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Molecular genetics of pancreatic intraepithelial neoplasia

  • Georg Feldmann
  • Robert Beaty
  • Ralph H. Hruban
  • Anirban Maitra
Topics: Current understanding of precursors to pancreatic cancer

Abstract

Background

Recent evidence suggests that noninvasive precursor lesions, classified as pancreatic intraepithelial neoplasia (PanIN), can progress to invasive pancreatic cancer. This review will discuss the major genetic alterations in PanIN lesions.

Methods

A comprehensive review of the literature was performed in order to find studies on the molecular profile of human PanIN lesions. In addition, recent publications on genetically engineered mouse models of preinvasive neoplasia and pancreatic cancers were reviewed.

Results

PanINs demonstrate abnormalities at the genomic (DNA), transcriptomic (RNA), and proteomic levels, and there is a progressive accumulation of molecular alterations that accompany the histological progression from low-grade PanIN-1A to high-grade PanIN-3 lesions. Molecular changes in PanINs can be classified as “early” (KRAS2 mutations, telomere shortening, p21WAF1/CIP1 up-regulation, etc.), “intermediate” (cyclin D1 up-regulation, expression of proliferation antigens, etc.), or “late” (BRCA2 and TP53 mutations, DPC4/SMAD4/MADH4 inactivation, etc.). All the genetic changes observed in PanINs are also found in invasive ductal adenocarcinomas, where they usually occur at a higher frequency. Genetically engineered mice expressing mutant Kras in the pancreas, with or without additional genetic alterations, provide a unique in vivo platform to study the pancreatic cancer progression model.

Conclusions

Molecular studies have been instrumental in establishing that PanIN lesions are the noninvasive precursors for invasive ductal adenocarcinomas. The availability of molecular date provides the basis for designing rational early detection strategies and therapeutic intervention trials before pancreatic neoplasms invade, with the intention of alleviating the dismal prognosis associated with this disease.

Keywords

Pancreatic Cancer Prostate Stem Cell Antigen Familial Pancreatic Cancer Pancreatic Intraepithelial Neoplasia PanIN Lesion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag Tokyo 2007

Authors and Affiliations

  • Georg Feldmann
    • 1
  • Robert Beaty
    • 1
  • Ralph H. Hruban
    • 1
    • 2
  • Anirban Maitra
    • 1
    • 2
    • 3
  1. 1.Department of PathologyThe Sol Goldman Pancreatic Cancer Research CenterBaltimoreUSA
  2. 2.Department of OncologyThe Sol Goldman Pancreatic Cancer Research CenterBaltimoreUSA
  3. 3.McKusick–Nathans Institute of Genetic MedicineJohns Hopkins University School of MedicineBaltimoreUSA

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