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.
Copyright 2002 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Aged
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Aged, 80 and over
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / physiology*
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Child
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Cyclin-Dependent Kinase Inhibitor p15
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Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / physiology*
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Cyclin-Dependent Kinase Inhibitor p18
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Cyclin-Dependent Kinase Inhibitor p19
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclin-Dependent Kinases / biosynthesis
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Cyclin-Dependent Kinases / genetics
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Cyclin-Dependent Kinases / physiology*
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DNA Mutational Analysis
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DNA, Neoplasm / genetics
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Enzyme Inhibitors
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Female
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Granulosa Cell Tumor / enzymology*
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Granulosa Cell Tumor / genetics
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Granulosa Cell Tumor / pathology
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Humans
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Middle Aged
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Ovarian Neoplasms / enzymology*
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / pathology
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Retinoblastoma Protein / biosynthesis
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / physiology
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Tumor Suppressor Protein p14ARF / biosynthesis
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Tumor Suppressor Protein p14ARF / genetics
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Tumor Suppressor Protein p14ARF / physiology
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Tumor Suppressor Proteins / biosynthesis
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology
Substances
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CDKN2B protein, human
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CDKN2C protein, human
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CDKN2D protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p15
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p18
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Cyclin-Dependent Kinase Inhibitor p19
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DNA, Neoplasm
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Enzyme Inhibitors
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Retinoblastoma Protein
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinases