BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study.
There is a clear association between germ-line BRCA1 mutations and inherited ovarian cancer; however, the association between BRCA1 mutations and sporadic ovarian cancer remains ambiguous. The frequency of BRCA1 promoter hypermethylation as an epigenetic means of BRCA1 inactivation was determined for a large, population-based cohort of ovarian cancer patients. BRCA1 promoter hypermethylation was determined by methylation-specific restriction digestion of tumor DNA, followed by Southern blot analysis and confirmed by methylation-specific PCR. BRCA1 promoter hypermethylation was observed in 12 of 98 ovarian tumors. BRCA1 methylation status of the primary tumor was conserved in six recurrent tumors after interim chemotherapy. None of the 12 tumors with BRCA1 promoter hypermethylation demonstrated BRCA1 protein expression by immunohistochemistry. BRCA1 methylation was only seen in ovarian cancer patients without a family history suggestive of a breast/ ovarian cancer syndrome. Therefore, the 12 BRCA1 methylated tumors represented 15% (12 of 81) of the sporadic cancers analyzed in this study. Although the clinical significance of BRCA1 promoter hypermethylation is yet to be determined, promoter hypermethylation may be an alternative to mutation in causing the inactivation of the BRCA1 tumor suppressor gene in sporadic ovarian cancer.
Baldwin
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RL
Division of Gynecologic Oncology, The Burns and Allen Research Institute. Cedars-Sinai Medical Center, Los Angeles, California 90048 USA. baldwin@cshs.org
Nemeth
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E
Tran
H
H
Shvartsman
H
H
Cass
I
I
Narod
S
S
Karlan
B Y
BY
D000483:Alleles; D015139:Blotting, Southern; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology; D019398:Genes, BRCA1 / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic / Q000235:genetics