p16(INK4a) alterations in chronic pancreatitis-indicator for high-risk lesions for pancreatic cancer

Background. p16INK4a alterations are considered to be an early event in pan creatic tumorigenesis and have been described in duct lesions adjacent to p ancreatic cancers. This study evaluates whether duct lesions in chronic pan creatitis tissues of patients without pancreatic cancer also harbor genetic alterations in the p16INK4a tumor-suppressor gene, and thus represent high -risk precursors for pancreatic cancer. Methods. Tissues were obtained from 20 pancreatic specimens taken from pati ents operated on for histologically verified chronic pancreatitis. Pancreat ic intraductal neoplasias (PanIN) were identified in hematoxylin-and-eosin- stained slides. p16 protein expression was investigated immunohistochemical ly in all specimens. DNA from PanIN and non-PanIN tissue was analyzed genet ically for p16INK4a mutations by single-strand conformation variation analy sis and direct sequencing of the encoding region. Additionally, p16INK4a pr omoter methylation was analyzed by a methylation specific polymerase test. Results. PanIN-1a lesions were identified in 10 of the 20 chronic pancreati tis specimens. Four of these 10 PanIn-1a specimens (40%), but none of the 2 0 non-PanIN tissues, revealed a loss of p16 expression in immunohistochemis try. The mutational analysis of the p16INK4a gene showed 1 known polymorphi sm (c.442G > A; A148T) but no mutations. Two of the 10 specimens with PanIN revealed an inactivating hypermethylation of the p16INK4a promoter. Conclusions. This study shows for the first time that p16INK4a alterations can be observed in a considerable number of PanIN1 in chronic pancreatitis tissues not associated with pancreatic cancer. Therefore, p16INK4a alterati ons, especially promoter methylation, might indicate high-risk precursors i n chronic pancreatitis that might progress to cancer.