Cited by 648BRCA gene mutations in cancerDNA Repair MechanismsPARP inhibition in cancer therapy

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BRCA1 and BRCA2 and the genetics of breast and ovarian cancer

Welcsh, P. L.·2001·Human Molecular Genetics

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Abstract

Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose individuals to breast and ovarian cancers. Progress in determining the function of BRCA1 and BRCA2 suggests that they are involved in two fundamental cellular processes: DNA damage repair and transcriptional regulation. We evaluate current knowledge of BRCA1 and BRCA2 functions to explain why mutations in BRCA1 and BRCA2 lead specifically to breast and ovarian cancer. The BRCA1 and BRCA2 genes contain unusually high densities of repetitive elements. These features of the BRCAs genomic regions contribute to chromosomal instability of these genes. We propose that somatic alterations of BRCA1 and BRCA2 are common and driven by rearrangements between repetitive elements. Inherited and somatic mutations occur in BRCA1 and BRCA2; virtually all somatic mutations are the result of large genomic rearrangements. What are the consequences of such large somatic mutations of BRCA1 and BRCA2 in women with or without inherited mutations? The breast and ovary are estrogen-responsive tissues. Beginning in puberty, the breast epithelium proliferates rapidly in response to fluctuating levels of estrogen. We present a genetic model outlining how BRCA-deficient cells may gain uncontrolled proliferation leading to tumor formation. Central to this model of BRCA-mediated tumorigenesis are estrogen-mediated proliferation of breast and ovarian epithelium and the distinctive genomic context of the BRCA genes.

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(2020) · PeerJ · doi:10.7287/peerj.9908v0.2/reviews/1

Authors: Welcsh, P. L.
Affiliations: University of Washington (US)
Corresponding author: Welcsh, P. L.
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2001-04-01
Volume: 10
Issue: 7
Pages: 705-713
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/10.7.705
OpenAlex: W2124371549
Cited by: 648
References: 93
Citations by year: 2026: 11 · 2025: 16 · 2024: 25 · 2023: 19 · 2022: 19 · 2021: 26 · 2020: 27 · 2019: 33 · 2018: 30 · 2017: 36 · 2016: 34 · 2015: 31 · 2014: 29 · 2013: 25 · 2012: 17
FWCI: 4.10
Type: journal article
Language: en
Open access: closed
Locations: Human Molecular Genetics (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01ca027632-22)
National Cancer Institute (CA27632)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Keywords: BRCA1, BRCA2, hereditary breast cancer, hereditary ovarian cancer, germline mutations, somatic mutations, DNA repair, transcriptional regulation, repetitive elements, chromosomal instability, genome rearrangement, carcinogenesis, tumor suppressor
MeSH terms: Breast Neoplasms, Cell Division, Chromosomes, Estrogens, Female, Humans, Models, Biological, Mutation, Neoplasm Proteins, Ovarian Neoplasms, Repetitive Sequences, Nucleic Acid, Transcription Factors, Gene Deletion, Genes, BRCA1, Genetic Predisposition to Disease, BRCA2 Protein

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BRCA1 and BRCA2 and the genetics of breast and ovarian cancer

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