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The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Another aspect of BRCA1 is that it can be used in a prognostic manner to predict a patient’s response to chemotherapy. For example, BRCA1 plays an important role in stimulating the repair of damaged DNA in cells. Thus, a mutation in the BRCA gene can cause hypersensitivity to DNA-damaging chemotherapeutic agents. In particular, BRCA1 mutations can make tumor cells significantly more sensitive to PARP inhibition, increasing the rate of apoptosis. This has been used as a biomarker to select patients for treatment with PARP inhibitors such as olaparib (LynparzaTM). Conversely, BRCA1 mutations can influence the outcome of treatment with antitubulin agents such as the taxanes (e.g., paclitaxel) and the vinca alkaloids (e.g., vinblastine) causing resistance to these therapies.
Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Robert D. Morgan, Andrew R. Clamp, Gordon C. Jayson
The cumulative lifetime risk of developing ovarian cancer in carriers of mutations in BRCA1 or BRCA2 is 40–60% and 10–30%, respectively.18 This compares with a lifetime risk in the general population of approximately 1%. The pattern of inheritance of BRCA1/2 is autosomal dominant with incomplete penetrance. Women diagnosed with BRCA-mutant ovarian cancer have a better 5-year prognosis, even after adjustment for disease stage and age.19 This is likely due to the hypersensitivity of BRCA-deficient tumor cells to DNA-damaging agents, such as carbo- and cisplatin, and pegylated liposomal doxorubicin.
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 expression and mutation of BRCA1/2 genes in ovarian cancer: a global systematic study
Published in Expert Review of Molecular Diagnostics, 2023
Dinh-Toi Chu, Mai Vu Ngoc Suong, Hue Vu Thi, Thuy-Duong Vu, Manh-Hung Nguyen, Vijai Singh
Among genes linked to ovarian cancer, Breast Cancer 1 (BRCA1) gene and Breast Cancer 2 (BRCA2) gene are two of the most prominent. The population frequencies for BRCA1 and BRCA2 mutations were estimated 0.024% and 0.041%, respectively [12]. Even though the probability of finding any cases with mutation in both BRCA genes is significantly low (from 1/700,000 to 1/250,000), it is possible to find a presence of double heterozygosity in BRCA genes [13]. BRCA1 and BRCA2 genes are located on chromosomes 17 and 13, respectively [14]. BRCA1/2 proteins relate to the homologous recombination (HR) pathway and non-homologous end-joining, which lead to the repair of double-strand breaks (DSBs) on DNA [14,15]. As a result, mutations in BRCA1 and BRCA2 genes cause impaired HR, which is not feasible to repair damaged chromosomes and unrepairable DSBs and forms ovarian tumors [14,16]. In fact, 65–85% of genetic abnormalities are related to ovarian carcinomas, which are germline mutations in BRCA1/2 genes [7]. The lifetime risk of developing ovarian tumors due to BRCA1 mutations and BRCA2 mutations in women are 15–45% and 10–40%, respectively, [17].
Impact of BRCA mutations and hormone receptor status on reproductive potential in breast cancer patients undergoing fertility preservation
Published in Gynecological Endocrinology, 2022
Sung Woo Kim, Tae Hee Kim, Ji Yeon Han, Seul Ki Kim, Jung Ryeol Lee, ung Chul Jee, Chang Suk Suh, Seok Hyun Kim
One of most critical limitation of the present study is deficient description about starting dose, COS duration, and total dose of gonadotropin. Other limitations are the retrospective nature and a relatively small patient population. Women who had children or were diagnosed with progressed disease usually did not undergo a COS cycle. Therefore, the population of the current study could not represent all TNBC patients. In addition, the data of BRCA1 carriers were not separated from BRCA2 carriers, because only four patients had BRCA1 mutation only in this cohort. Consequently, differences between BRCA1 and BRCA2 mutations could not be investigated in this study. Another limitation was insufficient data about fertilization rate, quantity and quality of embryos. We could not compare the quality of embryos because the sample size was too small.
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
In contrast to BRCA1, BRCA2 is crucial for recruiting an essential HR protein RAD51C to DSB sites, therefore the role of BRCA2 in the DSB repair by HR is more direct and selective [9]. Nonetheless, BRCA2 as well as BRCA1 aberrations in tumor cells lead to HR deficiency (HRD) and the so called ‘BRCAness’ phenotype, which correlates with high platinum-sensitivity and thus predicts better clinical outcome in OC. Interestingly, several reports evidenced that patients with BRCA2 mutation showed a greater survival advantage compared with patients carrying a BRCA1 mutation. This was especially highlighted in the analyses done by Norquist et al. showing that BRCA2 but not BRCA1 mutation carriers exhibited a statistically significant improved PFS and OS when compared with patients without mutations [18]. In this evaluation the difference in PFS between BRCA2 and BRCA1 mutated OC was particularly pronounced in the first 3 years. With regard to OS, the improvement for BRCA2 carriers was in fact due to a sustained long-term better OS paralleled with a distinctive decline in long-term OS for BRCA1 mutated patients, which is probably due to the occurrence of secondary tumors [18,19]. Based on the herein revealed findings, we suppose that not only mutations in BRCA2, but also low BRCA2 expression on transcriptome level may cause relevant HR pathway alterations.