title: Abnormalities of the ARF-p53 pathway in primary angiosarcomas of the liver.
abstract: The INK4a-ARF locus, located on chromosome 9p21, encodes 2 cell cycle-regulatory proteins, p16(INKa) and p14(ARF), acting through the Rb-CDK4 and p53 pathways. This study was done to investigate the contribution of the INK4a-ARF locus in tumorigenesis of angiosarcoma of the liver. Alterations of p14(ARF), p16(INKa), and p53 in primary liver angiosarcoma from 19 patients were analyzed by methylation-specific polymerase chain reaction (MSP), restriction enzyme-related polymerase chain reaction (RE-PCR), microsatellite analysis, and DNA sequencing. As a control group, 12 angiosarcomas from other organs were analyzed. Promoter methylation of p14(ARF) was found in 5 of 19 cases (26%), and p16(INKa) showed aberrant promoter methylation in 12 of 19 cases (63%). One tumor (5%) had homozygous deletion of the INK4a-ARF locus. Methylation and deletion correlated with loss of mRNA transcription. Methylated p14(ARF) appeared in the context of a methylated p16(INKa) promoter in 3 cases of the 5 angiosarcomas methylated at p14(ARF). p14(ARF) aberrant methylation was not related to the presence of p53 mutations, which was detected in 6 of 19 (32%) cases. Alterations of the INK4a-ARF locus or p53 as were not established independent prognostic factors in these tumors. In conclusion, our data indicate that the INK4a-ARF locus is frequently inactivated in angiosarcoma of the liver and occurs independently of p53 mutations.
authors.affiliation: Institute of Occupational Medicine, University of Hannover, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Weihrauch
authors.forename: Anett
authors.initials: A
authors.lastname: Markwarth
authors.forename: Gerhard
authors.initials: G
authors.lastname: Lehnert
authors.forename: Christian
authors.initials: C
authors.lastname: Wittekind
authors.forename: Renate
authors.initials: R
authors.lastname: Wrbitzky
authors.forename: Andrea
authors.initials: A
authors.lastname: Tannapfel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D006394:Hemangiosarcoma / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D016610:Tissue Embedding / Q000379:methods; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014752:Vinyl Chloride / Q000009:adverse effects
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D014752:Vinyl Chloride