Genomic instability at both the base pair level and the chromosomal level is detectable in earliest PanIN lesions in tissues of chronic pancreatitis.
OBJECTIVE
Chronic pancreatitis (CP) is a predisposing disease for pancreatic carcinoma (PC), however, precise molecular mechanisms of cancer development in the background of CP are ill defined.


METHODS
A total of 443 laser-microdissected pancreatic intraepithelial neoplasias (PanINs), acinar-ductal metaplasia (ADM), and normal ducts from 21 patients with CP were analyzed for loss of heterozygosity (LOH) and immunohistochemical protein expression of p53, p16, and DPC4. Pancreatic intraepithelial neoplasias were analyzed for mutations in p53, p16, and Ki-ras genes by ABI sequencing. Aneuploidy was determined by fluorescence in situ hybridization with probes for chromosomes 3, 7, 8, and 17.


RESULTS
Loss of heterozygosity rate in PanIN-1 and ADM was between 1.7% (p53) and 5.8% (p16). In PanIN-3, p53 protein overexpression and loss of expression for p16 and DPC4 protein were seen. Heterozygous mutations of p53 and p16 without LOH were found in PanIN-1A and ADM, whereas homozygous mutations were found in PanIN-3. Aneuploidy increased from PanIN-1A to PanIN-3. Ki-ras mutations were discovered first in PanIN-1.


CONCLUSIONS
Heterozygous mutations of p53- and p16 genes together with chromosomal instability occur early in CP and are clonally expanded, but final inactivation mostly by LOH happens later in pancreatic carcinogenesis. Determination of aneuploidy in pancreatic juice may be of value for early detection and risk assessment in patients with long-standing CP.
Department of General and Visceral Surgery, University Goettingen, Goettingen, Germany.
Mario
M
Baumgart
Meike
M
Werther
Anke
A
Bockholt
Maria
M
Scheurer
Josef
J
Rüschoff
Wolfgang
W
Dietmaier
B Michael
BM
Ghadimi
Ernst
E
Heinmöller
D000328:Adult; D000368:Aged; D005260:Female; D019942:Genes, p16; D011905:Genes, ras; D042822:Genomic Instability; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics*; D050500:Pancreatitis, Chronic / Q000235:genetics*; D011230:Precancerous Conditions / Q000235:genetics*; D051901:Smad4 Protein / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016159:Tumor Suppressor Protein p53