Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor β-catenin mutations Journal Article


Authors: Abraham, S. C.; Klimstra, D. S.; Wilentz, R. E.; Yeo, C. J.; Conlon, K.; Brennan, M.; Cameron, J. L.; Wu, T. T.; Hruban, R. H.
Article Title: Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor β-catenin mutations
Abstract: Solid-pseudopapillary tumors (SPTs) are unusual pancreatic neoplasms of low malignant potential that most frequently affect young women. Genetic events contributing to the development of SPTs are unknown. Whereas the more common ductal adenocarcinomas of the pancreas essentially never harbor β-catenin or APC gene mutations, we have recently identified alterations of the APC/β-catenin pathway in other nonductal pancreatic neoplasms including pancreatoblastomas and acinar cell carcinomas. We analyzed a series of 20 SPTs for somatic alterations of the APC/β-catenin pathway using immunohistochemistry for β-catenin protein accumulation, direct DNA sequencing of β-catenin exon 3, and direct DNA sequencing of the mutation cluster region in exon 15 of the APC gene in those SPTs that did not harbor β-catenin mutations. Immunohistochemical labeling for cyclin D1 was performed to evaluate the overexpression of this cell-cycle protein as one of the putative downstream effectors of β-catenin dysregulation. In addition, we analyzed the SPTs for genetic alterations commonly found in pancreatic ductal adenocarcinomas, including mutations in the K-ras oncogene and p53 and Dpc4 tumor suppressor genes, using direct DNA sequencing of K-ras and immunostaining for p53 and DPC4. Almost all SPTs harbored alterations in the APC/β-catenin pathway. Nuclear accumulation of β-catenin protein was present in 95% (19 of 20), and activating β-catenin oncogene mutations were identified in 90% (18 of 20) of the SPTs. Seventy-four percent (14 of 19) showed overexpression of cyclin D1, ranging from 10 to 70% of tumor nuclei. In contrast, no K-ras mutations were present in any of the 20 SPTs, and Dpc4 expression was intact in all 16 SPTs for which immunohistochemical labeling was successful. Overexpression of p53 was limited to only 3 of 19 (15.8%) SPTs. These results emphasize the two distinct, divergent genetic pathways of neoplastic progression in pancreatic ductal and nonductal neoplasms.
Keywords: immunohistochemistry; adolescent; adult; clinical article; human tissue; aged; middle aged; gene cluster; gene mutation; exon; mutation; pancreatic neoplasms; cell cycle protein; gene overexpression; gene expression; protein p53; gene expression regulation; tumor suppressor gene; molecular sequence data; pancreas duct; pancreas tumor; pancreas adenocarcinoma; base sequence; dna sequence; trans-activators; oncogene k ras; genes, ras; tumor growth; cyclin d1; acinar cell carcinoma; beta catenin; apc protein; genes, p53; carcinoma, ductal, breast; cytoskeletal proteins; cystadenoma, papillary; humans; human; male; female; priority journal; article
Journal Title: American Journal of Pathology
Volume: 160
Issue: 4
ISSN: 0002-9440
Publisher: Elsevier Science, Inc.  
Date Published: 2002-04-01
Start Page: 1361
End Page: 1369
Language: English
PUBMED: 11943721
PROVIDER: scopus
PMCID: PMC1867216
DOI: 10.1016/S0002-9440(10)62563-1
DOI/URL:
Notes: Export Date: 14 November 2014 -- Source: Scopus
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MSK Authors
  1. Murray F Brennan
    788 Brennan
  2. Kevin C Conlon
    114 Conlon
  3. David S Klimstra
    857 Klimstra