Evidence of a role for the INK4 family of cyclin-dependent kinase inhibitors in ovarian granulosa cell tumors

Genes Chromosomes Cancer. 2002 Oct;35(2):176-81. doi: 10.1002/gcc.10108.

Abstract

Granulosa cell tumors (GCTs) of the ovary are relatively rare and account for <5% of all ovarian cancers. The molecular pathogenesis of these tumors is not well understood. We tested the hypothesis that cyclin-dependent kinase inhibitors, specifically the inhibitors of the cyclin-dependent kinase 4 (INK4) family, are targets for altered gene expression in GCTs. The status of RB1, INK4A, INK4B, INK4C, INK4D, and ARF in 13 adult and 2 juvenile ovarian GCTs was determined by reverse transcription-polymerase chain reaction of total RNA and exon-specific sequencing of genomic DNA. Tumors showing loss of INK4A expression were assayed further by exon-deletion analysis and methylation-specific PCR. None of the juvenile tumors demonstrated altered expression, but 7/12 (58%) adult GCTs lacked expression of INK4A, INK4B, or both. In one of these cases, we noted a homozygous deletion of the INK4A locus, and in the remaining tumors we found hypermethylation of the promoter region, a mechanism that can lead to gene inactivation. These data support a role for the INK4 family of CDK inhibitors in the biology of GCTs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / physiology*
  • Child
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / physiology*
  • Cyclin-Dependent Kinase Inhibitor p18
  • Cyclin-Dependent Kinase Inhibitor p19
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / biosynthesis
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / physiology*
  • DNA Mutational Analysis
  • DNA, Neoplasm / genetics
  • Enzyme Inhibitors
  • Female
  • Granulosa Cell Tumor / enzymology*
  • Granulosa Cell Tumor / genetics
  • Granulosa Cell Tumor / pathology
  • Humans
  • Middle Aged
  • Ovarian Neoplasms / enzymology*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Retinoblastoma Protein / biosynthesis
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / physiology
  • Tumor Suppressor Protein p14ARF / biosynthesis
  • Tumor Suppressor Protein p14ARF / genetics
  • Tumor Suppressor Protein p14ARF / physiology
  • Tumor Suppressor Proteins / biosynthesis
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology

Substances

  • CDKN2B protein, human
  • CDKN2C protein, human
  • CDKN2D protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p18
  • Cyclin-Dependent Kinase Inhibitor p19
  • DNA, Neoplasm
  • Enzyme Inhibitors
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinases