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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Recommendations for biomarker testing in epithelial ovarian cancer: a National Consensus Statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology
Oaknin, A., Guarch, R., Barretina-Ginesta, M.-P., Hardisson, D., González-Martı́n, A., Matías‐Guiu, X., Fidalgo, J. A. P., Vieites, B., Romero, I., & Palacios, J. (2017) · Clinical & Translational Oncology · doi:10.1007/s12094-017-1719-x · Cited by 15
“BRCA1 promoter hypermethylation was identified in 5–30% of ovarian carcinomas, mainly HGSOC [47].”
Background
Breast cancer patients with hypermethylation in the promoter of BRCA1 gene exhibit favorable clinical status
Krasteva, M. E., Bozhanov, S. S., Antov, G., Gospodinova, Z. I., & Angelova, S. G. (2012) · Neoplasma · doi:10.4149/neo_2012_011 · Cited by 14
Targeting DNA repair in breast cancer
Paluch–Shimon, S., & Evron, E. (2019) · The Breast · doi:10.1016/j.breast.2019.06.007 · Cited by 14
Heritability of cervical tumours
Magnusson, P. K. E., Lichtenstein, P., & Gyllensten, U. B. (2000) · International Journal of Cancer · doi:10.1002/1097-0215(20001201)88:5 · Cited by 179
Impact of Structural Racism and Social Determinants of Health on Disparities in Breast Cancer Mortality
Falcone, M., Salhia, B., Halbert, C. H., Torres, E. T. R., Stewart, D. B., Stern, M. C., & Lerman, C. E. (2024) · Cancer Research · doi:10.1158/0008-5472.can-24-1359 · Cited by 16
A Phase Ib, Open-label Study Evaluating the Safety and Efficacy of Ipatasertib plus Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer
Pook, D. W., Geynisman, D. M., Carles, J., de Braud, F., Joshua, A. M., Perez‐Gracia, J. L., Pérez, C. L., Shin, S. J., Fang, B. S., Barve, M. A., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-2585 · Cited by 13
Impact of germline and somatic BRCA1/2 mutations: tumor spectrum and detection platforms
Wu, H., Wu, X., & Liang, Z. (2017) · Gene Therapy · doi:10.1038/gt.2017.73 · Cited by 13
Tsc2 mutation induces renal tubular cell nonautonomous disease
Kumar, P., Zadjali, F., Yao, Y., Johnson, D. L., Siroky, B. J., Astrinidis, A., Vogel, P., Gross, K. W., & Bissler, J. J. (2021) · Genes & Diseases · doi:10.1016/j.gendis.2021.03.010 · Cited by 13
“However, not all tumors exhibit losses of heterozygosity at this locus,(57) and there is little convincing evidence that the WT allele in these tumors is silenced by epigenetic mechanisms.(60) To better understand the role of BRCA1 in gynecological malignancy, Chodankar et al used a Cre-lox system to inactivate Brca1…”
Background
Cancer du sein chez l'homme
Beyrouti, M. I., Beyrouti, R., Beyrouti, R., Amar, M. B., Affes, N., Frikha, F., Abid, M., Mnif, H., Ayadi, L., & Ghorbel, A. (2007) · La Presse Médicale · doi:10.1016/j.lpm.2007.03.033 · Cited by 13
BRCA1 involvement in toxicological responses and human cancer etiology
Georgakilas, A. G., Aziz, K., Ziech, D., Georgakila, S., & Panayiotidis, M. I. (2009) · Toxicology Letters · doi:10.1016/j.toxlet.2009.04.006 · Cited by 13
Metastasis of Colorectal Cancer
Beauchemin, N., & Huot, J. (2010) · Cancer metastasis · doi:10.1007/978-90-481-8833-8 · Cited by 13
Induced pluripotent stem cell technology for dissecting the cancer epigenome
Semi, K., & Yamada, Y. (2015) · Cancer Science · doi:10.1111/cas.12758 · Cited by 12
PARP Inhibitors: A Major Therapeutic Option in Endocrine-Receptor Positive Breast Cancers
Collet, L., Péron, J., Penault-Llorca, F. M., Pujol, P., Lopez, J., Freyer, G., & You, B. (2022) · Cancers · doi:10.3390/cancers14030599 · Cited by 12
“In addition, silencing methylation of BRCA1 and BRCA2 promoters was reported in 2–4% of patients [39,43,46].”
Background
MicroRNA-155-5p, Reduced by Curcumin-Re-Expressed Hypermethylated BRCA1, Is a Molecular Biomarker for Cancer Risk in BRCA1-methylation Carriers
Al‐Moghrabi, N., Al‐Showimi, M., Al‐Yousef, N., & AlOtai, L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24109021 · Cited by 12
“BRCA1 inactivation via DNA promoter methylation is an alternative mechanism involved in sporadic BC and OC carcinogenesis [5,6].”
Background
The Use of Reverse Phase Protein Arrays (RPPA) to Explore Protein Expression Variation within Individual Renal Cell Cancers
O’Mahony, F. C., Nanda, J., Laird, A., Mullen, P., Caldwell, H., Overton, I. M., Eöry, L., O’Donnell, M., Faratian, D., Powles, T. B., et al. (2013) · Journal of Visualized Experiments · doi:10.3791/50221 · Cited by 11
Cell-based high-throughput screens for the discovery of chemotherapeutic agents
Fox, J. T., & Myung, K. (2012) · Oncotarget · doi:10.18632/oncotarget.513 · Cited by 12
“For example, 13% of breast cancers [11], 23% of advanced ovarian cancers [12], 6% of cervical cancers [13], and 4% of non–small-cell lung cancers [14] do not express BRCA1, a component of the HR machinery; missense mutations of the FANCA gene, whose protein product plays a key role in inter-strand crosslink repair, ha…”
Background
Roles of DNA mutation in the coding region and DNA methylation in the 5′ flanking region of BRCA1 in canine mammary tumors
Hengbin, Q. I. U., & Deigui, L. I. N. (2016) · Journal of Veterinary Medical Science · doi:10.1292/jvms.15-0557 · Cited by 12
“DNA methylation of this gene is one of the principle mechanisms for silencing BRCA1 [6].”
Background
Unlocking the Molecular Mechanisms of DNA Repair and Platinum Drug Resistance in Cancer Chemotherapy
Yu, J. (2009) · Current Drug Therapy · doi:10.2174/157488509787081895 · Cited by 11
Mixed Ovarian Germ Cell Tumor in a BRCA2 Mutation Carrier
Hamel, N., Wong, N., Alpert, L., Galvez, M., & Foulkes, W. D. (2007) · International Journal of Gynecological Pathology · doi:10.1097/01.pgp.0000228142.52054.0f · Cited by 12
“Although a GCT could have arisen in the context of haploinsufficiency, this has not been recorded in BRCA 1/2-related ovarian cancer in the absence of LOH (11,12); and therefore, we do not favor this explanation.”
Influential
Standardization of the methylation-specific PCR method for analyzing BRCA1 and ER methylation
Lan, V. T. T., Ha, N. T., Uyển, N. Q., Duong, N. T., Hương, N. T. T., Thuan, T. B., Duong, P. A. T., & To, T. V. (2014) · Molecular Medicine Reports · doi:10.3892/mmr.2014.1990 · Cited by 12
Regulation of the BRCA1 promoter in ovarian surface epithelial cells and ovarian carcinoma cells
Graves, M. L., Zhou, L., MacDonald, G., Mueller, C. R., & Roskelley, C. D. (2007) · FEBS Letters · doi:10.1016/j.febslet.2007.03.072 · Cited by 12
“The primer sequences used for BRCA1 transcript amplification were 5 0-ATGCTGAATGAGCATGATTTG-3 0 (Forward); 5 0AGAGTGCTACACTGTCCAAC-3 0 (Reverse) which generate a 352 bp fragment [16].”
Method
Epigenetic Changes in Aging and Age-related Disease
Rowbotham, D. A. (2015) · Journal of Aging Science · doi:10.4172/2329-8847.1000130 · Cited by 13
“Further, in malignant cells, tumor-type-specific transcriptional silencing of tumour suppressor genes (TSGs) is strongly correlated with hypermethylation of their associated promoters [64-76].”
Background
Alteration of O6‐methylguanine‐DNA methyltransferase in colorectal neoplasms in sporadic and familial adenomatous polyposis patients
Kim, S. H., Bae, S. I., Lee, H. S., & Kim, W. H. (2003) · Molecular Carcinogenesis · doi:10.1002/mc.10116 · Cited by 12
“The primer sequences for the unmethylated products were 50-TTT GTG TTT TGA TGT TTG TAG GTT TTT GT-30 (sense primer) and 50-AAC TCC ACA CTC TTC CAA AAA CAA AAC A-30 (antisense primer), and for the methylated products 50-TTT CGA CGT TCG TAG GTT TTC GC-30 (sense primer) and 50-GCA CTC TTC CGA AAA CGA AAC G-30 (antisense…”
Method
Estrogen-induced reactive oxygen species, through epigenetic reprogramming, causes increased growth in breast cancer cells
Roy, P., Kandel, R., Sawant, N. A., & Singh, K. P. (2023) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2023.112092 · Cited by 11
Recommendations for Clinical Molecular Laboratories for Detection of Homologous Recombination Deficiency in Cancer
Hsiao, S. J., Black, D. R., Devereaux, K. A., Hagemann, I. S., Jennings, L. J., Mandelker, D. L., Paulson, V., Shiller, M., Stockley, T. L., Vail, E., et al. (2025) · Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2025.05.003 · Cited by 14
The association between the methylation frequency of BRCA1/2 gene promoter and occurrence and prognosis of breast carcinoma
Li, S., He, Y., Li, C., Liu, X., Shen, Y. H., Wu, Y., Bai, N., & Li, Q. (2020) · Medicine · doi:10.1097/md.0000000000019345 · Cited by 11
“…2009 Israel – 6 94 8 122 Real-time PCR CCS TT PT 7 Sturgeon 2012 USA Mean:67 192 112 147 87 Pyrosequencing CCS TB NB 8 Wei 2005 USA – 39 92 0 3 MSP CS TT PT 7 Cho 2015 USA – 18 1003 13 1023 MSP CS TB NB 8 Esteller 2000 USA – 11 73 0 84 MSP CS TT PT 8 Dobrovic 1997 Australia – 2 5 0 2…”
Epigenetics in cancer development, diagnosis and therapy
Chu, D., Ngo, A.-D., & Wu, C. (2023) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2023.01.009 · Cited by 10
Methylation biomarkers for pleomorphic lobular breast cancer - a short report
Moelans, C. B., Vlug, E. J., Ercan, C., Bult, P., Buerger, H., Cserni, G., van Diest, P. J., & Derksen, P. W. B. (2015) · Cellular Oncology · doi:10.1007/s13402-015-0241-9 · Cited by 11
“tients [37, 38].”
Association of mutation and hypermethylation of p21 gene with susceptibility to breast cancer: a study from north India
Akhter, N., Akhtar, S., Ahmad, M. M., Haque, S., Siddiqui, S., Hasan, S. I., Shukla, N. K., & Husain, S. A. (2014) · Molecular Biology Reports · doi:10.1007/s11033-014-3159-9 · Cited by 11
“In the case of breast tumors, there is evidence of hypermethylation of functionally important genes including those involved in DNA repair (BRCA1) [24], cell cycle regulation (p16) [25], cell adhesion (E-cadherin) [26], hormone and receptor-mediated cell signaling receptors including ER (estrogen receptor) and RAR-b2…”
BackgroundResult
Magnetic bead-based electrochemical assay for determination of DNA methyltransferase activity
Dudová, Z., Bartošík, M., & Fojta, M. (2017) · Electrochimica Acta · doi:10.1016/j.electacta.2017.02.104 · Cited by 11
Clinical factors of response in patients with advanced ovarian cancer participating in early phase clinical trials
George, A. J., Kristeleit, R. S., Rafii, S., Michie, C. O., Bowen, R. L., Michalarea, V., van Hagen, T., Wong, M., Rallis, G., Molife, L. R., et al. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2017.01.020 · Cited by 11
“Recent studies have investigated the role of somatic aberrations in ovarian cancer oncogenesis, with each histological subtype demonstrating distinct patterns of genomic abnormality prevalence within different pathways [10-20].”
Background
Practical consensus recommendations on management of triple-negative metastatic breast cancer
Rangarao, R., Smruti, B. K., Singh, K., Gupta, A., Batra, S., Choudhary, R. K., Gupta, A., Sahani, S., Kabra, V., Parikh, P. M., et al. (2018) · South Asian Journal of Cancer · doi:10.4103/sajc.sajc_118_18 · Cited by 11
“In sporadic triplenegative breast cancer, dysregulation of BRCA1, a protein with critical roles in the homologousrecombination–dependent DNA-repair pathway, has been attributed to a number of mechanisms, including BRCA1-promoter methylation and overexpression of the negative regulators ID4 and HMG.[21-24]”
Background
The Epigenetic Landscape in the Treatment of Gynecologic Malignancies
Eskander, R. N. (2018) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_200203 · Cited by 11
How latent viruses cause breast cancer: An explanation based on the microcompetition model
Polansky, H., & Schwab, H. (2018) · Bosnian Journal of Basic Medical Sciences · doi:10.17305/bjbms.2018.3950 · Cited by 11
Microfluidic MeDIP-seq for low-input methylomic analysis of mammary tumorigenesis in mice
Zhu, Y., Cao, Z., & Lu, C. (2019) · The Analyst · doi:10.1039/c8an02271b · Cited by 11
Data-driven selection and parameter estimation for DNA methylation mathematical models
Larson, K. A., Zagkos, L., Auley, M. T. M., Roberts, J. A., Kavallaris, N. I., & Anastasios Matzavinos, A. (2019) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2019.01.012 · Cited by 11

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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