2.50
Hdl Handle:
http://hdl.handle.net/2336/12543
Title:
Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer
Authors:
Birgisdottir, Valgerdur; Stefansson, Olafur A; Bodvarsdottir, Sigridur K; Hilmarsdottir, Holmfridur; Jonasson, Jon G; Eyfjord, Jorunn E
Citation:
Breast Cancer Res. 2006, 8(4):R38
Issue Date:
17-Jun-2006
Abstract:
INTRODUCTION: BRCA1 or BRCA2 germline 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 BRCA mutations are not found in sporadic breast tumours. BRCA1 methylation has been shown to occur in sporadic breast tumours and to be associated with reduced gene expression. We examined the frequency of BRCA1 methylation in 143 primary sporadic breast tumours along with BRCA1 copy number alterations and tumour phenotype. METHODS: Primary sporadic breast tumours were analysed for BRCA1alpha promoter methylation by methylation specific PCR and for allelic imbalance (AI) at BRCA1 and BRCA2 loci by microsatellite analysis and TP53 (also known as p53) mutations by constant denaturing gel electrophoresis. The BRCA1 methylated tumours were analysed for BRCA1 copy alterations by fluorescence in situ hybridisation and BRCA1 expression by immunostaining. RESULTS: BRCA1 methylation was found in 13/143 (9.1%) sporadic breast tumours. The BRCA1 methylated tumours were significantly associated with estrogen receptor (ER) negativity (P = 0.0475) and displayed a trend for BRCA1 AI (P = 0.0731) as well as young-age at diagnosis (< or = 55; P = 0.0898). BRCA1 methylation was not associated with BRCA2 AI (P = 0.5420), although a significant association was found between BRCA1 AI and BRCA2 AI (P < 0.0001).Absent/markedly reduced BRCA1 expression was observed in 9/13 BRCA1 methylated tumours, most of which had BRCA1 deletion. An elevated TP53 mutation frequency was found among BRCA1 methylated tumours (38.5%) compared with non-methylated tumours (17.2%). The BRCA1 methylated tumours were mainly of tumour grade 3 (7/13) and infiltrating ductal type (12/13). Only one methylated tumour was of grade 1. CONCLUSION: BRCA1 methylation is frequent in primary sporadic breast tumours. We found an indication for BRCA1 methylation to be associated with AI at the BRCA1 locus. Almost all BRCA1 methylated tumours with absent/markedly reduced BRCA1 expression (8/9) displayed BRCA1 deletion. Thus, epigenetic silencing and deletion of the BRCA1 gene might serve as Knudson's two 'hits' in sporadic breast tumorigenesis. We observed phenotypic similarities between BRCA1 methylated and familial BRCA1 tumours, based on BRCA1 deletion, TP53 mutations, ER status, young age at diagnosis and tumour grade.
Description:
To access full text version of this article. Please click on the hyperlink "Full Text" at the bottom of this page
Additional Links:
http://breast-cancer-research.com/content/8/4/R38

Full metadata record

DC FieldValue Language
dc.contributor.authorBirgisdottir, Valgerdur-
dc.contributor.authorStefansson, Olafur A-
dc.contributor.authorBodvarsdottir, Sigridur K-
dc.contributor.authorHilmarsdottir, Holmfridur-
dc.contributor.authorJonasson, Jon G-
dc.contributor.authorEyfjord, Jorunn E-
dc.date.accessioned2007-07-03T14:03:10Z-
dc.date.available2007-07-03T14:03:10Z-
dc.date.issued2006-06-17-
dc.date.submitted2007-07-03-
dc.identifier.citationBreast Cancer Res. 2006, 8(4):R38en
dc.identifier.issn1465-542X-
dc.identifier.pmid16846527-
dc.identifier.doi10.1186/bcr1522-
dc.identifier.urihttp://hdl.handle.net/2336/12543-
dc.descriptionTo access full text version of this article. Please click on the hyperlink "Full Text" at the bottom of this pageen
dc.description.abstractINTRODUCTION: BRCA1 or BRCA2 germline 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 BRCA mutations are not found in sporadic breast tumours. BRCA1 methylation has been shown to occur in sporadic breast tumours and to be associated with reduced gene expression. We examined the frequency of BRCA1 methylation in 143 primary sporadic breast tumours along with BRCA1 copy number alterations and tumour phenotype. METHODS: Primary sporadic breast tumours were analysed for BRCA1alpha promoter methylation by methylation specific PCR and for allelic imbalance (AI) at BRCA1 and BRCA2 loci by microsatellite analysis and TP53 (also known as p53) mutations by constant denaturing gel electrophoresis. The BRCA1 methylated tumours were analysed for BRCA1 copy alterations by fluorescence in situ hybridisation and BRCA1 expression by immunostaining. RESULTS: BRCA1 methylation was found in 13/143 (9.1%) sporadic breast tumours. The BRCA1 methylated tumours were significantly associated with estrogen receptor (ER) negativity (P = 0.0475) and displayed a trend for BRCA1 AI (P = 0.0731) as well as young-age at diagnosis (< or = 55; P = 0.0898). BRCA1 methylation was not associated with BRCA2 AI (P = 0.5420), although a significant association was found between BRCA1 AI and BRCA2 AI (P < 0.0001).Absent/markedly reduced BRCA1 expression was observed in 9/13 BRCA1 methylated tumours, most of which had BRCA1 deletion. An elevated TP53 mutation frequency was found among BRCA1 methylated tumours (38.5%) compared with non-methylated tumours (17.2%). The BRCA1 methylated tumours were mainly of tumour grade 3 (7/13) and infiltrating ductal type (12/13). Only one methylated tumour was of grade 1. CONCLUSION: BRCA1 methylation is frequent in primary sporadic breast tumours. We found an indication for BRCA1 methylation to be associated with AI at the BRCA1 locus. Almost all BRCA1 methylated tumours with absent/markedly reduced BRCA1 expression (8/9) displayed BRCA1 deletion. Thus, epigenetic silencing and deletion of the BRCA1 gene might serve as Knudson's two 'hits' in sporadic breast tumorigenesis. We observed phenotypic similarities between BRCA1 methylated and familial BRCA1 tumours, based on BRCA1 deletion, TP53 mutations, ER status, young age at diagnosis and tumour grade.en
dc.format.extent504649 bytes-
dc.format.mimetypeapplication/pdf-
dc.language.isoenen
dc.publisherBioMed Central Ltden
dc.relation.urlhttp://breast-cancer-research.com/content/8/4/R38en
dc.subject.meshAllelic Imbalanceen
dc.subject.meshBreast Neoplasmsen
dc.subject.meshGene Deletionen
dc.subject.meshFemaleen
dc.subject.meshGene Silencingen
dc.subject.meshGenes, BRCA1en
dc.subject.meshGenes, p53en
dc.subject.meshGerm-Line Mutationen
dc.subject.meshMethylationen
dc.subject.meshPhenotypeen
dc.titleEpigenetic silencing and deletion of the BRCA1 gene in sporadic breast canceren
dc.typeArticleen
dc.identifier.journalBreast cancer research : BCRen
dc.format.digYES-
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