ArticleAmerican journal of human genetics2018
A Dominantly Inherited 5' UTR Variant Causing Methylation-Associated Silencing of BRCA1 as a Cause of Breast and Ovarian Cancer.
Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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61 citing papers in PubMed, 97 citations in OpenAlex.
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- Constitutional epimutations in LTBP4, a component of the TGF-β signaling, and in BRCA1, as potential drivers of early-onset colorectal cancer.Clinical epigenetics · 2025Article
- Genetic regulation of the estrogen receptor and inherited predisposition to breast cancer.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The role of untranslated region variants in Mendelian disease: a review.European journal of human genetics : EJHG · 2025Review
- BRCA1 promoter hypermethylation is not associated with germline variants in Polish breast cancer patients.Hereditary cancer in clinical practice · 2025Article
- 5'UTR gene regions in germline DNA sequencing panels: lessons from the analysis of breast and ovarian cancer patients of Tatar and Bashkir ethnic origin.Familial cancer · 2025Article
- Constitutional Epimutations: From Rare Events Toward Major Cancer Risk Factors?JCO precision oncology · 2025Review
- MGMT epimutations and risk of incident cancer of the colon, glioblastoma multiforme, and diffuse large B cell lymphomas.Clinical epigenetics · 2025Article
- Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement.Nature communications · 2024Article
- Methylation marks in blood DNA reveal breast cancer risk in patients fulfilling hereditary disease criteria.NPJ precision oncology · 2024Article
- Epigallocatechin Gallate for the Treatment of Benign and Malignant Gynecological Diseases-Focus on Epigenetic Mechanisms.Nutrients · 2024Review
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- The role of aberrant DNA methylation in cancer initiation and clinical impacts.Therapeutic advances in medical oncology · 2024Article
- Unraveling noncoding DNA variants and epimutations: a paradigm shift in hereditary cancer research.Future oncology (London, England) · 2024Review
- Blood-based DNA methylation in advanced Nasopharyngeal Carcinoma exhibited distinct CpG methylation signature.Scientific reports · 2023Article
- Prenatal BRCA1 epimutations contribute significantly to triple-negative breast cancer development.Genome medicine · 2023Article
- Early-Onset Ovarian Cancer <30 Years: What Do We Know about Its Genetic Predisposition?International journal of molecular sciences · 2023Review
1 more citing papers are in PubMed but not listed here.
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12 authors at 8 institutions in 1 country.
Funding
Abstract
Pathogenic variants in BRCA1 or BRCA2 are identified in ∼20% of families with multiple individuals affected by early-onset breast and/or ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1 or BRCA2 have not explained the missing heritability. Here, we report a dominantly inherited 5' UTR variant associated with epigenetic BRCA1 silencing due to promoter hypermethylation in two families affected by breast and ovarian cancer. BRCA1 promoter methylation of ten CpG dinucleotides in families who are affected by breast and/or ovarian cancer but do not have germline BRCA1 or BRCA2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing. RNA and DNA sequencing of BRCA1 from lymphocytes was undertaken to establish allelic expression and the presence of germline variants. BRCA1 promoter hypermethylation was identified in 2 of 49 families in which multiple women are affected by grade 3 breast cancer or high-grade serous ovarian cancer. Soma-wide BRCA1 promoter hypermethylation was confirmed in blood, buccal mucosa, and hair follicles. Pyrosequencing showed that DNA was ∼50% methylated, consistent with the silencing of one allele, which was confirmed by clonal bisulfite sequencing. RNA sequencing revealed the allelic loss of BRCA1 expression in both families and that this loss of expression segregated with the heterozygous variant c.-107A>T in the BRCA1 5' UTR. Our results establish a mechanism whereby familial breast and ovarian cancer is caused by an in cis 5' UTR variant associated with epigenetic silencing of the BRCA1 promoter in two independent families. We propose that methylation analyses be undertaken to establish the frequency of this mechanism in families affected by early-onset breast and/or ovarian cancer without a BRCA1 or BRCA2 pathogenic variant.
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