Chromosome 9p21 loss and p16 inactivation in primary sclerosing cholangitis-associated cholangiocarcinoma

Background. Cholangiocarcinoma is a frequent complication of primary sclero sing cholangitis and is a leading cause of mortality in patients with this disease. The tumor suppressor gene p16 is commonly inactivated in many neop lasms; however, the role of p16 in the pathogenesis of cholangiocarcinoma i s unclear. Therefore, we examined the role of p16 inactivation in the patho genesis of cholangiocarcinoma associated with primary sclerosing cholangiti s, Materials and methods. Paraffin-embedded sections from PO patients who deve loped cholangiocarcinoma in the setting of primary sclerosing cholangitis w ere examined. Chromosomal loss at 9p21 was determined using microsatellite analysis. Methylation of a CpG island in the promoter region of the p16 gen e was determined using methylation-specific polymerase chain reaction. p16 inactivation was also determined using immunohistochemistry. Results. Allelic loss at chromosome 9p21 was present in 9 of 10 tumors (90% ). Methylation of the p16 promoter was present in 2 of the 8 tumors examine d (25%). Four of seven tumors (57%) analyzed by immunohistochemistry demons trated an absence of p16 nuclear staining. Conclusions. Loss of chromosome 9p21 and inactivation of the p16 tumor supp ressor gene are common events in primary sclerosing cholangitis-associated cholangiocarcinoma and may play a role in the high incidence of cholangioca rcinoma in patients with primary sclerosing cholangitis. (C) 1999 Academic Press.