Abnormalities of the ARF-p53 pathway in primary angiosarcomas of the liver

Hum Pathol. 2002 Sep;33(9):884-92. doi: 10.1053/hupa.2002.126880.


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.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA Methylation
  • DNA, Neoplasm / analysis
  • Female
  • Hemangiosarcoma / genetics*
  • Hemangiosarcoma / metabolism
  • Hemangiosarcoma / secondary
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Loss of Heterozygosity
  • Male
  • Microsatellite Repeats
  • Middle Aged
  • Polymerase Chain Reaction
  • Retrospective Studies
  • Sequence Analysis, DNA
  • Tissue Embedding / methods
  • Tumor Suppressor Protein p14ARF / genetics*
  • Tumor Suppressor Protein p14ARF / metabolism
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Vinyl Chloride / adverse effects


  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA, Neoplasm
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • Vinyl Chloride