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BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
BRCA1 and 2 are tumor suppressor genes that are located on chromosomes 17 and 13, respectively. Wild-type BRCA genes code for proteins that are integral for HR. The BRCA1 protein migrates to the DNA double strand break (DSB) site to recruit proteins that aid in DNA repair and is involved in cell cycle replication arrest. BRCA2 is directly involved in repairing DNA, at least in part by chaperoning RAD51, a recombination enzyme [127, 128].
BRCA1-BRCA2 and ovarian cancer
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
The gene BRCA1 on chromosome 17q12-21 was identified in 199017, and subsequently cloned in 19949,18. BRCA1 consists of 22 exons encoding 5592 nucleotides, with approximately 60% of the coding sequence contained in a single exon (exon 11), the remaining 21 exons being relatively small. Over 130 different mutations have been reported in BRCA1, most of them identified throughout the coding region in families with multiple cases of breast or ovarian cancer. Two mutations, 185delAG and 5382insC, occur with a relatively high frequency and account for about 22% of all mutations detected, although these data are biased by selective testing for these specific mutations. The former mutation is particularly common in Ashkenazi Jews (about 1% frequency)19, and is present in almost 20% of Ashkenazi Jews with early-onset breast cancer20–21. Mutations predicted to result in protein truncation or absence of BRCA1 protein (i.e. frameshift, non-sense, splice site and regulatory mutations, and large genomic deletions) account for approximately 90% of all mutations reported.
The Role of Epigenetics in Breast Cancer: Implications for Diagnosis, Prognosis, and Treatment
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Amy M. Dworkin, Tim H.-M. Huang, Amanda E. Toland
Germline mutations of BRCA1 and BRCA2 are responsible for familial breast cancers. Somatic mutations in sporadic cases are rare, but chromosomal losses occur in 30% to 50% of sporadic tumors, respectively (26). BRCA1 acts as a tumor suppressor gene for both breast and ovarian cancer (16). It encodes a multifunctional protein involved in DNA repair, cell cycle checkpoint control, protein ubiquitinylation, and chromatin remodeling (19). In vitro studies showed that decreased BRCA1 expression in cells led to increased levels of tumor growth, while increased expression of BRCA1 led to growth arrest and apoptosis. Inactivation of BRCA1 by promoter methylation is seen in 7% to 31% of sporadic breast cancer cases (27). It is believed that aberrant methylation pairs with loss of heterozygosity to reduce BRCA1 expression in invasive sporadic breast tumors (16,19,22,26,28). The magnitude of the decrease of functional BRCA1 protein correlates with disease prognosis (19,22). Phenotypically, BRCA1-methylated tumors are similar to tumors with germline mutations. Higher-grade tumors tend to show complete loss of BRCA1 protein. In contrast to BRCA1, BRCA2 does not show as high a degree of promoter methylation (16).
Clinical impact of BRCA2 mRNA expression in high-grade serous ovarian cancer: validation using the TCGA cohort
Published in Acta Oncologica, 2021
Irina Tsibulak, Verena Wieser, Hannah Welponer, Katharina Leitner, Hubert Hackl, Christian Marth, Heidelinde Fiegl, Alain G. Zeimet
On the other hand, our preceding findings that low BRCA1 expression on the transcriptome level was independently associated with favorable OS in HGSOC patients could not be confirmed in this large cohort. However, it is important to notice the limitations of the present dataset, such as incomplete clinical data, but also the rather unrealistic low number of BRCA mutated tumors as compared to data from literature as well as to our originally examined cohort [4–6,10,18,19]. Furthermore, the optimal cutoff to discriminate between ‘low’ and ‘high’ BRCA expression was the same for BRCA2 in both cohorts, but not for BRCA1 (90th percentile in the original study vs. 14th percentile in the present study). However, even at the best discriminatory level of the 14th percentile neither for PFS nor for OS BRCA1 transcript levels proved to be of statistical predictive value regarding disease outcome. This is probably due to multifaceted functional character of the BRCA1 protein, which has multiple functional domains and interacts with multiple proteins. Besides DNA repair BRCA1 is also involved in various crucial cellular processes, such as transcriptional regulation, cell cycle control, apoptosis and others more. Such a broad involvement in various cellular pathways, can easily have opposing effects on disease outcome and may preclude BRCA1 mRNA expression as an ideal candidate for a clinically relevant biomarker in OC.
Development and implementation of precision therapies targeting base-excision DNA repair in BRCA1-associated tumors
Published in Expert Review of Precision Medicine and Drug Development, 2019
Adel Alblihy, Katia A. Mesquita, Maaz T. Sadiq, Srinivasan Madhusudan
BRCA1 was first identified in 1990 by King et al. and mapped to chromosome 17q21 [5]. BRCA1 functions as a tumor suppressor gene and contains 22 coding exons distributed over 100 kb of genomic DNA. The BRCA1 protein is a highly phosphorylated nuclear protein with a molecular weight of approximately 220 KDa. It contains nuclear import and export signals to facilitate movement between the nucleus and cytoplasm, which help it to perform as tumor suppressor gene. BRCA1 consists of 1863 amino acid residues, including one N-terminal RING domain, two nuclear localization signals and two BRCA1 carboxyl-terminal (BRCT) domains (Figure 1) [6,7]. In cancer patients with mutations in this gene, BRCA1 mutations mostly occur in the N-terminal RING domain encoded by exons 2–7, coding regions including exons 11–13 and BRCT domains encoded by exons 16–24 [8]. These three domains are crucial for the interaction of BRCA1 with multiple partner proteins (Figure 1) and subcellular localization of BRCA1. They are responsible for several of its functions, such as responding to and repairing DNA lesions, regulation of cell cycle and transcription regulation. The structures of the RING and BRCT domains have been studied. However, these domains only account for a small part of the BRCA1 protein. Exons 11–13 encode the majority of the BRCA1 protein, and the structure of this region needs to be elucidated [9,10].
Gynecological–endocrinological aspects in women carriers of BRCA1/2 gene mutations
Published in Climacteric, 2018
A. Doren, A. Vecchiola, B. Aguirre, P. Villaseca
When DNA mutations or alterations occur, BRCA1 and BRCA2 proteins can stop the damage of breaks in the double strand of DNA, as well as stop damage in the replication fork (the replication fork is the location where DNA replication occurs), by triggering homologous recombination. Both genes, BRCA1 and BRCA2, mediate homologous recombination: BRCA1 protein participates by modulating signal transduction pathways that are involved in homologous recombination; BRCA2 protein participates directly by forming a complex with the recombinase RAD51 (enzyme involved in the homologous recombination and repair of DNA)15,16.