Chromosome 9p21 loss and p16 inactivation in primary sclerosing cholangitis-associated cholangiocarcinoma.
BACKGROUND
Cholangiocarcinoma is a frequent complication of primary sclerosing cholangitis and is a leading cause of mortality in patients with this disease. The tumor suppressor gene p16 is commonly inactivated in many neoplasms; however, the role of p16 in the pathogenesis of cholangiocarcinoma is unclear. Therefore, we examined the role of p16 inactivation in the pathogenesis of cholangiocarcinoma associated with primary sclerosing cholangitis.


METHODS
Paraffin-embedded sections from 10 patients who developed cholangiocarcinoma in the setting of primary sclerosing cholangitis were examined. Chromosomal loss at 9p21 was determined using microsatellite analysis. Methylation of a CpG island in the promoter region of the p16 gene 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 examined (25%). Four of seven tumors (57%) analyzed by immunohistochemistry demonstrated an absence of p16 nuclear staining.


CONCLUSIONS
Loss of chromosome 9p21 and inactivation of the p16 tumor suppressor gene are common events in primary sclerosing cholangitis-associated cholangiocarcinoma and may play a role in the high incidence of cholangiocarcinoma in patients with primary sclerosing cholangitis.
Ahrendt
S A
SA
Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA.
Eisenberger
C F
CF
Yip
L
L
Rashid
A
A
Chow
J T
JT
Pitt
H A
HA
Sidransky
D
D
D000328:Adult; D000818:Animals; D001650:Bile Duct Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D002642:Chick Embryo; D018281:Cholangiocarcinoma / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015209:Cholangitis, Sclerosing / Q000150:complications*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology; D019942:Genes, p16 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008745:Methylation; D018895:Microsatellite Repeats; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000502:physiology
D019941:Cyclin-Dependent Kinase Inhibitor p16