title: Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas : frequent alterations in the APC/beta-catenin pathway and chromosome 11p.
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.
authors.affiliation: Division of Gastrointestinal/Liver Pathology, the Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA. sabraham@jhmi.edu
authors.forename: S C
authors.initials: SC
authors.lastname: Abraham
authors.forename: T T
authors.initials: TT
authors.lastname: Wu
authors.forename: D S
authors.initials: DS
authors.lastname: Klimstra
authors.forename: L S
authors.initials: LS
authors.lastname: Finn
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.forename: C J
authors.initials: CJ
authors.lastname: Yeo
authors.forename: J L
authors.initials: JL
authors.lastname: Cameron
authors.forename: R H
authors.initials: RH
authors.lastname: Hruban
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000150:complications* / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D008967:Molecular Biology; D009154:Mutation / Q000235:genetics; D009373:Neoplasms, Germ Cell and Embryonal / Q000150:complications* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000150:complications* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics; D051176:beta Catenin
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D051176:beta Catenin