Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas: Frequent alterations in the APC/β-catenin pathway and chromosome 11p Journal Article


Authors: Abraham, S. C.; Wu, T. T.; Klimstra, D. S.; Finn, L. S.; Lee, J. H.; Yeo, C. J.; Cameron, J. L.; Hruban, R. H.
Article Title: Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas: Frequent alterations in the APC/β-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)/β-catenin pathway and chromosome 11p, using immunohistochemistry for β-catenin, 5q and 11p allelic loss assays, and direct DNA sequencing of exon 3 of the β-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/β-catenin pathway were detected in 67% (six of nine), including five neoplasms with activating mutations of the β-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 β-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 extracoIonic manifestation of FAP.
Keywords: immunohistochemistry; adolescent; adult; child; clinical article; human tissue; protein expression; child, preschool; middle aged; unclassified drug; gene mutation; exon; mutation; dna-binding proteins; clinical feature; histopathology; pancreas cancer; pancreatic neoplasms; genetic analysis; protein localization; alleles; gene product; protein p53; carcinogenesis; tumor suppressor gene; dna; pancreas duct; pancreas adenocarcinoma; base sequence; dna sequence; neoplasms, germ cell and embryonal; trans-activators; oncogene k ras; genes, ras; molecular biology; loss of heterozygosity; beta catenin; chromosomes, human, pair 11; adenomatous polyposis coli protein; apc protein; adenomatous polyp; genes, p53; cytoskeletal proteins; smad4 protein; chromosome 5q; adenomatous polyposis coli; chromosome 11p; pancreatoblastoma; humans; human; male; female; priority journal; article
Journal Title: American Journal of Pathology
Volume: 159
Issue: 5
ISSN: 0002-9440
Publisher: Elsevier Science, Inc.  
Date Published: 2001-11-01
Start Page: 1619
End Page: 1627
Language: English
PUBMED: 11696422
PROVIDER: scopus
PMCID: PMC1867075
DOI: 10.1016/S0002-9440(10)63008-8
DOI/URL:
Notes: Export Date: 21 May 2015 -- Source: Scopus
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MSK Authors
  1. David S Klimstra
    865 Klimstra