CpG methylation of the FHIT, FANCF, cyclin-D2, BRCA2 and RUNX3 genes in Granulosa cell tumors (GCTs) of ovarian origin.
BACKGROUND
Granulosa cell tumors (GCTs) are relatively rare and are subtypes of the sex-cord stromal neoplasms. Methylation induced silencing in the promoters of genes such as tumor suppressor genes, DNA repair genes and pro-apoptotic genes is recognised as a critical factor in cancer development.


METHODS
We examined the role of promoter hypermethylation, an epigenetic alteration that is associated with the silencing tumor suppressor genes in human cancer, by studying 5 gene promoters in 25 GCTs cases by methylation specific PCR and RT-PCR. In addition, the compatible tissues (normal tissues distant from lesion) from three non-astrocytoma patients were also included as the control.


RESULTS
Frequencies of methylation in GCTs were 7/25 (28 % for FHIT), 6/25 (24% for FNACF), 3/25 (12% for Cyclin D2), 1/25 (4% for BRCA2) and 14/25 (56%) in RUNX3 genes. Correlation of promoter methylation with clinical characteristics and other genetic changes revealed that overall promoter methylation was higher in more advanced stage of the disease. Promoter methylation was associated with gene silencing in GCT cell lines. Treatment with methylation or histone deacetylation-inhibiting agents resulted in profound reactivation of gene expression.


CONCLUSIONS
These results may have implications in better understanding the underlying epigenetic mechanisms in GCT development, provide prognostic indicators, and identify important gene targets for treatment.
Dhillon
Varinderpal S
VS
CSIRO Health Sciences and Nutrition, Gate No 13, Kintore Avenue, PO Box 10041, Adelaide BC, Adelaide SA 5000, Australia. varinderpal.dhillon@csiro.au
Shahid
Mohd
M
Husain
Syed Akhtar
SA
D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D000328:Adult; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D024682:BRCA2 Protein / Q000235:genetics*; D045744:Cell Line, Tumor; D050677:Core Binding Factor Alpha 3 Subunit; D018899:CpG Islands / Q000235:genetics*; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics*; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics*; D052219:Fanconi Anemia Complementation Group F Protein; D005260:Female; D020868:Gene Silencing / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006106:Granulosa Cell Tumor / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D024682:BRCA2 Protein; D050677:Core Binding Factor Alpha 3 Subunit; D056742:Cyclin D2; D016213:Cyclins; D004268:DNA-Binding Proteins; D052219:Fanconi Anemia Complementation Group F Protein; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D000099170:Bis(5'-adenosyl)triphosphatase; C080336:CCND2 protein, human; C499901:FANCF protein, human; C493729:Runx3 protein, human