Molecular genetics of pancreatic intraepithelial neoplasia.
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, p21(WAF1/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.
Feldmann
Georg
G
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Ross Bldg 632, Johns Hopkins University School of Medicine, 720 Rutland Ave., Baltimore, MD 21205, USA.
Beaty
Robert
R
Hruban
Ralph H
RH
Maitra
Anirban
A
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002278:Carcinoma in Situ / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics*; D018450:Disease Progression; D006801:Humans; D008967:Molecular Biology / Q000379:methods*; D009154:Mutation; D009857:Oncogenes / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm