The DOI matches its Crossref record; 39 of the 41 references it cites were found in a registry or an index.
Promoter Hypermethylation and BRCA1 Inactivation in Sporadic Breast and Ovarian Tumors
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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“Given that changes in BRCA1 promoter status contribute to sporadic tumors [64,65], mutations outside the reading frame or changes in promoter methylation status could alter FANCJ expression and contribute to tumorigenesis.”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [65]
In the citing paper
“Given that changes in BRCA1 promoter status contribute to sporadic tumors [64,65], mutations outside the reading frame or changes in promoter methylation status could alter FANCJ expression and contribute to tumorigenesis.”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [65]
Citations
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A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1
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Gene expression profiling predicts clinical outcome of breast cancer
van 't Veer, L. J., Dai, H., van de Vijver, M. J., He, Y. D., Hart, A. A. M., Mao, M., Peterse, H. L., van der Kooy, K., Marton, M. J., Witteveen, A. T., et al. (2002) · Nature · doi:10.1038/415530a · Cited by 9,536
“The one sporadic tumour that was classified as a BRCA1 tumour was shown to contain methylation of the BRCA1 promoter, indicating an epigenetic modification of BRCA1”
Integrated genomic analyses of ovarian carcinoma
Perou, C. M. (2019) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/hvp3-wg08 · Cited by 7,927
Foulkes, W. D., Smith, I. E., & Reis-Filho, J. S. (2010) · New England Journal of Medicine · doi:10.1056/nejmra1001389 · Cited by 4,719
The fundamental role of epigenetic events in cancer
Jones, P. A., & Baylin, S. B. (2002) · Nature Reviews Genetics · doi:10.1038/nrg816 · Cited by 5,648
Esteller, M. (2008) · New England Journal of Medicine · doi:10.1056/nejmra072067 · Cited by 3,767
Self-citation
Metadata
- 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
- 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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