Evidence of a role for the INK4 family of cyclin-dependent kinase inhibitors in ovarian granulosa cell tumors.
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.
Department of Oncology, University of Calgary, Calgary, Canada.
Mayi Y
MY
Arcellana-Panlilio
R Maarten
RM
Egeler
Eva
E
Ujack
Anthony
A
Magliocco
Gavin C E
GC
Stuart
Stephen M
SM
Robbins
Max J
MJ
Coppes
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002648:Child; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050764:Cyclin-Dependent Kinase Inhibitor p19; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors; D005260:Female; D006106:Granulosa Cell Tumor / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology
C493966:CDKN2B protein, human; C493971:CDKN2C protein, human; C493974:CDKN2D protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050764:Cyclin-Dependent Kinase Inhibitor p19; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins; D018844:Cyclin-Dependent Kinases