Bibliographic Details
| Title: |
Epigenetic silencing and deletion of the BRCA1gene in sporadic breast cancer |
| Authors: |
Birgisdottir, Valgerdur, Stefansson, Olafur, Bodvarsdottir, Sigridur, Hilmarsdottir, Holmfridur, Jonasson, Jon, Eyfjord, Jorunn |
| Source: |
Breast Cancer Research; August 2006, Vol. 8 Issue: 4 p1-10, 10p |
| Abstract: |
BRCA1or BRCA2germline mutations increase the risk of developing breast cancer. Tumour cells from germline mutation carriers have frequently lost the wild-type allele. This is predicted to result in genomic instability where cell survival depends upon dysfunctional checkpoint mechanisms. Tumorigenic potential could then be acquired through further genomic alterations. Surprisingly, somatic BRCAmutations are not found in sporadic breast tumours. BRCA1methylation has been shown to occur in sporadic breast tumours and to be associated with reduced gene expression. We examined the frequency of BRCA1methylation in 143 primary sporadic breast tumours along with BRCA1copy number alterations and tumour phenotype. Primary sporadic breast tumours were analysed for BRCA1αpromoter methylation by methylation specific PCR and for allelic imbalance (AI) at BRCA1and BRCA2loci by microsatellite analysis and TP53(also known as p53) mutations by constant denaturing gel electrophoresis. The BRCA1methylated tumours were analysed for BRCA1copy alterations by fluorescence in situhybridisation and BRCA1 expression by immunostaining. BRCA1methylation was found in 13/143 (9.1%) sporadic breast tumours. The BRCA1methylated tumours were significantly associated with estrogen receptor (ER) negativity (P = 0.0475) and displayed a trend for BRCA1AI (P = 0.0731) as well as young-age at diagnosis (≤ 55; P = 0.0898). BRCA1methylation was not associated with BRCA2AI (P = 0.5420), although a significant association was found between BRCA1AI and BRCA2AI (P < 0.0001). Absent/markedly reduced BRCA1 expression was observed in 9/13 BRCA1methylated tumours, most of which had BRCA1deletion. An elevated TP53mutation frequency was found among BRCA1methylated tumours (38.5%) compared with non-methylated tumours (17.2%). The BRCA1methylated tumours were mainly of tumour grade 3 (7/13) and infiltrating ductal type (12/13). Only one methylated tumour was of grade 1. BRCA1methylation is frequent in primary sporadic breast tumours. We found an indication for BRCA1methylation to be associated with AI at the BRCA1locus. Almost all BRCA1methylated tumours with absent/markedly reduced BRCA1 expression (8/9) displayed BRCA1deletion. Thus, epigenetic silencing and deletion of the BRCA1gene might serve as Knudson's two 'hits' in sporadic breast tumorigenesis. We observed phenotypic similarities between BRCA1methylated and familial BRCA1tumours, based on BRCA1deletion, TP53mutations, ER status, young age at diagnosis and tumour grade. |
| Database: |
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