcinoma of Fetal Lung Type: Up-Regulation of the Wnt Signaling Pathway May Be a Common Denominator for the Development of Tumors that Form Morules

“…After submission of the manuscript, Abraham and associates reported frequent ␤-catenin gene mutations in sporadic pancreatoblastomas (43).…”

Solid Pseudopapillary Neoplasm of the Pancreas Associated with Familial Adenomatous Polyposis

“…The FAP-related mutation in APC activates the Wnt/β-catenin signaling pathway. As a result, the cytoplasmic β-catenin expression increases, as it does in cases involving the SPN-related CTNNB1 mutation (20). Therefore, patients with FAP may develop tumors commonly seen in those with CTNNB1.…”

A Rare Case of FAP in Kashmir Valley

“…However nowadays, a best diagnostic tool available is the genetic test which enables the early detection of the FAP predisposition even before the appearance of polyps on the colonic lumen. These genetic tests involves the isolation of the genomic DNA from the tissue/ blood of the potential high risk patients which is then subjected to analysis of APC gene mutations using PCR-SSCP technique [14,15].…”