Cited by 1,233BRCA gene mutations in cancerEpigenetics and DNA MethylationBreast Lesions and Carcinomas

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Promoter Hypermethylation and BRCA1 Inactivation in Sporadic Breast and Ovarian Tumors

Esteller, M.·2000·Journal of the National Cancer Institute

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Abstract

BACKGROUND: Inherited mutations in the BRCA1 gene may be responsible for almost half of inherited breast carcinomas. However, somatic (acquired) mutations in BRCA1 have not been reported, despite frequent loss of heterozygosity (LOH or loss of one copy of the gene) at the BRCA1 locus and loss of BRCA1 protein in tumors. To address whether BRCA1 may be inactivated by pathways other than mutations in sporadic tumors, we analyzed the role of hypermethylation of the gene's promoter region. METHODS: Methylation patterns in the BRCA1 promoter were assessed in breast cancer cell lines, xenografts, and 215 primary breast and ovarian carcinomas by methylation-specific polymerase chain reaction (PCR). BRCA1 RNA expression was determined in cell lines and seven xenografts by reverse transcription-PCR. P values are two-sided. RESULTS: The BRCA1 promoter was found to be unmethylated in all normal tissues and cancer cell lines tested. However, BRCA1 promoter hypermethylation was present in two breast cancer xenografts, both of which had loss of the BRCA1 transcript. BRCA1 promoter hypermethylation was present in 11 (13%) of 84 unselected primary breast carcinomas. BRCA1 methylation was strikingly associated with the medullary (67% methylated; P =.0002 versus ductal) and mucinous (55% methylated; P =.0033 versus ductal) subtypes, which are overrepresented in BRCA1 families. In a second series of 66 ductal breast tumors informative for LOH, nine (20%) of 45 tumors with LOH had BRCA1 hypermethylation, while one (5%) of 21 without LOH was methylated (P =.15). In ovarian neoplasms, BRCA1 methylation was found only in tumors with LOH, four (31%) of 13 versus none of 18 without LOH (P =.02). The BRCA1 promoter was unmethylated in other tumor types. CONCLUSION: Silencing of the BRCA1 gene by promoter hypermethylation occurs in primary breast and ovarian carcinomas, especially in the presence of LOH and in specific histopathologic subgroups. These findings support a role for this tumor suppressor gene in sporadic breast and ovarian tumorigenesis.

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Authors: Esteller, M.
Affiliations: Roswell Park Comprehensive Cancer Center (US)
Corresponding author: Esteller, M.
ORCID: Esteller, M.
Venue: Journal of the National Cancer Institute
Publisher: Oxford University Press (OUP)
Published: 2000-04-05
Volume: 92
Issue: 7
Pages: 564-569
ISSN: 0027-8874 (ISSN-L)
1460-2105
DOI: 10.1093/jnci/92.7.564
OpenAlex: W2160234594
Cited by: 1,233
References: 41
Citations by year: 2026: 20 · 2025: 33 · 2024: 37 · 2023: 46 · 2022: 49 · 2021: 40 · 2020: 53 · 2019: 43 · 2018: 60 · 2017: 48 · 2016: 52 · 2015: 69 · 2014: 56 · 2013: 57 · 2012: 69
FWCI: 22.63
Type: journal article
Language: en
Open access: closed
Locations: JNCI Journal of the National Cancer Institute (publishedVersion)
PubMed (publishedVersion)
EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
Funders: National Cancer Institute (R01CA043318, CA 43318)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Health Sciences › Medicine › Pathology and Forensic Medicine › Breast Lesions and Carcinomas
Keywords: BRCA1 promoter hypermethylation, sporadic breast cancer, ovarian cancer, loss of heterozygosity, gene silencing, tumor suppressor, medullary breast carcinoma, mucinous breast carcinoma, histological subtypes, epigenetic silencing, breast cancer xenografts
MeSH terms: Breast Neoplasms, Female, Humans, Methylation, Ovarian Neoplasms, Promoter Regions, Genetic, RNA, RNA, Neoplasm, Transplantation, Heterologous, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Carcinoma, Ductal, Breast, Genes, BRCA1, Loss of Heterozygosity, Reverse Transcriptase Polymerase Chain Reaction

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Promoter Hypermethylation and BRCA1 Inactivation in Sporadic Breast and Ovarian Tumors

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