Molecular genetics of pancreatic intraepithelial neoplasia

Georg Feldmann, Robert Beaty, Ralph H Hruban, Anirban Maitra

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)224-232
Number of pages9
JournalJournal of Hepato-Biliary-Pancreatic Surgery
Volume14
Issue number3
DOIs
StatePublished - May 2007

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Molecular Biology
Pancreatic Neoplasms
Neoplasms
Adenocarcinoma
Up-Regulation
Telomere Shortening
Mutation
Cyclin D1
Proteomics
Pancreas
RNA
Antigens
DNA

ASJC Scopus subject areas

  • Surgery

Cite this

Molecular genetics of pancreatic intraepithelial neoplasia. / Feldmann, Georg; Beaty, Robert; Hruban, Ralph H; Maitra, Anirban.

In: Journal of Hepato-Biliary-Pancreatic Surgery, Vol. 14, No. 3, 05.2007, p. 224-232.

Research output: Contribution to journalArticle

Feldmann, Georg ; Beaty, Robert ; Hruban, Ralph H ; Maitra, Anirban. / Molecular genetics of pancreatic intraepithelial neoplasia. In: Journal of Hepato-Biliary-Pancreatic Surgery. 2007 ; Vol. 14, No. 3. pp. 224-232.
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