p16INK4A-alterations in primary angiosarcoma of the liver.
OBJECTIVE
Alterations in the p16 (CDKN2/MTS-1/INK4A) gene have been implicated in the tumorigenesis of different human cancers. Recent evidence shows that transcriptional silencing as a consequence of hypermethylation of CpG islands is the predominant mechanism of p16INK4a gene inactivation in malignant epithelial tumors. This study was performed to determine whether alterations of p16 are involved in the development of angiosarcoma of the liver.


METHODS
The status of p16 was evaluated in 17 angiosarcomas of the liver by methylation-specific PCR (MSP), microsatellite analysis, DNA sequencing and immunohistochemical staining. The results obtained were correlated with histopathological variables and with patient survival.


RESULTS
Hypermethylation of the 5' CpG island of the p16 gene was found in 12 out of 17 (71%) angiosarcomas examined. Homozygous deletion at the p16 region was present in one case (6%), and loss of heterozygosity was present in two cases (12%). We failed to detect p16 gene missense mutations. The status of p16 correlated with neither histopathological factors nor with the prognosis of the patients with angiosarcomas.


CONCLUSIONS
These data suggest that inactivation of the p16 gene is a frequent event in angiosarcomas of the liver. The most common somatic alteration is promotor methylation of the p16 gene. We failed to establish p16 as independent prognostic factors in these tumors.
Tannapfel
A
A
Institute of Pathology, University of Leipzig, Germany. tana@medizin.uni-leipzig.de
Weihrauch
M
M
Benicke
M
M
Uhlmann
D
D
Hauss
J
J
Wrbitzky
R
R
Wittekind
C
C
D000368:Aged; D000369:Aged, 80 and over; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D017353:Gene Deletion; D006394:Hemangiosarcoma / Q000378:metabolism* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D019656:Loss of Heterozygosity; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016019:Survival Analysis
D019941:Cyclin-Dependent Kinase Inhibitor p16