The Precision Medicine Approach in Oncology
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
BRCA1 and BRCA2 are examples of genes that increase the risk of developing breast and ovarian cancer in women, and male breast cancer and prostate cancer in men. BRCA1 provides the instructions needed by a cell to produce tumor suppressor proteins necessary to prevent uncontrollable cell growth and division, thus preventing tumor establishment, growth, and spread. Women carrying the faulty BRCA1 gene have a 60–90% lifetime risk of breast cancer and a 40–60% risk of ovarian cancer (i.e., for every 100 women, 60–90 will develop breast cancer in their lifetime and 40–60 will develop ovarian cancer). There are also population differences; although faulty BRCA genes affect around 1 in every 400 people in most populations, those of Ashkenazi Jewish descent are at much higher risk with as many as 1 in 40 carrying a faulty gene. Recent research has identified over 100 new gene variants associated with an increased risk of breast, prostate, and ovarian cancer. Individually, these new gene variants may only slightly increase the risk of cancer, but the presence of a combination of them could mean a high risk overall.
The reproductive system
Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella in Essentials of Human Physiology and Pathophysiology for Pharmacy and Allied Health, 2019
Genetic factors: It is estimated that 5%–10% of breast cancers are due to an inherited genetic mutation. The presence of mutations in two breast cancer genes BRCA1 or BRCA2 can increase a woman’s risk for breast cancer significantly. Fifty to sixty-five percent of women with the BRCA1 mutation will develop breast cancer by 70 years of age. Although approximately 45% of women with the BRCA2 mutation will develop breast cancer by this same age. The presence of these gene mutations can also significantly increase woman’s risk for developing ovarian cancer. The BRCA1 and BRCA2 genes normally produce tumor-suppressor proteins; however, the protective effect of these genes appears to be lost if they are mutated.
The Role of Epigenetics in Breast Cancer: Implications for Diagnosis, Prognosis, and Treatment
Brian Leyland-Jones in Pharmacogenetics of Breast Cancer, 2020
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).
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].
Breast cancer genetics and risk assessment: an overview for the clinician
Published in Climacteric, 2023
L. Larkin
Approximately 5–10% of breast cancer in developed countries is associated with BRCA1 and BRCA2 [11–13], the most common single hereditary gene mutations associated with breast cancer. BRCA1 and BRCA2 are very highly penetrant genes associated with a lifetime risk of developing breast cancer approaching 80%. Approximately 5–15% of women who are negative for BRCA1 and BRCA2 will be found to carry one of the other highly penetrant genes or moderately penetrant genes associated with HBC [13–15] Highly penetrant genes associated with a lifetime risk of breast cancer of >30% include TP53, PTEN, CDH1, STK11 and PALB2. Moderately penetrant genes associated with a 17–30% lifetime risk include CHEK2, ATM, BARD1, BRIP1, NBN, NF1, RAD51D and MSH6 [16]. Breast cancer risk and recommendations for screening and risk reduction vary by gene. In general, screening breast magnetic resonance imaging is recommended for women at >20% lifetime risk, which includes women with mutations in highly penetrant genes and the majority (but not all) of moderately penetrant genes. Consideration of chemoprevention is recommended for women with mutations in high and moderately penetrant genes [13].
HLA class-I and class-II restricted neoantigen loads predict overall survival in breast cancer
Published in OncoImmunology, 2020
Yingxue Ren, Yesesri Cherukuri, Daniel P. Wickland, Vivekananda Sarangi, Shulan Tian, Jodi M. Carter, Aaron S. Mansfield, Matthew S. Block, Mark E. Sherman, Keith L. Knutson, Yi Lin, Yan W. Asmann
BRCA1 and BRCA2 are the two most important breast cancer susceptibility genes mutated in 21–40% of all inherited BRCA.22–24BRCA1 and BRCA2 deficiency has been associated with higher TMB.25 We evaluated 835 BRCAs for presence of any of 115 known deleterious BRCA1/BRCA2 germline mutations26 and identified individuals with BRCA1/BRCA2 somatic mutations from TCGA data. As shown in Figure 5, cases with deleterious germline BRCA1/BRCA2 variants, compared to those with wild-type BRCA1/BRCA2, had suggestively higher TMB (Figure 5a, left panel, p = .067) but neoantigen loads were not significantly different (Figure 5b, left panel). The cases with germline and somatic BRCA1/BRCA2 mutations had both significantly higher TMB (Figure 5a, right panel, p = 2.76E-06) and neoantigen loads than BRCAs with wild-type genes (Figure 5b, right panel, p = .009).
Related Knowledge Centers
- Brca2
- Breast
- Caretaker Gene
- DNA
- DNA Repair
- Protein
- Tumor Suppressor Gene
- Chromosome
- Gene
- Sequence Homology