p16(INK4a) alterations in chronic pancreatitis-indicator for high-risk lesions for pancreatic cancer.
BACKGROUND
p16(INK4a) alterations are considered to be an early event in pancreatic tumorigenesis and have been described in duct lesions adjacent to pancreatic cancers. This study evaluates whether duct lesions in chronic pancreatitis tissues of patients without pancreatic cancer also harbor genetic alterations in the p16(INK4a) tumor-suppressor gene, and thus represent high-risk precursors for pancreatic cancer.


METHODS
Tissues were obtained from 20 pancreatic specimens taken from patients operated on for histologically verified chronic pancreatitis. Pancreatic intraductal neoplasias (PanIN) were identified in hematoxylin-and-eosin-stained slides. p16 protein expression was investigated immunohistochemically in all specimens. DNA from PanIN and non-PanIN tissue was analyzed genetically for p16(INK4a) mutations by single-strand conformation variation analysis and direct sequencing of the encoding region. Additionally, p16(INK4a) promoter methylation was analyzed by a methylation specific polymerase test.


RESULTS
PanIN-1a lesions were identified in 10 of the 20 chronic pancreatitis specimens. Four of these 10 PanIN specimens (40%), but none of the 20 non-PanIN tissues, revealed a loss of p16 expression in immunohistochemistry. The mutational analysis of the p16(INK4a) gene showed 1 known polymorphism (c.442G > A; A148T) but no mutations. Two of the 10 specimens with PanIN revealed an inactivating hypermethylation of the p16(INK4a) promoter.


CONCLUSIONS
This study shows for the first time that p16(INK4a) alterations can be observed in a considerable number of PanIN1 in chronic pancreatitis tissues not associated with pancreatic cancer. Therefore, p16(INK4a) alterations, especially promoter methylation, might indicate high-risk precursors in chronic pancreatitis that might progress to cancer.
Gerdes
B
B
Department of General Surgery, Philipps University of Marburg, Baldingerstrasse, 35033 Marburg, Germany.
Ramaswamy
A
A
Kersting
M
M
Ernst
M
M
Lang
S
S
Schuermann
M
M
Wild
A
A
Bartsch
D K
DK
D000328:Adult; D000368:Aged; D001483:Base Sequence; D002908:Chronic Disease; D019175:DNA Methylation; D017931:DNA Primers / Q000235:genetics; D005260:Female; D019942:Genes, p16; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000235:genetics*; D010195:Pancreatitis / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic; D012307:Risk Factors
D017931:DNA Primers