Epigenetic factors controlling the BRCA1 and BRCA2 genes in sporadic ovarian cancer.
Hypermethylation of the BRCA1 promoter has previously been shown to cause reduced mRNA expression in both breast and ovarian cancers. Nothing is yet known of the expression pattern or methylation status of the promoter region of BRCA2 in sporadic ovarian cancer. Whereas our analysis of 30 sporadic ovarian carcinomas showed a statistically significant reduction of BRCA1 mRNA expression (P = 0.001), it also showed, in contrast, overexpression of BRCA2 mRNA (P = 0.002) in tumor compared with nontumor. Hypermethylation of the BRCA1 promoter highly correlated with decreased BRCA1 expression (P = 0.017). Methylated CpGs at the BRCA2 promoter were either absent or at very low levels in tumor DNA, whereas they were present at high levels in nontumor DNA. Such hypomethylation also correlated with elevated levels of BRCA2 mRNA (P = 0.043) and showed a statistically significant correlation with tumor stage (P = 0.037). This supports the role of methylation in BRCA2 contributing to the pathogenesis of sporadic ovarian cancer. Furthermore, 14 (58.2%) and 9 (56.3%) of all of the cases with aberrant BRCA mRNA expression and methylation patterns, respectively, demonstrated opposing mRNA expression and methylation patterns of the BRCA1 and BRCA2 genes within the same cases. Our findings suggest that both genes may be involved in the development of sporadic ovarian cancer.
Department of Pathology, Queen Mary Hospital and the University of Hong Kong, Hong Kong.
Kelvin Y K
KY
Chan
Hilmi
H
Ozçelik
Annie N Y
AN
Cheung
Hextan Y S
HY
Ngan
Ui-Soon
US
Khoo
D000483:Alleles; D001483:Base Sequence; D019175:DNA Methylation; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012333:RNA, Messenger