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Zhang, Yinuo. "BRCA1, BRCA2 and primary ovarian insufficiency". E3S Web of Conferences 165 (2020): 05009. http://dx.doi.org/10.1051/e3sconf/202016505009.
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BRCA1 and BRCA2 genes belong to the family of ataxia-telangiectasia-mutated (ATM)-mediated DNA DSB repair genes that play a critical role in the DNA double-strand break (DSB) repair. Mutations in BRCA genes significantly increase the lifetime risk of breast, ovarian, fallopian tube and primary peritoneal cancers. In addition to the increased risk for multiple malignancies, recent literature suggest that mutations in BRCA genes could lead to decreased ovarian reserve and subsequent ovarian aging. In this review, we will focus on role of BRCA1 and BRCA2 in ovarian function, particularly ovarian aging and primary ovarian insufficiency. Serum AMH values are generally lower in BRCA1 mutation carriers but not in BRCA2 mutation carriers. BRCA2 carriers were more likely to have chemotherapy-induced amenorrhea DNA not stable, linking with ovarian aging. The mechanism by which BRCAs mutation in the pathogenesis of POI is the inpaired function of repairing DNA breaks. Future studies investigating the knockout models to elucidate the role of the BRCAs genes in ovarian development and oocyte maturation will be interesting.
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McNevin, Ciara S., Karen Cadoo, Anne-Marie Baird, Pierre Murchan, Orla Sheils, Ray McDermott i Stephen Finn. "Pathogenic BRCA Variants as Biomarkers for Risk in Prostate Cancer". Cancers 13, nr 22 (14.11.2021): 5697. http://dx.doi.org/10.3390/cancers13225697.
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Studies have demonstrated that men with Prostate Cancer (PCa) harboring BRCA2/BRCA1 genetic aberrations, are more likely to have worse disease and a poorer prognosis. A mutation in BRCA2 is known to confer the highest risk of PCa for men (8.6 fold in men ≤65 years) making BRCA genes a conceivable genomic biomarker for risk in PCa. These genes have attracted a lot of research attention however their role in the clinical assessment and treatment of PCa remains complex. Multiple studies have been published examining the relationship between prostate cancer and BRCA mutations. Here BRCA mutations are explored specifically as a biomarker for risk in PCa. It is in this context, we examined the prognostic, clinical and therapeutic role of BRCA2/BRCA1 mutations across the evolution of PCa. The impact of the inclusion of BRCA genes on genetic screening will also be outlined.
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Schwartz, Zachary Phillip, Mae Zakhour, Andrew John Li, Christine S. Walsh, Bj Rimel, Monica Alvarado, Scott E. Lentz i Ilana Cass. "Comparison of risk-reducing surgery in women with BRCA and non-BRCA ovarian cancer susceptibility genes." Journal of Clinical Oncology 37, nr 15_suppl (20.05.2019): 1547. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.1547.
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1547 Background: Risk reducing gynecologic surgery (RRSO) is standard of care for women with BRCA mutations. The optimal management for women with non-BRCA ovarian cancer susceptibility mutations remains unclear. We sought to characterize the practice patterns for these women at our two institutions. Methods: Women with germline ovarian cancer susceptibility genes who had a RRSO were identified from 1/2000-1/2019 in an IRB approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. Continuous variables were analyzed with Kruskal-Wallis and categorical variables analyzed with chi square and t-tests. Results: 152 BRCA1, 95 BRCA2, and 63 Non-BRCA mutation carriers were identified—50 Lynch (22 MLH1, 13 MSH2, 13 MSH6, 2 PMS2) and 13 Other (6 BRIP1, 2 RAD51C, 5 RAD51D). There was no difference between age at testing, age at RRSO, and interval between testing and RRSO between groups. Genetic counseling was higher in Non-BRCA patients. Family history of ovarian cancer was more common in women with BRCA1 and Other germline mutations compared to BRCA2 and Lynch. Family and personal history of breast cancer was high in all groups except Lynch carriers. Prophylactic mastectomy was seen mostly in BRCA mutation carriers. Concomitant hysterectomy was performed in the majority of women (BRCA1 59%, BRCA2 57%, and Other 62%), with the highest frequency in Lynch carriers (86%, p<.01). Occult cancer was only seen in BRCA mutation carriers: BRCA1 (7%), BRCA2 (2%), Lynch (0%), Other (0%). Conclusions: In this cohort, women with Non-BRCA mutations are managed similarly to women with BRCA mutations. We observed no occult cancers in Non-BRCA patients. The optimal role of surgery as a risk reducing strategy in this group requires further study. [Table: see text]
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Sahnane, Nora, Ileana Carnevali, Giorgio Formenti, Jvan Casarin, Sofia Facchi, Raffaella Bombelli, Eleonora Di Lauro i in. "BRCA Methylation Testing Identifies a Subset of Ovarian Carcinomas without Germline Variants That Can Benefit from PARP Inhibitor". International Journal of Molecular Sciences 21, nr 24 (19.12.2020): 9708. http://dx.doi.org/10.3390/ijms21249708.
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Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in BRCA1 and BRCA2 genes. Although promoter methylation is a well-known mechanism of gene transcriptional repression, few data have been published about BRCA gene methylation in EOCs. In this retrospective study, we quantitatively analyzed by pyrosequencing a selected series of 90 formalin-fixed (FFPE) primary EOCs without BRCA germline mutations. We identified 20/88 (22.7%) EOCs showing BRCA promoter methylation, including 17/88 (19.3%) in BRCA1 and 4/86 (4.6%) in BRCA2 promoters, one of which showing concomitant BRCA1 methylation. Mean methylation levels were 49.6% and 45.8% for BRCA1 and BRCA2, respectively, with methylation levels ≥50% in 10/20 methylated EOCs. Constitutive BRCA methylation was excluded by testing blood-derived DNA. In conclusion, pyrosequencing methylation analysis of BRCA genes is a robust, quantitative and sensitive assay applicable to FFPE samples. Remarkably, a considerable subset of germline BRCA-negative EOCs showed somatic methylation and, likely, HRD. A subpopulation of women with BRCA methylation, even without BRCA mutations, could potentially benefit from PARP-inhibitors; further clinical studies are needed to clarify the predictive role of somatic BRCA methylation of PARP-therapy response.
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Incorvaia, Lorena, Chiara Brando, Alessandro Perez, Marco Bono, Daniela Cancelliere, Alessia Pivetti, Nadia Barraco i in. "Real life use of biomarkers of homologous recombination deficiency (HRD) status beyond BRCA to predict the effectiveness of PARP inhibitors in ovarian cancer patients." Journal of Clinical Oncology 41, nr 16_suppl (1.06.2023): 10592. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.10592.
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10592 Background: Testing for BRCA mutations (BRCAm) and genomic instability can identify epithelial ovarian cancer (OC) patients most likely to benefit from PARP-inhibitors (PARPi). However, current biomarkers of non- BRCA Homologous Recombination Repair (HRR) mutations are insufficient for guiding use of PARPi in the clinic. Despite non- BRCA HRR pathway gene mutations are rare, these patients may benefit from PARPi. Furthermore, recent preclinical findings showed that sensitivity to PARPi could be associated also with mutations in mismatch repair (MMR) genes, although sensitivity in the clinic is not proven. Methods: We report our real-life experience to assess the HRD status beyond BRCAm in newly-diagnosed OC patients, with the use of HRR gene panel and HRD genomic instability tests. After primary diagnosis, tumor and germline BRCA (g BRCA) status were assessed and, if BRCA WT, tumor HRR deficiency status were centrally determined by myChoiceCDx (Myriad) assay. NGS panel evaluating 20 MMR and HRR-genes beyond BRCA1/2 was proposed to patients with significant personal and/or family history of cancer, resulted negative to g BRCA testing. Results: From January 2017 to January 2023, 540 unselected epithelial OC patients, aging 27 to 81, were tested for tumor and g BRCA status; 109 were carriers of germline pathogenic or likely pathogenic variants (PVs) in BRCA1/2 genes (20.2%): 72 in BRCA1 (66.1%) and 37 in BRCA2 gene (33.9%). Additional 19 patients showed somatic PVs confined to tumor samples (3.5%).In the population of 70 BRCA WT patients tested by multigene panel testing, 14 germline PVs in HRR-associated (7.1%) or MMR-associated genes (12.8%) were found, including 5 in MUTYH (35.7%), 2 in ATM (14.3%), 2 in MLH1 (14.3%), 2 in PMS2 (14.3%), 1 in RAD51C (7.14%), 1 in RAD51D (7.14%), and 1 in CHEK2 gene (7.14%).Out of 72 samples analyzed by HRD genomic instability test, 23 cases were identified as HRD positive (31.9%), with a median GIS score of 65.5 (44-83). Median GIS were 35 (1-72) in the 6 cases of non- BRCA mutated tumors (8.3%), 40 (4-82) in the 17 tumor with non- BRCA variant of uncertain significance (VUS) (23.6%), and 27 (2-83) in the WT samples. Median GIS were significantly higher in tumors with PVs/VUS of RAD51 than BRIP1 (55.5 vs 35). Conclusions: HRRm gene panel and HRD genomic instability tests are not interchangeable to study HRR deficiency beyond BRCAm. HRD genomic instability test is effective to identify patients most likely to gain benefit from PARPi, but not for predicting familial risk of cancer. In our population, NGS panel evaluating HRR genes, beyond BRCA1/2, improved the detection rate of HRRm by 7%, with additional finding of MMR germline mutations, and important clinical implications for family members. Prospective data are expected to evaluate the effectiveness of PARPi in these population.
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Журман, В. Н., Н. Г. Плехова i М. Л. Филипенко. "Mutational Status of BRCA Genes in Ovarian Cancer". Евразийский онкологический журнал, nr 2 (16.08.2022): 118–25. http://dx.doi.org/10.34883/pi.2022.10.2.016.
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Носители герминальных мутаций генов – супрессоров опухолей BRCA1/2 (Brest cancer gene 1/2) имеют повышенный риск развития рака молочной железы, яичников. Также в результате соматических мутаций функциональность BRCA теряется только в одной клетке, которая может стать мутагенной и дать начало злокачественной опухоли.Материалы и методы. Проводили анализ генов BRCA1/2 образцов ДНК из лейкоцитов (n=143) и фиксированных в формалине и залитых в парафин (FFPE) тканей опухоли (n=208) пациентов (n=306) с раком яичника. Мультиплексная амплификация целевых последовательностей ДНК осуществлялась с помощью ПЦР, данные секвенирования обрабатывались с использованием программного обеспечения BRCA-analyzer. Установлено, что в группе BRCA1/2-положительных пациенток, как и в группе отрицательных, преимущественно выявлен рак яичника высокой степени злокачественности (high-grade). Согласно спектру патогенных мутаций генов BRCA определено, что 101 пациент с раком яичника был носителем мутаций гена BRCA1 (88,1%) и 6 мутаций гена BRCA2 (11,9%). Не обнаружено ни одного обследуемого с одновременным носительством мутаций в обоих генах. Было определено 86 пациентов – носителей герминальных мутаций гена BRCA1, гена BRCA2 – 11 человек. Достоверное различие показателей общей продолжительности жизни было обнаружено между группами обследованных, где у пациентов с наличием мутаций она составила 62 месяца (р=0,003). Таким образом, показано, что мутации BRCA1/2 связаны с повышением продолжительности общей выживаемости, но улучшение наблюдалось только у пациентов с первичным и рецидивирующим заболеванием, а не у пациентов с запущенным заболеванием. Тем не менее, мутации BRCA1 и BRCA2 по отдельности не были связаны с указанным показателем, хотя эти результаты были ограничены небольшим количеством исследований. Дальнейшее выяснение характеристик мутаций и их влияния на выживаемость пациентов и ответ на терапию может привести к более индивидуализированному подходу к лечению рака яичников и улучшению результатов. Carriers of germinal mutations of BRCA1/2 tumor suppressor genes (Brest cancer gene 1/2) have an increased risk of developing breast and ovarian cancer. Also, as a result of somatic mutations, BRCA functionality is lost only in one cell, which can become mutagenic and give rise to a malignant tumor.Materials and methods. BRCA1/2 genes of DNA samples from leukocytes (n=143) and formalin-fixed and paraffin-coated (FFPE) tumor tissues (n=208) of patients (n=306) with ovarian cancer were analyzed. Multiplex amplification of target DNA sequences was carried out using PCR, sequencing data was processed using BRCA-analyzer software. It was found that in the BRCA group of 1–2 positive patients, as well as in the negative group, ovarian cancer of a high degree of malignancy (high-grade) was mainly detected. According to the spectrum of pathogenic mutations of BRCA genes, it was determined that 101 ovarian cancer patients were carriers of BRCA1 gene mutations (88.1%) and 6 BRCA2 gene mutations (11.9%). Not a single subject with simultaneous carrier of mutations in both genes was found. 86 patients were identified as carriers of germinal mutations of the BRCA1 gene and the BRCA2 – 11 gene in humans. A significant difference in the overall life expectancy was found between the groups examined, where in patients with mutations it was 62 months (p=0.003). Thus, it was shown that BRCA1/2 mutations are associated with an increase in the duration of overall survival, but the improvement was observed only in patients with primary and recurrent disease, and not in patients with advanced disease. However, BRCA1 and BRCA2 mutations were not individually associated with this indicator, although these results were limited by a small number of studies. Further elucidation of mutation characteristics and their impact on patient survival and response to therapy may lead to a more individualized approach to ovarian cancer treatment and improved outcomes.
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McNevin, Ciara S., Karen Cadoo, Anne-Marie Baird, Stephen P. Finn i Ray McDermott. "PARP Inhibitors in Advanced Prostate Cancer in Tumors with DNA Damage Signatures". Cancers 14, nr 19 (29.09.2022): 4751. http://dx.doi.org/10.3390/cancers14194751.
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Since 2010, significant progress has been made in the treatment of metastatic castrate resistant prostate cancer (mCRPC). While these advancements have improved survival, mCRPC remains a lethal disease, with a precision medicine framework that is lagging behind compared to other cancers. Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) studies in prostate cancer (PCa) have focused primarily on the homologous recombination repair (HRR) genes, specifically BRCA1 and BRCA2. While homologous recombination deficiency (HRD) can be prompted by germline or somatic BRCA1/2 genetic mutations, it can also exist in tumors with intact BRCA1/BRCA2 genes. While the sensitivity of PARPi in tumors with non-BRCA DNA damage signatures is not as well established, it has been suggested that genomic alterations in DNA damage repair (DDR) genes other than BRCA may confer synthetic lethality with PARPI in mCRPC. The aim of this review is to summarize the literature on PARPi and their activity treating BRCA and non BRCA tumors with DNA damage signatures.
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Meireles, Pedro Antunes, Catarina Bexiga, Sofia Fragoso, Sidónia Santos, Teresa Duarte i Fátima Vaz. "Abstract PO3-08-03: Comparing prognosis for BRCA1, BRCA2 and non-BRCA breast cancer". Cancer Research 84, nr 9_Supplement (2.05.2024): PO3–08–03—PO3–08–03. http://dx.doi.org/10.1158/1538-7445.sabcs23-po3-08-03.
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Abstract BACKGROUND Breast Cancer (BC) is the most diagnosed malignancy and the leading cause of cancer death in women worldwide. Approximately 10% of BC cases are hereditary, and up to 25% have been linked to germline variants of specific genes. Germline pathogenic variants (PV) in BRCA1 and BRCA2 genes, which account for 20% of familial BC cases, are highly penetrant and are associated with Hereditary Breast/Ovarian Cancer Syndrome. BRCA1 e BRCA2 are tumor suppressor genes, which interact with recombination/DNA repair proteins in pathways that participate in preserving intact chromosome structure, particularly on the DNA double chain. So far, more than 7000 PV were identified on these genes, including the Portuguese founder mutation (BRCA2 c.156_157insAlu), which accounts for a great proportion of BC cases in our country. BRCA1 and BRCA2 associated BC have distinct clinicopathological characteristics. Long-term follow-up data related to prognosis and survival of either BRCA1 or BRCA2 BC patients is conflicting. Two large meta-analysis report worse overall survival for both, when compared to sporadic BC, whereas two other large meta-analysis concluded on worse overall survival only for BRCA1 patients, with similar overall survival for BRCA2 patients. One meta-analysis reports similar survival for both groups. We report the analysis of our cohort of BRCA1/2 BC patients included in our multidisciplinary program. Our goal is to compare clinicopathological characteristics and prognosis between BRCA1 and BRCA2 BC and with a control group without germline PV (non-BRCA). METHODS Prospective follow-up was proposed to patients with a diagnosed BRCA1/2 PV. This study included BRCA1/2 patients with BC as first cancer diagnosis, observed between January 2000-May 2023. A control group, with similar phenotype and histological characteristics, without germline PV was used. Statistical analysis was performed to compare characteristics and prognosis between BRCA1 and BRCA2 and non-BRCA BC. ANOVA test was used to compare the age at diagnosis; chi-square was used to compare categorical variables, such as histological subtype and clinical staging at diagnosis; log rank was used to compare the primary and secondary endpoints – overall survival (OS) and invasive disease-free survival (iDFS), respectively. RESULTS From 1077 individuals who tested positive for BRCA1/2 PV, 345 patients had BC, mostly with a BRCA2 PV (66.4%). A control group of 339 individuals was assembled. BRCA2 BC was mostly luminal, as non-BRCA patients, compared with BRCA1 (73.8% vs. 65.8% vs. 25.9%, p< 0.001) and BRCA1 was mostly triple negative, compared with non-BRCA and BRCA2 (65.5% vs. 16.5% vs. 13.3%, p< 0.001). For a mean follow-up time of 10.6 years (±5.6), recurrence was similar, with central nervous system (CNS) metastases being more frequent for BRCA1 (66.7% vs. 23.7% in non-BRCA, and vs. 9.1% in BRCA2, p< 0.001), and bone metastases were predominant for BRCA2 BC (57.5% vs 33.3% in non-BRCA, and vs. 9.1% in BRCA1, p=0.003). Non-BRCA BC showed longer time to recurrence (99.3 months vs. 76.5 months in BRCA2 BC, and vs. 61.2 months in BRCA1 BC, p=0.010), although longer OS was observed in BRCA2 BC (136.2 months vs. 121.7 months in BRCA1 BC, and vs. 113.2 months in non-BRCA, p< 0.001). Development of second primary tumors was more frequent in BRCA2 patients, compared with BRCA1 (20.9% vs 9.2%, p=0.002). DISCUSSION In the Portuguese population, BRCA2 BC is more frequent than BRCA1 BC. Relapses occurred later for BRCA2 BC, affecting mostly the bone, whereas BRCA1 BC relapsed in CNS. As it is stated in the literature, BRCA1 BC is consistent with triple negative, as BRCA2 BC is more associated with luminal subtype. Differences in iDFS favored non-BRCA patients, whereas OS was significantly improved in BRCA2 BC patients. This is the biggest cohort presented in the Portuguese population and one of the biggest presenting BRCA2 BC patients. Table 1 Characteristics of patients according to BRCA1/2 mutation status (n = 684) Citation Format: Pedro Antunes Meireles, Catarina Bexiga, Sofia Fragoso, Sidónia Santos, Teresa Duarte, Fátima Vaz. Comparing prognosis for BRCA1, BRCA2 and non-BRCA breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-08-03.
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Brankovic-Magic, Mirjana, Jelena Dobricic, Radmila Jankovic, Irene Konstantopoulou, Drakoulis Yannoukakos i Sinisa Radulovic. "Identifying and testing for hereditary susceptibility to breast/ovarian cancer in Serbia: Where are we now?" Archive of Oncology 14, nr 3-4 (2006): 131–35. http://dx.doi.org/10.2298/aoo0604131b.
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About 90% of all breast cancers can be considered as sporadic, without inherited gene alteration. The rest of breast cancers (about 5 to 10%) are considered hereditary, most commonly caused by alterations of BRCA1/2 tumor suppressor genes. Lifetime risks for breast and ovarian cancers are increased among BRCA1/2 mutation carriers - 4 to 8 and 10 to 20 fold higher respectively. Due to the small proportion of hereditary form of disease, as well as to the high cost, BRCA testing is not screening test for general population. It is addressed to selected part of population that fit to recommended criteria. Full coding region sequencing of both genes is "gold standard" for detection of BRCA mutation. Concerning BRCA testing in Serbia, complete or partial sequencing of BRCA1/2 coding region was performed in 60 samples. The presence of 4 BRCA1 known mutations, previously detected elsewhere, has been shown: 185delAG, C61G, 3447del4 and 5382insC (detected twice). In BRCA1 gene, exon 16, an unclassified variant M1652I was found. Polymorphic variants in BRCA1 (8 polymorphisms) and BRCA2 (5 polymorphisms) genes were also detected. The majority of found BRCA1 and BRCA2 polymorphic variants are the missense ones and their influence on breast/ovarian cancer risk in our population has to be proved. Identification of BRCA mutations carriers and establishment of spectra and frequency of BRCA mutations should enable introduction of BRCA1/2 testing into the clinical practice of Serbia. .
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Foglietta, Jennifer, Vienna Ludovini, Fortunato Bianconi, Lorenza Pistola, Maria Sole Reda, Antonella Al-Refaie, Francesca Romana Tofanetti i in. "Prevalence and Spectrum of BRCA Germline Variants in Central Italian High Risk or Familial Breast/Ovarian Cancer Patients: A Monocentric Study". Genes 11, nr 8 (12.08.2020): 925. http://dx.doi.org/10.3390/genes11080925.
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Hereditary breast and ovarian cancers are mainly linked to variants in BRCA1/2 genes. Recently, data has shown that identification of BRCA variants has an immediate impact not only in cancer prevention but also in targeted therapeutic approaches. This prospective observational study characterized the overall germline BRCA variant and variant of uncertain significance (VUS) frequency and spectrum in individuals affected by breast (BC) or ovarian cancer (OC) and in healthy individuals at risk by sequencing the entire BRCA genes. Of the 363 probands analyzed, 50 (13.8%) were BRCA1/2 mutated, 28 (7.7%) at BRCA1 and 23 (6.3%) at BRCA2 gene. The variant c.5266dupC p.(Gln1756Profs) was the most frequent alteration, representing 21.4% of the BRCA1 variants and 12.0% of all variants identified. The variant c.6313delA p.(Ile2105Tyrfs) of BRCA2 was the most frequent alteration observed in 6 patients. Interestingly, two new variants were identified in BRCA2. In addition, 25 different VUS were identified; two were reported for the first time in BRCA1 and two in BRCA2. The number of triple-negative BCs was significantly higher in patients with the pathogenic BRCA1/2-variant (36.4%) than in BRCA1/2 VUS (16.0%) and BRCA1/2 wild-type patients (10.7%) (p < 0.001). Our study reveals that the overall frequency of BRCA germline variants in the selected high-risk Italian population is about 13.8%. We believe that our results could have significant implications for preventive strategies for unaffected BRCA-carriers and effective targeted treatments such as PARP inhibitors for patients with BC or OC.
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Bracci, Ciarapica, Zabaleta, Tartaglione, Pirozzi, Giuliani, Piva i in. "BRCA1 and BRCA2 Gene Expression: Diurnal Variability and Influence of Shift Work". Cancers 11, nr 8 (9.08.2019): 1146. http://dx.doi.org/10.3390/cancers11081146.
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BRCA1 and BRCA2 genes are involved in DNA double-strand break repair and related to breast cancer. Shift work is associated with biological clock alterations and with a higher risk of breast cancer. The aim of this study was to investigate the variability of expression of BRCA genes through the day in healthy subjects and to measure BRCA expression levels in shift workers. The study was approached in two ways. First, we examined diurnal variation of BRCA1 and BRCA2 genes in lymphocytes of 15 volunteers over a 24-hour period. Second, we measured the expression of these genes in lymphocytes from a group of shift and daytime workers. The change in 24-hour expression levels of BRCA1 and BRCA2 genes was statistically significant, decreasing from the peak at midday to the lowest level at midnight. Lower levels for both genes were found in shift workers compared to daytime workers. Diurnal variability of BRCA1 and BRCA2 expression suggests a relation of DNA double-strand break repair system with biological clock. Lower levels of BRCA1 and BRCA2 found in shift workers may be one of the potential factors related to the higher risk of breast cancer.
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Guo, Li yuan, Tiantian Han, Didi Guo, Juan Ma, Yaping Zhao, Fanfeng Bu, Siqi Chen, Wanglong Deng i Ran Ding. "Retrospective analysis of non-BRCA gene pathogenicity variation in Chinese patients with ovarian cancer." Journal of Clinical Oncology 40, nr 16_suppl (1.06.2022): 10584. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.10584.
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10584 Background: Ovarian cancer (OC) is the most lethal gynecologic cancer. Pathogenic (harmful) variants（PV) in BRCA1 and BRCA2 are the strongest hereditary risk factors for the development of ovarian cancer. To date, there is little information regarding the frequency of non- BRCA gene PV in Chinese women with OC that undergo genetic cancer risk assessment. In this study we analyzed wild-type BRCA1/2 OC patients (pts) registered in our database. Methods: Peripheral blood of 766 women, diagnosed with ovarian cancer, were taken from the recruited cases with the consent of performing germline genetic testing. Germline mutations including SNV, small INDEL were analyzed by next-generation sequencing (NGS). The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Of 766 OC pts, 460 pts (60%) underwent BRCA1/2 testing only, while 306 pts (40%) consented in multigene panel testing (MGPT). BRCA1/2 detection rate was 16.8% (129/766), while the detection rate for non- BRCA genes was 7.5% (23/306). There was a significant statistical difference in average age that the non- BRCA gene pathogenicity variation group was higher than the BRCA gene pathogenicity variation group (62 vs. 57, p=0.018). Wild-type B RCA1/2 OC pathogenic variants (PV), were diagnosed in BLM (n=4, 17.4%), ERCC5 (n=2, 8.7%), MUTYH (n=2, 8.7%), RAD51C (n=2, 8.7%), RAD51D (n=2, 8.7%), ATM (n=1, 4.4%), BRIP1 (n=1, 4.4%), CDH1 (n=1, 4.4%), CHEK2 (n=1, 4.4%), ERCC4 (n=1, 4.4%), LZTR1 (n=1, 4.4%), MSH3 (n=1, 4.4%), PALB2 (n=1, 4.4%), PMS2 (n=1, 4.4%), RAD50 (n=1, 4.4%) and SLX4 (n=1, 4.4%) genes. Of all the 23 non- BRAC gene pathogenicity variations, 57% (13/23) lay in the Homologous Recombination Repair (HRR) pathways. Moreover, a 48-year-old woman with ovarian cancer with two pathogenic variants of the [ BRCA2- MUTYH] genes was detected in the retrospective cohort study. Conclusions: BLM, ERCC5, MUTYH, RAD51C and RAD51D genes are the main contributors to hereditary wild-type BRCA1/2 OC in our cohort. The average age of non- BRCA gene pathogenicity variation group was higher than the BRCA gene pathogenicity variation group. Therefore, multi-gene PANEL detection is recommended for ovarian cancer patients, especially for older patients.
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Dias Nunes, Joana, Isabelle Demeestere i Melody Devos. "BRCA Mutations and Fertility Preservation". International Journal of Molecular Sciences 25, nr 1 (22.12.2023): 204. http://dx.doi.org/10.3390/ijms25010204.
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Hereditary cancers mostly affect the adolescent and young adult population (AYA) at reproductive age. Mutations in BReast CAncer (BRCA) genes are responsible for the majority of cases of hereditary breast and ovarian cancer. BRCA1 and BRCA2 act as tumor suppressor genes as they are key regulators of DNA repair through homologous recombination. Evidence of the accumulation of DNA double-strand break has been reported in aging oocytes, while BRCA expression decreases, leading to the hypothesis that BRCA mutation may impact fertility. Moreover, patients exposed to anticancer treatments are at higher risk of fertility-related issues, and BRCA mutations could exacerbate the treatment-induced depletion of the ovarian reserve. In this review, we summarized the functions of both genes and reported the current knowledge on the impact of BRCA mutations on ovarian ageing, premature ovarian insufficiency, female fertility preservation strategies and insights about male infertility. Altogether, this review provides relevant up-to-date information on the impact of BRCA1/2 mutations on fertility. Notably, BRCA-mutated patients should be adequately counselled for fertility preservation strategies, considering their higher sensitivity to chemotherapy gonadotoxic effects.
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Szentmartoni, Gyongyver, Dorottya Mühl, Renata Csanda, Attila Marcell Szasz, Zoltan Herold i Magdolna Dank. "Predictive Value and Therapeutic Significance of Somatic BRCA Mutation in Solid Tumors". Biomedicines 12, nr 3 (6.03.2024): 593. http://dx.doi.org/10.3390/biomedicines12030593.
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Ten percent of patients with breast cancer, and probably somewhat more in patients with ovarian cancer, have inherited germline DNA mutations in the breast and ovarian cancer genes BRCA1 and BRCA2. In the remaining cases, the disease is caused by acquired somatic genetic and epigenetic alterations. Targeted therapeutic agents, such as poly ADP-ribose polymerases (PARP) inhibitors (PARPi), have emerged in treating cancers associated with germline BRCA mutations since 2014. The first PARPi was FDA-approved initially for ovarian cancer patients with germline BRCA mutations. Deleterious variants in the BRCA1/BRCA2 genes and homologous recombination deficiency status have been strong predictors of response to PARPi in a few solid tumors since then. However, the relevance of somatic BRCA mutations is less clear. Somatic BRCA-mutated tumors might also respond to this new class of therapeutics. Although the related literature is often controversial, recently published case reports and/or randomized studies demonstrated the effectiveness of PARPi in treating patients with somatic BRCA mutations. The aim of this review is to summarize the predictive role of somatic BRCA mutations and to provide further assistance for clinicians with the identification of patients who could potentially benefit from PARPi.
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Barbero, Giovanna, Roberta Zuntini, Pamela Magini, Laura Desiderio, Michela Bonaguro, Anna Myriam Perrone, Daniela Rubino i in. "Characterization of BRCA Deficiency in Ovarian Cancer". Cancers 15, nr 5 (28.02.2023): 1530. http://dx.doi.org/10.3390/cancers15051530.
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BRCA testing is recommended in all Ovarian Cancer (OC) patients, but the optimal approach is debated. The landscape of BRCA alterations was explored in 30 consecutive OC patients: 6 (20.0%) carried germline pathogenic variants, 1 (3.3%) a somatic mutation of BRCA2, 2 (6.7%) unclassified germline variants in BRCA1, and 5 (16.7%) hypermethylation of the BRCA1 promoter. Overall, 12 patients (40.0%) showed BRCA deficit (BD), due to inactivation of both alleles of either BRCA1 or BRCA2, while 18 (60.0%) had undetected/unclear BRCA deficit (BU). Regarding sequence changes, analysis performed on Formalin-Fixed-Paraffin-Embedded tissue through a validated diagnostic protocol showed 100% accuracy, compared with 96.3% for Snap-Frozen tissue and 77.8% for the pre-diagnostic Formalin-Fixed-Paraffin-Embedded protocol. BD tumors, compared to BU, showed a significantly higher rate of small genomic rearrangements. After a median follow-up of 60.3 months, the mean PFS was 54.9 ± 27.2 months in BD patients and 34.6 ± 26.7 months in BU patients (p = 0.055). The analysis of other cancer genes in BU patients identified a carrier of a pathogenic germline variant in RAD51C. Thus, BRCA sequencing alone may miss tumors potentially responsive to specific treatments (due to BRCA1 promoter methylation or mutations in other genes) while unvalidated FFPE approaches may yield false-positive results.
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Woodward, Emma R., i Stefan Meyer. "Fanconi Anaemia, Childhood Cancer and the BRCA Genes". Genes 12, nr 10 (27.09.2021): 1520. http://dx.doi.org/10.3390/genes12101520.
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Fanconi anaemia (FA) is an inherited chromosomal instability disorder characterised by congenital and developmental abnormalities and a strong cancer predisposition. In less than 5% of cases FA can be caused by bi-allelic pathogenic variants (PGVs) in BRCA2/FANCD1 and in very rare cases by bi-allelic PGVs in BRCA1/FANCS. The rarity of FA-like presentation due to PGVs in BRCA2 and even more due to PGVs in BRCA1 supports a fundamental role of the encoded proteins for normal development and prevention of malignant transformation. While FA caused by BRCA1/2 PGVs is strongly associated with distinct spectra of embryonal childhood cancers and AML with BRCA2-PGVs, and also early epithelial cancers with BRCA1 PGVs, germline variants in the BRCA1/2 genes have also been identified in non-FA childhood malignancies, and thereby implying the possibility of a role of BRCA PGVs also for non-syndromic cancer predisposition in children. We provide a concise review of aspects of the clinical and genetic features of BRCA1/2-associated FA with a focus on associated malignancies, and review novel aspects of the role of germline BRCA2 and BRCA1 PGVs occurring in non-FA childhood cancer and discuss aspects of clinical and biological implications.
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Oktay, Kutluk, Ja Yeon Kim, David Barad i Samir N. Babayev. "Association of BRCA1 Mutations With Occult Primary Ovarian Insufficiency: A Possible Explanation for the Link Between Infertility and Breast/Ovarian Cancer Risks". Journal of Clinical Oncology 28, nr 2 (10.01.2010): 240–44. http://dx.doi.org/10.1200/jco.2009.24.2057.
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Purpose Germline mutations in BRCA genes are associated with breast and ovarian cancer susceptibility. Because infertility is associated with breast and ovarian cancer risks, we hypothesized that the mutations in the BRCA gene may be associated with low response to fertility treatments. Methods We performed ovarian stimulation in 126 women with breast cancer by using letrozole and gonadotropins for the purpose of fertility preservation by embryo or oocyte cryopreservation. As surrogates of ovarian reserve, the oocyte yield and the incidence of low response were compared with ovarian stimulation according to BRCA mutation status. Results Of the 82 women who met the inclusion criteria, 47 women (57%) had undergone BRCA testing, and 14 had a mutation in BRCA genes, of which two were of clinically undetermined significance. In BRCA mutation–positive patients, low ovarian response rate was significantly higher compared with BRCA mutation–negative patients (33.3 v 3.3%; P = .014) and with BRCA-untested women (2.9%; P = .012). All BRCA mutation–positive low responders had BRCA1 mutations, but low response was not encountered in women who were only BRCA2 mutation positive. Compared with controls, BRCA1 mutation– but not BRCA2 mutation–positive women produced lower numbers of eggs (7.4 [95% CI, 3.1 to 17.7] v 12.4 [95% CI, 10.8 to 14.2]; P = .025) and had as many as 38.3 times the odds ratio of low response (95% CI, 4.1 to 353.4; P = .001). Conclusion BRCA1 mutations are associated with occult primary ovarian insufficiency. This finding may, at least in part, explain the link between infertility and breast/ovarian cancer risks.
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Lee, Yen-Chien, Yen-Ling Lee i Chung-Yi Li. "BRCA Genes and Related Cancers: A Meta-Analysis from Epidemiological Cohort Studies". Medicina 57, nr 9 (30.08.2021): 905. http://dx.doi.org/10.3390/medicina57090905.
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Background and Objectives:BRCA1 and BRCA2 are genes located in different chromosomes that are disproportionately associated with hereditary breast and ovarian cancer syndrome. Their association with other cancers remains to be explored. Materials and Methods: We systematically reviewed cohort studies to explore the association of BRCA 1 and BRCA2 with various cancers except lung cancer. We searched PubMed, Medline (EBSCOhost) and relevant articles published up to 10 May 2021. The odds ratio, standardised morbidity rate and cancer-specific standardised incidence ratio were pooled together as relative risk (RR) estimates. Results: Twelve studies were included for analysis. BRCA mutation increased pancreatic and uterine cancers by around 3–5- and 1.5-fold, respectively. BRCA mutation did not increase brain cancer; colorectal cancer; prostate, bladder and kidney cancer; cervical cancer; or malignant melanoma. BRCA2 increased gastric cancer with RR = 2.15 (1.98–2.33). Conclusion: The meta-analysis results can provide clinicians and relevant families with information regarding increased specific cancer risk in BRCA1 and BRCA2 mutation carriers.
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Sekine, Masayuki, Koji Nishino i Takayuki Enomoto. "Differences in Ovarian and Other Cancers Risks by Population and BRCA Mutation Location". Genes 12, nr 7 (8.07.2021): 1050. http://dx.doi.org/10.3390/genes12071050.
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Hereditary breast and ovarian cancer is caused by a germline mutation in BRCA1 or BRCA2 genes. The frequency of germline BRCA1/2 gene mutation carriers and the ratio of germline BRCA1 to BRCA2 mutations in BRCA-related cancer patients vary depending on the population. Genotype and phenotype correlations have been reported in BRCA mutant families, however, the correlations are rarely used for individual risk assessment and management. BRCA genetic testing has become a companion diagnostic for PARP inhibitors, and the number of families with germline BRCA mutation identified is growing rapidly. Therefore, it is expected that analysis of the risk of developing cancer will be possible in a large number of BRCA mutant carriers, and there is a possibility that personal and precision medicine for the carriers with specific common founder mutations will be realized. In this review, we investigated the association of ovarian cancer risk and BRCA mutation location, and differences of other BRCA-related cancer risks by BRCA1/2 mutation, and furthermore, we discussed the difference in the prevalence of germline BRCA mutation in ovarian cancer patients. As a result, although there are various discussions, there appear to be differences in ovarian cancer risk by population and BRCA mutation location. If it becomes possible to estimate the risk of developing BRCA-related cancer for each BRCA mutation type, the age at risk-reducing salpingo-oophorectomy can be determined individually. The decision would bring great benefits to young women with germline BRCA mutations.
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Spizzo, Gilbert, Alberto Puccini, Joanne Xiu, Richard M. Goldberg, Axel Grothey, Anthony Frank Shields, Sukeshi Patel Arora i in. "Frequency of BRCA mutation in biliary tract cancer and its correlation with tumor mutational burden (TMB) and microsatellite instability (MSI)." Journal of Clinical Oncology 37, nr 15_suppl (20.05.2019): 4085. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.4085.
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4085 Background: Biliary tract cancers constitute ~3% of cancers worldwide with incidence increasing, especially for intrahepatic cholangiocarcinoma (IHC). The prognosis of these tumors remains dismal and novel treatment strategies are needed to improve overall survival. BRCA mutations occur in biliary tract cancers but their frequency in distinct sites of biliary tract cancer is unknown. Moreover, no data are available correlating BRCA mutation with immunogenic markers such as TMB, MSI, or PD-L1 expression. Methods: Tumor samples from 1288 primary biliary tract cancers, comprising IHC (n = 746), extrahepatic cholangiocarcinoma (EHC) (n = 189), gallbladder (GBC) (n=353) were profiled at Caris Life Sciences, Phoenix, AZ. Testing included NextGen SEQ (MiSeq on 47 genes, NextSeq on 592 genes) and PD-L1 IHC (SP142). TMB was calculated based on somatic nonsynonymous missense mutations, and MSI was evaluated by NGS of known MSI loci. Results: BRCA mutations were detected in 3.6% (N = 46) of samples ( BRCA1 0.6%, BRCA2 3%), no differences were seen based on the site of the tumor. In GBC and IHC BRCA2 mutations (4.0% and 2.7%) were more frequent than BRCA1 (0.3% and 0.4, p < 0.05) while in EHC, similar frequency was observed ( BRCA1: 2.1%; BRCA2: 2.6%). There was no significant association with gender or age. In BRCA-mutant biliary tract cancer the most frequently mutated genes were TP53 (55.6%), ARID1A (52.2%) and KRAS (26.1%), KMT2D/C (20%, 13%) and CDKN2A(13%). Overall, BRCA mutations were associated with a higher rate of MSI-H (19.5% vs 1.7%, p = 0.001) and higher TMB in both MSI-H and MSS tumors (p<0.05). When investigated separately, BRCA association with elevated TMB was seen in IHC and EHC, but not in GBC. No correlation was seen with PD-L1 expression. TP53, KMT2D/C, RB1, PTEN, KDM6A mutations and FGFR1 amplifications were significantly higher in BRCA mutated tumors (p < 0.05). Conclusions: BRCA mutations are found in a significant subgroup of biliary tract tumors and are associated with an immunogenic tumor profile. These data provide rationale for trials testing PARP inhibitors in combination with immunotherapy and targeted therapies in patients with BRCA-mutant biliary tract cancers that are MSS.
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Seeber, Andreas, Alberto Puccini, Joanne Xiu, Richard M. Goldberg, Axel Grothey, Anthony Frank Shields, Mohamed E. Salem i in. "Association of BRCA-mutant pancreatic cancer with high tumor mutational burden (TMB) and higher PD-L1 expression." Journal of Clinical Oncology 37, nr 15_suppl (20.05.2019): 4133. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.4133.
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4133 Background: In the U.S. 56,000 Americans are expected to be diagnosed with pancreatic cancer in 2019. Prognosis in pancreatic cancer is poor. Therefore, new treatment strategies are urgently needed to improve survival. BRCA1 and BRCA2 mutations have been described to be the most common genetic mutations involved in familial pancreatic cancer. The optimal treatment regimen to use in BRCA-mutant pancreatic cancer has still to be established. Moreover, no data are available on association of BRCA mutation with immune-associated markerssuch as tumor mutational burden (TMB), microsatellite instability (MSI) or PD-L1 expression. Methods: Tumor samples of 2824 patients with pancreatic ductal adenocarcinoma were analyzed for BRCA mutation by NGS and for other genes (MiSeq on 47 genes, NextSeq on 592 genes) at Caris Life Sciences, Phoenix, AZ. TMB was calculated based on somatic nonsynonymous missense mutations, and MSI was evaluated by NGS of known MSI loci. PD-L1 expression was evaluated using immunohistochemistry. Results: In 4.4% (N = 124) of all pancreatic adenocarcinoma samples BRCA mutations were detected. BRCA2 mutations were more common: 3.1% (N = 89) vs 1.1% BRCA1 mutations (N = 35). BRCA mutations were associated with younger age ( BRCA1: 61 yrs for mutated vs. 64 for wild-type, p = 0.07; BRCA2: 61 yrs vs. 64, p = 0.002; both: p < 0.001). BRCA mutations were associated with higher MSI-H frequency (4.8% vs. 1.2%, p = 0.002), elevated PD-L1 expression (22% vs. 11%, p < 0.001) and higher TMB (mean 8.7 mut/MB vs. 6.5, p < 0.001); the differences remain significant in MSS tumors (p < 0.05). BRCA-mutant pancreatic carcinomas showed a significantly lower mutation frequencies in TP53 (59% vs 73%, p = 0.001), CKDN2A (13% vs 25%, p = 0.006), but higher frequencies in APC (6.5% vs 2.2%), KMT2A (1.9% vs 0.2%), AMER1 (1.9 vs 0.5%) and SETD2 (3.7% vs 0.4%) mutations (p < 0.05 for all comparisons). Conclusions: BRCA mutations are found in a significant subgroup of pancreatic ductal adenocarcinoma and these carcinomas are associated with an immunogenic tumor profile. These data suggest evaluating PARP inhibitors in combination with immunotherapy in patients with BRCA-mutant pancreatic adenocarcinoma especially in tumors that are MSS.
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Seeber, Andreas, Kai Zimmer, Florian Kocher, Alberto Puccini, Joanne Xiu, Chadi Nabhan, Andrew Elliott i in. "Molecular characteristics of BRCA1/2 and PALB2 mutations in pancreatic ductal adenocarcinoma". ESMO Open 5, nr 6 (listopad 2020): e000942. http://dx.doi.org/10.1136/esmoopen-2020-000942.
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IntroductionPoly-(ADP)-ribose polymerase (PARP) inhibitors are successfully used for treatment of BRCA-mutated (mut) breast cancers and are under extensive evaluation for BRCA- and PALB2-mutated pancreatic ductal adenocarcinoma (PDAC). However, the optimal treatment regimen for BRCA/PALB2-mutated PDCA has yet to be established. Moreover, limited data are available on the association of BRCA/PALB2 gene alterations with other comutations and immunological biomarkers.Material and methodsTumour samples of 2818 patients with PDAC were analysed for BRCA1/2 PALB2 mutations and other genes by next-generation sequencing (NGS) (MiSeq on 47 genes, NextSeq on 592 genes). TMB was calculated based on somatic non-synonymous missense mutations. MSI-H/dMMR was evaluated by NGS, and PD-L1 expression was determined using immunohistochemistry.ResultsIn 4.2% (n=124) of all PDAC samples BRCA mutations have been detected. BRCA2 mutations were more commonly observed than BRCA1 mutations (3.1%(n=89) vs 1.1% [n=35], p<0.0001). BRCA2 mutation was associated with an older age (64 vs 61 years for wild-type (wt), p=0.002) and PALB2 mutation was observed more frequently in female than in male patients. BRCA and PALB2 mutations were associated with MSI-H/dMMR compared with wt (BRCA: 4.8% vs 1.2%, p=0.002; PALB2: 6.7% vs 1.3 %, p=0.18), PD-L1 expression of >1.0% (BRCA: 21.8% vs wt 11.2%, p<0.001, PALB2: 0.0% vs 12.4 %, p=0.38) and high TMB (BRCA: mean 8.7 vs 6.5 mut/MB, p<0.001; PALB2: 10.6 mut/Mb vs 6.6 mut/Mb, p=0.0007). Also, PD-L1 expression and TMB differed between BRCA and PALB2 mutation and wt samples in MSS tumours (p<0.05). BRCA-mutated and PALB2-mutated PDACs were characterised by a different mutational profile than was observed in wt tumours.ConclusionsBRCA and PALB2 mutations were found in a significant subgroup of PDACs. These mutations were associated with a distinct molecular profile potentially predictive for response to immune-checkpoint inhibitor therapy. Therefore, these data provide a rationale to evaluate PARP inhibitors in combination with immune-checkpoint inhibitors in patients with BRCA/PALB2-mutated PDAC.
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Richters, Lisa Katharina, Philip C. Schouten, Stefan Kommoss, Jan Hauke, Alexander Burges, Dimo Dietrich, Ahmed El-Balat i in. "BRCA-like classification in ovarian cancer: Results from the AGO-TR1-trial." Journal of Clinical Oncology 35, nr 15_suppl (20.05.2017): 5546. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.5546.
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5546 Background: BRCA associated cancers show a distinct pattern of genomic gains and losses that is associated with impaired repair of DNA double-strand breaks via homologous recombination (HR). We investigated whether BRCA1- and BRCA2-like classifiers could predict BRCA1 and BRCA2 mutation status in ovarian cancer. In addition, we explored whether promoter hypermethylation or mutations in other genes involved in DNA repair associate with a BRCA-like profile in ovarian cancer. Methods: The AGO-TR1 cohort study (NCT02222883 ) enrolled 525 consecutive patients with primary (PR) and platinum sensitive relapsed (RE) ovarian cancer to perform paired mutational analysis of germline and tumor tissue. We performed mutation panel sequencing, BRCA1 promoter hypermethylation and low-coverage whole genome sequencing to classify samples as BRCA1-like or BRCA2-like in 298 ovarian cancer samples (PR: n = 159, RE: n = 139). Results: A BRCA-like profile was observed in 58.1% of the samples without germline or somatic mutation in BRCA1/2 (n = 179; BRCA1-like: n = 26, BRCA2-like: n = 23, BRCA1- and 2-like: n = 55). There was no significant difference between PR- and RE-cases (54.5% vs 61.3%). 64 of 70 BRCA1 germline mutation carriers could be identified by the BRCA1-like classifier (sensitivity: 0.91). The BRCA2-like classifier identified BRCA2 germline mutation carrier with a sensitivity of 0.71 (17 of 24). The complementary use of both classifiers led to the detection of 22 of 25 somatic mutations in BRCA1 (16/16) or - 2 (6/9). Remarkably, 12 of 13 tumor samples from germline RAD51C mutation carriers were recognized by the BRCA1-like classifier (sensitivity: 0.92). No correlation of PALB2 mutation status (n = 7) with BRCA-like profile was observed. Of 28 tumor samples with a BRCA1 promoter hypermethylation 26 had a BRCA1-like profile (sensitivity: 0.93). Conclusions: A high number of ovarian cancer cases display a BRCA-like profile. Mutations (germline and somatic) in BRCA1, BRCA2, RAD51C as well as BRCA1 hypermethylation strongly associate with a BRCA-like profile and can explain 146 of 212 cases. Future studies will investigate whether the classifiers identify patients who benefit from HR-deficiency directed approaches beyond the BRCA mutation status. Clinical trial information: NCT02222883.
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Shweash, Muhannad, Saddam Jumaa Naseer, Maisam Khider Al-anii i Thulfiqar Fawwaz Mutar. "A MOLECULAR-BASED APPROACH TO INVESTIGATE BREAST CANCER 1 AND BREAST CANCER 2 STATUS IN OVARIAN CANCER AMONG IRAQI WOMEN". Asian Journal of Pharmaceutical and Clinical Research 11, nr 7 (7.07.2018): 199. http://dx.doi.org/10.22159/ajpcr.2018.v11i7.25217.
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Objective: Cancer ovary is one of the fatal gynecologic malignancies worldwide. Since breast cancer (BRCA) genes are considered tumor suppressor genes and play important roles in cancer by repairing of chromosomal damage with the error repair of DNA breaks. Therefore, breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) gene mutations strongly enhance the development of ovarian cancer risk among women. Here, we report that both genes are an essential mediator of progress ovarian cancer, to determine the influence of BRCA1 and BRCA2 mutations in the improvement of ovarian cancer.Methods: A total of 25 subjects were chosen for the genetic studies, and three groups were recruited: fifteen ovarian cancer patients group, five healthy controls, and five first-degree relatives to a known case of ovarian cancer patients.Results: A genetic analysis revealed that a strong correlation exists between both gene mutations’ status in ovarian cancer, and BRCA gene mutations (185delAG, 5382insC, and 4153delA in BRCA1 and 6174delT in BRCA2) remained to establish to have a relatively high frequency among people in this study among ovarian cancer patients. Furthermore, seven patients with ovarian cancer carried all of the four investigated mutations, and five had three mutations.Conclusion: Otherwise, BRCA gene frequency showed low prevalence among first-degree relatives, and to a lesser extent among healthy controls, with only a few had all of the mutations combined. These data demonstrate for the first time a molecular link between BRCA1 and BRCA2 mutations in ovarian cancer progression in Iraq.
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Hou, Minmin, Li Sun, Xiuzhang Yu, Pengyao Du, Chuang Liu, Fanfan Meng, Yaxuan Zhang i Ling Li. "The landscape of BRCA1 and BRCA2 alterations in Chinese ovarian cancer patients." Journal of Clinical Oncology 41, nr 16_suppl (1.06.2023): e17565-e17565. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e17565.
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e17565 Background: BRCA1 and BRCA2 are tumour suppressor genes, involved in the homologous repair of double-stranded DNA breaks, located at 17q21.31 and 13q13.1, respectively. Germline BRCA1/2 mutations are identified in 13-15% of ovarian cancers (OC), while an additional 5-7% of ovarian cancers harbor somatic BRCA1/2 mutations among foreign populations. To determine the landscape of germline and somatic pathogenic BRCA1 and BRCA2 alterations in Chinese patients with ovarian cancer tested by next‐generation sequencing (NGS), with the aim of defining the best strategy to be implemented in future routine testing. Methods: 472 normal-paired samples from Chinese patients with ovarian cancers were analyzed using hybridization capture-based next generation sequencing. Somatic and germline mutations were identified including 500 genes associated with tumor development. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (InDels), copy number alterations (CNA) and gene fusions and rearrangements. Results: Overall, 472 ovarian cancer patients underwent somatic and/or germline NGS analysis, the BRCA1 and BRCA2 genes sequenced in this study covers all targeted coding exons and exon-intron boundaries. Among these patients, 54/472 (11.4%) patients carried BRCA( BRCA1/2) mutations. Inside, there were 43/472 (9.1%) patients occurred somatic BRCA mutations, 62.8% (27/43) of variants were in BRCA1 and 37.2% (16/43) were in BRCA2. Furthermore, 3 cases carried BRCA1 and BRCA2 somatic co-mutation, of which only 1 showed BRCA1/ BRCA2 copy number losses. In 54 OC patients who carried BRCA mutations, 10 patients occured copy number alterations, of which 6 patients showed BRCA1 copy number losses, 4 patients showed BRCA2 copy number losses, and 1 patient showed BRCA2 copy number gains. Germline BRCA variant was detected in 18/472 (3.8%) patients, 66.7% (12/18) of variants were in BRCA1 and 33.3% (6/18) were in BRCA2. Of the 12 BRCA1 germline mutations, 11 were pathogenic heterozygous mutations (c.2679_2682del; c.2101_2102del; c.5085_5086insT; c.1660G > T; c.4810C > T; c.1504_1508del; c.1465G > T; c.1480C > T; c.2110_2111del; c.4185+1G > A; c.81-2A > G), one was likely pathogenic heterozygous mutation (c.5216A > G). Of the 6 BRCA 2 germline mutations, four were pathogenic heterozygous mutations (c.5722_5723del; c.5291C > G; c.5164_5165del; c.3109C > T), one was likely pathogenic heterozygous mutation (c.869_870del), and one was uncertain significance heterozygous mutation (c.7976+3A > G). Conclusions: This study revealed the molecular features of BRCA1 and BRCA2 in Chinese ovarian cancer patients, which could help to identify therapeutic targets and personalize therapy management, leading to improved patient outcomes as predictive biomarkers or platinum-based therapy.
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De Bono, Johann S., Nobuaki Matsubara, Nicolas Penel, Niven Mehra, Michael Paul Kolinsky, Emmanuelle Bompas, Susan Feyerabend i in. "Exploratory gene-by-gene analysis of olaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): PROfound." Journal of Clinical Oncology 39, nr 6_suppl (20.02.2021): 126. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.126.
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126 Background: The Phase 3 PROfound trial (NCT02987543) met its primary endpoint and key secondary endpoints, including improved overall survival (OS) for olaparib in men with mCRPC with alterations in BRCA1, BRCA2, or ATM (Cohort A). We report gene-by-gene analysis of olaparib antitumor activity among the 15 prespecified homologous recombination repair (HRR) genes. Methods: Pts were randomized to olaparib (300 mg bid; n=256) or physician’s choice of enzalutamide or abiraterone (control; n=131). Exploratory analyses in pts with alterations in BRCA1 and/or BRCA2 (BRCA, regardless of co-occurring alterations with other HRR genes) or in single genes were conducted. Results: Evidence of olaparib antitumor activity was observed in subgroups with >10 pts (table). Data for pts with alterations in only BRCA1, BRCA2, PPP2R2A, RAD51B, RAD54L, PALB2, BRIP1, CHEK1, BARD1, and RAD51D will be reported (no FANCL or RAD51C enrolled). Conclusions: Small subgroups limit interpretation for some genes. Olaparib antitumor activity is greatest in pts with BRCA alterations, with a spectrum of clinical sensitivity to olaparib as defined by rPFS and OS across the broader population with alterations in other HRR genes. Clinical trial information: NCT02987543. [Table: see text]
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Atchley, Deann P., Constance T. Albarracin, Adriana Lopez, Vicente Valero, Christopher I. Amos, Ana Maria Gonzalez-Angulo, Gabriel N. Hortobagyi i Banu K. Arun. "Clinical and Pathologic Characteristics of Patients With BRCA-Positive and BRCA-Negative Breast Cancer". Journal of Clinical Oncology 26, nr 26 (10.09.2008): 4282–88. http://dx.doi.org/10.1200/jco.2008.16.6231.
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Purpose Mutations in the BRCA1 and BRCA2 genes confer greater risk of developing breast cancer. We determined whether tumor pathologic features and clinical features differ in patients with and without BRCA mutations. Patients and Methods Tumor pathologic features and clinical characteristics were examined in 491 women with breast cancer who underwent genetic testing for BRCA mutations between 1997 and 2006. A retrospective review of medical records was conducted to determine clinical characteristics including ethnicity, age and clinical stage at diagnosis, age at parity, number of full-term pregnancies, use of oral contraceptives and hormone replacement therapy, and BRCA mutation status. Tumor pathology was reviewed to determine histologic type, tumor grade, and estrogen receptor, progesterone receptor, and HER-2/neu status. Results Of the 491 patients with identified breast cancers, 391 patients were BRCA negative, and 86 patients were BRCA positive. Triple-negative breast cancer (ie, those with negative estrogen receptor, progesterone receptor, and HER-2/neu status) was diagnosed in 57.1% of the BRCA1-positive patients, 23.3% of the BRCA2-positive patients, and 13.8% of the BRCA-negative patients. BRCA1 mutation carriers had higher nuclear grade tumors than the other two groups (P < .001). Of the triple-negative cancer patients, BRCA2 mutation carriers were older when diagnosed than BRCA1 mutation carriers and noncarriers (P < .01). Conclusion These results suggest that tumors associated with BRCA1 mutations may be divided into two distinct groups, triple-negative and non–triple-negative groups. Future studies should seek to determine whether patients with BRCA1 mutations and triple-negative breast cancer respond to treatment better than BRCA-negative patients with similar tumor pathology.
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Novikova, EI, EA Kudinova, VK Bozhenko i VA Solodkiy. "Characteristics of BRCA-associated breast cancer in the population of the Russian Federation". Features of HIV and SARS-CoV-2 coinfection in a pandemic, nr 2021(1) (luty 2021): 24–29. http://dx.doi.org/10.24075/brsmu.2021.006.
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"Standard" diagnostic panels allow identification of only a few of BRCA1 and BRCA2 gene mutations most common in a population. Therefore, tests relying on such panels may return false negative results, since the coding regions of these genes may have other defects. For breast cancer (BC) patients, false negative test results may translate into selection of inadequate therapy by their doctors. This study aimed to identify the features of BRCA-associated breast cancer in the population of the Russian Federation. The study included breast cancer patients (n = 4440). At the first stage, all patients were screened for the eight most common BRCA1 and BRCA2 genes mutations with the help of real-time PCR. Next, patients that exhibited clinical signs of a hereditary disease (CSHD) in the absence of common mutations (n = 290) had the entire coding regions of BRCA1 and BRCA2 genes studied with next generation sequencing (NGS). "Standard" mutations in the BRCA1 and BRCA2 genes were identified in 169 (3.8%) cases. In the CSHD group, such mutations were revealed in 15.4% of cases. NGS uncovered 33 rare pathogenic BRCA1 and BRCA2 gene mutations in 40 out of 290 breast cancer patients (13.8%). It was concluded that among the residents of the Russian Federation, the range of pathogenic variants of BRCA-associated breast cancer is wide, and it stretches beyond the mutations considered by the "standard" diagnostic panels. Analysis of the entire coding regions of BRCA1 and BRCA2 genes allows increasing efficiency of detection of germline mutations in breast cancer patients at least twofold.
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Antunes Meireles, Pedro, Sofia Fragoso, Teresa Duarte, Sidónia Santos, Catarina Bexiga, Priscila Nejo, Ana Luís i in. "Comparing Prognosis for BRCA1, BRCA2, and Non-BRCA Breast Cancer". Cancers 15, nr 23 (3.12.2023): 5699. http://dx.doi.org/10.3390/cancers15235699.
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Background: Germline pathogenic variants (PV) in BRCA1 and BRCA2 genes, which account for 20% of familial breast cancer (BC) cases, are highly penetrant and are associated with Hereditary Breast/Ovarian Cancer Syndrome. Previous studies, mostly including higher numbers of BRCA1 BC patients, yielded conflicting results regarding BRCA1/2 BC outcomes. In the Portuguese population, BRCA2 BC is diagnosed more frequently than BRCA1 BC. We aimed to compare clinicopathological characteristics and prognosis between BC patients with BRCA1 and BRCA2 mutations and a control group without germline PV (BRCA-wt). Furthermore, we explored the frequency and outcomes of risk-reducing surgeries in BRCA-mutated patients. Methods: Prospective follow-up was proposed for patients with a diagnosed BRCA1/2 PV. For this study, a matched control group (by age at diagnosis, by decade, and by stage at diagnosis) included BC patients without germline PV. We compared overall survival (OS) and invasive disease-free survival (iDFS) within the three groups, and the use of risk-reducing surgeries among the BRCA cohort. Results: For a mean follow-up time of 113.0 months, BRCA-wt patients showed longer time to recurrence (p = 0.002) and longer OS (p < 0.001). Among patients with BRCA mutations, no statistical differences were found, although patients with BRCA2 BC had longer iDFS and OS. Uptake of risk-reducing surgeries (contralateral prophylactic mastectomy and salpingo-oophorectomy) were negative predictors of invasive disease and death, respectively. Conclusions: Testing positive for a BRCA PV is associated with a higher risk of relapse and death in patients with BC in the Portuguese population. Risk-reducing mastectomy and salpingo-oophorectomy were associated with lower incidence of relapse and longer median iDFS and OS, respectively.
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Incorvaia, Lorena, Alessia Fiorino, Anna Paola Carreca, Stefania Gori, Saverio Cinieri, Giuseppe Curigliano, Chiara Brando i in. "Heart toxicity effects (HTE) of anthracyclines-containing regimens (ACRs) in patients with breast cancer (BC) carrying mutational signature of homologous recombination deficiency (HRD)." Journal of Clinical Oncology 40, nr 16_suppl (1.06.2022): 10519. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.10519.
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10519 Background: BRCA1/2 genes ( BRCA) play a prominent role in the Homologous Recombination Repair (HRR) pathway. Following the technological progress and deeper knowledge on BRCA-related cancers, the demand for genetic testing is rapidly increasing. Beyond BRCA1/2, other genes are involved in the HRR, including ATM, PALB2, RAD51, and BARD1. Due to the important role in the cellular repair process, deleterious variants in HRR genes may cause inadequate DNA damage repair in cardiomyocytes. The role of BRCA1/2 as predisposing condition to cardiac dysfunction is debated, and the contribution by no- BRCA genes is still unknown. Methods: This is a multicenter, retrospective, study to investigate the risk of heart-insults from anthracyclines on adjuvant setting in BC patients carrying germline pathogenic or likely pathogenic variant (PV) (classes IV and V) in BRCA and no- BRCA HRR pathway genes. We collected genetic and clinical data, and evaluated the left ventricular ejection fraction (LVEF) at cardiac ultrasound, before starting ACR therapy, and at subsequent time points, according to clinical indications. Results: Three hundred and sixty (360) BC patients, aging 22 to 80, were included in this study; 131 patients were carriers of germline PVs in HRR pathway genes: 52 in BRCA1 gene (39.7%), 48 in BRCA2 gene (36.6%), and 31 harbored PVs in no- BRCA HRR pathway genes (23.7%), including PVs in PALB2, CHEK2, ATM, RAD51C, RAD50 and BARD1 genes. In the cohort of 229 patients without PVs, 47 showed variant of uncertain significance (VUS, class III), and 173 had genetic testing not informative. When LVEF between the groups was compared, the difference was not significant for the pre-treatment values. Notably, individuals carrying BRCA or other HRR gene deleterious variants, showed a statistically significant reduction of LVEF > 5% at the second time-point (3 month), compared to the LVEF pre-treatment values (p = 0.001). A marked LVEF reduction was in mutated patients treated with risk-reducing bilateral salpingo-oophorectomy prior to age 40, body mass index > 25, and type-II diabetes mellitus. The latter risk factor was probably related to increased risk developing insulin-resistance reported for BRCA-mutated patients. Conclusions: Our data suggest that PVs in BRCA or other genes involved in HRR pathway, can lead to impaired homologous recombination, thus increasing sensitivity of cardiac cells to DNA damaging chemotherapy in BC patients. In this subgroup of patients, other measurements such as the global longitudinal strain (GLS), and a more in-depth assessment of risk factors, could be proposed to optimize cardiovascular risk-management and to improve long-term survival.
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Abida, Wassim, Alan Haruo Bryce, Nicholas J. Vogelzang, Robert J. Amato, Ivor John Percent, Jeremy David Shapiro, Raymond S. McDermott i in. "Genomic characteristics of deleterious BRCA1 and BRCA2 alterations and associations with baseline clinical factors in patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled in TRITON2." Journal of Clinical Oncology 37, nr 15_suppl (20.05.2019): 5031. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.5031.
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5031 Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in patients with mCRPC who have a deleterious germline or somatic alteration in BRCA ( BRCA1 or BRCA2) or 1 of 13 other DNA damage repair genes. Here we present analyses of tumor genomics and baseline clinical characteristics in mCRPC patients with a deleterious alteration in BRCA. Methods: Plasma (baseline) and tissue (archival or baseline) samples from patients with a deleterious alteration in BRCA were analyzed using Foundation Medicine next-generation sequencing assays. The alterations and zygosity of the alterations that were detected, as well as the somatic/germline status from Color Genomics testing, were summarized. Associations between genomic alterations, DNA yield, allele frequency, and baseline clinical characteristics were investigated. Results: Results are shown in the Table for a cohort of 40 BRCA2 and 5 BRCA1 patients enrolled in TRITON2 (Abida W et al. Presented at ESMO 2018. Abst 793PD). A biallelic alteration was observed in 21 of the 22 BRCA2 patients (95%) for whom alteration zygosity could be determined. Among the 5 BRCA1 patients, 1 alteration was monoallelic and 4 were of unknown zygosity. Co-occurring alterations in cancer-related or DNA damage repair genes were observed in many patients with BRCA alterations. At baseline, cell-free DNA (cfDNA) yield correlated positively with the sum of target lesions (STL; P= 0.04), but not with prostate-specific antigen (PSA) levels ( P= 0.86). No correlation was observed between allele frequency of the BRCA alteration baseline STL ( P= 0.68) or PSA levels ( P= 0.97). Conclusions: Patients with a BRCA mutation enrolled in TRITON2 demonstrate a profile of genomic alterations consistent with that of prior studies of patients with mCRPC. Plasma cfDNA profiling showed a correlation between baseline cfDNA yield and measurable tumor burden, but not baseline PSA. Clinical trial information: NCT02952534. [Table: see text]
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Reisinger, Raquel, Sergiusz Wesolowski, Umang Swami, Pedro C. Barata, Edgar Javier Hernandez, Roberto Nussenzveig, Gordon Lemmon i in. "Differences in the genomic landscape of advanced prostate cancer (aPC) patients (pts) with BRCA1 versus BRCA2 mutations as detected by machine learning analysis of the comprehensive genomic profile (CGP) of cell-free DNA (cfDNA)." Journal of Clinical Oncology 39, nr 6_suppl (20.02.2021): 162. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.162.
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162 Background: PARP inhibitors (PARPi) provide significant clinical benefit for men with aPC with BRCA 1 and BRCA 2 mutations. However, in clinical trials, pts with BRCA1 mutations appeared to derive less benefit than pts with BRCA2 (De Bono et al., 2020). Probabilistic Graphical Models (PGMs) are artificial intelligence (AI) algorithms that capture multivariate, multi-level dependencies in complex patterns in large datasets while retaining human interpretability. We hypothesize that PGMs can reveal variants in BRCA1 and 2 that co-segregate with other known pathogenic variants and may explain the difference in response to PARPi therapy. Methods: Multilevel gene interdependencies between BRCA1 or BRCA2 were assessed using a Bayesian Network (BN) machine learning approach and Fisher’s exact test. CGP was performed by a validated cfDNA NGS panel that sequenced 74 clinically relevant cancer genes (Guardant360, Redwood City, CA). Only variants of known significance and those of unknown significance with a pathogenic REVEL score were included in the analysis. Results: Of 4671 men with aPC undergoing cfDNA CGP, 1248 men with somatic mutations in BRCA1, BRCA2, ATM, or combinations of the three were included in the analysis. The Bayesian network analysis demonstrated positive interdependencies between pathogenic variants in BRCA1 and 7 other genes. A positive interdependency between BRCA2 and 2 genes was present (table). ATM displayed negative interdependency with both BRCA 1 and 2. Conclusions: Our results demonstrate a decreased association of BRCA2 versus BRCA1 with known or predicted pathogenic variants at other loci. This may explain increased sensitivity of aPC with BRCA2 mutations to PARPi due to fewer concurrent resistance pathways. For example, alteration of ERBB2, which segregates strongly with BRCA1, is known to induce tumor progression and invasion in aPC and is associated with castration-resistance. These hypothesis-generating data reveal differential genomic signatures associated with BRCA1 as compared to BRCA2 and may inform development of future combinatorial treatment regimens for these pts. [Table: see text]
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Burciaga-Flores, Carlos H., Diana C. Perez-Ibave, Maria L. Garza-Rodriguez, Oscar Vidal-Gutierrez, Cynthia M. Villarreal-Garza i Dione Aguilar y. Mendez. "Abstract 3947: Non-BRCA variants in hereditary breast and ovarian cancer patients in the Northern Mexico population". Cancer Research 84, nr 6_Supplement (22.03.2024): 3947. http://dx.doi.org/10.1158/1538-7445.am2024-3947.
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Abstract Background: Hereditary cancer syndromes explain 5-10% of all cancer cases. Germline pathogenic variants in BRCA1 and BRCA2 genes (BRCA) are present in 2-3% of all breast cancer (BC), and 15% of all ovarian cancer (OC) cases. BRCA1 and BRCA2 pathogenic variants (PV) represent 25-28% of BC and 40% of OC patients with a positive familial history. BRCAs are the most studied genes for the prevalence, family history, preventive surgeries, and target treatment options in both BC and OC. There are other genes, important in the diagnosis, pathogenesis, and treatment options of the patients: TP53, PALB2, CHEK2, among others. This study aims to identify the prevalence of non- BRCA genes related to the development of hereditary breast and ovarian cancer syndrome in patients of Northeast Mexico. Methods: This is a multicenter study that recruited patients from two reference oncology centers in Nuevo Leon, Mexico: the CECIL (The CUCC Early Cancer Detection Clinic) Hereditary Cancer Registry and Hereditary Cancer Program from Tec Salud. From March of 2016 to March of 2023, a total of 872 patients meeting NCCN criteria were evaluated by Medical Geneticists from both centers and were tested with NGS multigene cancer panels. Results: A total of 665 (76.26%) patients with a clinical diagnosis of HBOC (Hereditary Breast Hereditary Cancer Syndrome) were included. We found 310 (46.6%) patients had at least one variant, 180 (58%) with at least one pathogenic variant, and 130 (41%) with a VUS (a variant of uncertain significance). BRCA1 was found in 79 (43.8%) and BRCA2 in 32 (17.7%) of all PV. Non-BRCA PV were found in 69 (38.3%) patients: 4 ATM, 2 BLM, 3 BRIP1, 22 CHEK2, 4 CDKN2A, 5 MUTYH, 10 PALB2, 4 RAD51C, 2 SDHA, 2 TP53, 2 WRN, CDH1, CDK4, DICER, MSH3, NBN, PTEN, RAD50, USH2A one of each. Is remarkable that 19 of the 22 patients with CHEK2 and 5 of the 10 patients with PALB2 had the recurrent PV c.707T>C and c.2167_2168del, respectively. Conclusions: Non-BRCA PV in Northern Mexico corresponds to one-third of the BC and OC cases, including HRD (homologous recombination deficiency) genes. HDR patient carriers are potential targets of iPARP therapies. This project reinforces the fact that multigene panels should be employed to ensure a complete diagnosis in hereditary cancer patients. Citation Format: Carlos H. Burciaga-Flores, Diana C. Perez-Ibave, Maria L. Garza-Rodriguez, Oscar Vidal-Gutierrez, Cynthia M. Villarreal-Garza, Dione Aguilar y Mendez. Non-BRCA variants in hereditary breast and ovarian cancer patients in the Northern Mexico population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3947.
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Allain, Dawn C., Kevin Sweet i Doreen M. Agnese. "Management Options after Prophylactic Surgeries in Women with BRCA Mutations: A Review". Cancer Control 14, nr 4 (październik 2007): 330–37. http://dx.doi.org/10.1177/107327480701400403.
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Background Although breast cancer is relatively common, only about 5% of cases are due to inheritance of highly penetrant cancer susceptibility genes. The majority of these are caused by mutations in the BRCA1 and BRCA2 genes, which are also associated with an increased risk of ovarian cancer. Increased surveillance, chemoprevention, and prophylactic surgeries are standard options for the effective medical management of mutation carriers. However, optimal management of female carriers who choose to undergo prophylactic surgeries is still poorly understood. Methods The authors provide an overview of the current literature regarding medical management options for women carriers of BRCA1 and BRCA2 gene mutations and the implications for those individuals who have chosen to undergo prophylactic surgeries. Results BRCA mutation carriers who opt for prophylactic surgeries are still at risk for development of malignancy, and appropriate monitoring is warranted. Conclusions There are limited data on the appropriate medical management for BRCA mutation carriers after prophylactic surgeries. However, a management plan can be extrapolated from the general management recommendations for surveillance and other risk-reducing strategies in BRCA-positive individuals.
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Oshi, Masanori, Shipra Gandhi, Rongrong Wu, Mariko Asaoka, Li Yan, Akimitsu Yamada, Kazutaka Narui i in. "Establishment of a novel BRCAness score that predicts response to PARP inhibitors." Journal of Clinical Oncology 40, nr 16_suppl (1.06.2022): 549. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.549.
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549 Background: BRCAness is a generic term used to describe characteristic features of homologous recombination deficiency (HRD) mimicking mutations in BRCA genes. Although clinical genetic testing has increased the detection of mutations in BRCA1 and BRCA2, we hypothesized that a measure to quantify BRCAness will identify the responders to PARP inhibitors that cause synthetic lethality in BRCA mutation tumors. Methods: The BRCAness score was established by using gene set variation analysis (GSVA) algorithm on 34 BRCA-mutation related genes. We investigated the clinical relevance of the score by performing silico analyses of 6245 breast cancer patients using multiple independent large cohorts in this study. Results: A score to quantify BRCAness was generated using gene set variation analysis algorithm on 34 BRCA1-mutation related genes selected by high AUC levels in ROC curve between BRCA1 mutation and wildtype breast cancer. The score was significantly associated with BRCA1 mutation, high overall mutation load and intratumoral heterogeneity as well as high HRD, DNA repair and MKI67 expression regardless of mutation in BRCA gene. High score tumor enriched not only DNA repair, but also five cell proliferation-related gene sets (E2F targets, G2M checkpoint, MYC targets v1 and v2, and MITOTIC signaling) in Hallmark collection (all false discovery rate < 0.10). Breast cancers with high score were significantly associated with higher infiltration of anti-cancerous immune cells and higher cytolytic activity. Not all breast cancer cell lines with BRCA-mutation showed high score and the other cells in human breast cancer tumor microenvironment were contributing to the score. We found that the BRCAness score was the highest in triple-negative among subtypes consistently in all cohorts (all p < 0.001). Finally, BRCAness was associated with response to chemotherapy and correlated strongly with response to PARP inhibitor in both triple-negative (AUC = 0.815) and ER-positive/HER2-negative breast cancer (AUC = 0.715). Conclusions: We established a novel BRCAness score using mRNA expression of BRCA-mutation-related genes and found that it associates with DNA repair and response to PARP inhibitor regardless of BRCA mutation.
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Tabaliuk, Y. O., L. A. Rybchenko, B. T. Klimuk i S. V. Klymenko. "Screening for mutations in BRCA1 and BRCA2 genes and related perspectives for the healthcare system". Visnik ukrains'kogo tovaristva genetikiv i selekcioneriv 18, nr 1-2 (29.01.2021): 44–57. http://dx.doi.org/10.7124/visnyk.utgis.18.1-2.1354.
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In the article there were looked some aspects of the knowledge regarding mutations in BRCA1 BRCA2 genes that have been accumulated since the first report on role of these genes in the development of breast and ovarian cancer. Most of them have practical worth related to the detection of mutations, as well as the prevention and treatment of associated ovarian cancer (the article focuses specifically on ovarian cancer, conditioned to relatively less amount of information on this pathology). There has been paid attention to the rational assignment of a genetic test on the presence of mutations in BRCA genes.Keywords: ovarian cancer, mutations in BRCA1 BRCA2 genes, screening of the presence mutations in BRCA1 BRCA2 genes.
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Girolimetti, Giulia, Anna Myriam Perrone, Donatella Santini, Elena Barbieri, Flora Guerra, Simona Ferrari, Claudio Zamagni, Pierandrea De Iaco, Giuseppe Gasparre i Daniela Turchetti. "BRCA-Associated Ovarian Cancer: From Molecular Genetics to Risk Management". BioMed Research International 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/787143.
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Ovarian cancer (OC) mostly arises sporadically, but a fraction of cases are associated with mutations in BRCA1 and BRCA2 genes. The presence of a BRCA mutation in OC patients has been suggested as a prognostic and predictive factor. In addition, the identification of asymptomatic carriers of such mutations offers an unprecedented opportunity for OC prevention. This review is aimed at exploring the current knowledge on epidemiological and molecular aspects of BRCA-associated OC predisposition, on pathology and clinical behavior of OC occurring in BRCA mutation carriers, and on the available options for managing asymptomatic carriers.
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Choi, Doo Ho, Min Hyuk Lee, Allen E. Bale, Darryl Carter i Bruce G. Haffty. "Incidence of BRCA1 and BRCA2 Mutations in Young Korean Breast Cancer Patients". Journal of Clinical Oncology 22, nr 9 (1.05.2004): 1638–45. http://dx.doi.org/10.1200/jco.2004.04.179.
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Purpose The prevalence of BRCA-associated breast carcinoma in the Korean population has not been evaluated extensively. Methods Sixty Korean women who developed breast cancer by age 40 years were studied. Lymphocyte specimens from peripheral blood were processed for BRCA1 and BRCA2 by complete sequencing. Family history through three generations was obtained. Available paraffin-embedded tissue blocks were processed for immunohistochemical staining. Results In the cohort of 60 patients, nine patients with 11 deleterious mutations (six in BRCA1 and five in BRCA2) and seven missense mutations of unknown significance were found. Two patients had deleterious mutations in both BRCA1 and BRCA2 (double mutant). One half of the mutations were novel, and no founder mutations were observed in this cohort. Most of the BRCA-associated patients had no family history of breast and/or ovarian cancer. The expression of HER-2/neu, cyclin D1, and hormone receptors was less common, and p53 overexpression was more common in BRCA-associated tumors. Conclusion The prevalence of BRCA1 and BRCA2 mutations in Korean women with breast cancer at a young age was high. However, the penetrance, as evidenced by the low frequency of breast and ovarian cancers in family members, appears to be low. These data suggest that there may be different genetic and etiologic factors affecting transmission and penetrance of the BRCA genes in Korean patients with breast cancer diagnosed at a young age.
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Panda, Anshuman, Mark N. Stein, Gregory Riedlinger, Gyan Bhanot i Shridar Ganesan. "Role for immune checkpoint blockade in BRCA2-mutant prostate cancer." Journal of Clinical Oncology 37, nr 8_suppl (10.03.2019): 59. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.59.
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59 Background: Except for rare cases with microsatellite instability, prostate cancer has low mutation burden and low response rate to immune checkpoint blockade (ICB). Genomic correlates of response to ICB in microsatellite stable (MSS) prostate cancer are currently unknown. Here we describe an exceptional response to ICB in BRCA2-mutant prostate cancer and explore immunologic features of BRCA-mutant tumors. Methods: A patient with BRCA2-mutant MSS prostate cancer who progressed on PARP inhibitor therapy was treated with pembrolizumab. Another 8 cases of BRCA2-mutant prostate cancer were evaluated for lymphocyte infiltration and PD-L1 expression by a pathologist. The Cancer Genome Atlas (TCGA) dataset was used to evaluate BRCA-mutant tumors from multiple histology. Presence of putative pathogenic mutations in BRCA1/2 were tested for association with mRNA levels of CD8+ T cell marker ( CD8A), immune checkpoint genes (in PD-1, CTLA-4 pathways), and expression of endogenous retroviruses (ERV). Markers of homologous recombination (HR) defects, namely number of Signature 3 mutations and large ( > 3bp) indels, were also analyzed. Results: Initial patient with BRCA2-mutant MSS prostate cancer had a rapid and ongoing response to pembrolizumab. Analysis of local cohort will be presented. In the TCGA prostate cancer dataset, BRCA2-mutant tumors showed significant overexpression of CD8A, PD-1 and CTLA-4 pathway genes, and ERV3-2. Similar results were observed in BRCA1-mutant (but not BRCA2-mutant) ER+ HER2− breast cancer, but not in BRCA-mutant triple-negative breast and ovarian cancer. Analyses of HR defect markers corroborated these observations. Conclusions: BRCA-mutation accompanied by ERV3-2 overexpression, observed in BRCA2-mutant prostate and BRCA1-mutant ER+ HER2− breast cancer, is associated with CD8+ T cell infiltration and checkpoint pathway upregulation. The effect of BRCA1/2 mutation on immunogenicity may be very tissue and/or cell-of-origin specific, with different cancer types having different levels of immune activation. The association between ERV expression and BRCA2-mutation in prostate cancer requires further investigation. BRCA2-mutant prostate cancers are a class of MSS tumors that may be sensitive to ICB.
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Secondino, Angela, Flavio Starnone, Iolanda Veneruso, Maria Di Tella, Serena Conato, Carmine De Angelis, Sabino De Placido i Valeria D’Argenio. "Evaluation of a Four-Gene Panel for Hereditary Cancer Risk Assessment". Genes 13, nr 4 (13.04.2022): 682. http://dx.doi.org/10.3390/genes13040682.
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BRCA1/2 are tumor suppressor genes involved in DNA double-strand break repair. They are the most penetrant genes for hereditary breast and ovarian cancers, but pathogenic variants in these two genes can be identified only in a fraction of hereditary cases. Following the diffusion of BRCA molecular testing and the availability of specific therapeutic strategies for the management of pathogenic variant carriers, the demand for the analysis of additional predisposing genetic factors has increased. Indeed, there is accumulating evidence regarding the role of other genes, including CHEK2 and PALB2. Both of them are involved in the same molecular pathway as BRCA genes, with CHEK2 being responsible for cell cycle stopping to allow the repair of DNA double-strand breaks and PALB2 being able to interact with BRCA1 and activate BRCA2. Thus, their role as additional hereditary cancer predisposing factors is intriguing. Accordingly, guidelines for hereditary cancer risk assessment have been updated to include the criteria for additional genes testing. In this context, we validated a commercially available kit allowing for the simultaneous analysis of BRCA1, BRCA2, CHEK2 and PALB2. Forty-eight patients, already tested for BRCA mutational status, were re-analyzed in the present study. Results comparison showed that the tested method was able to correctly identify all the variants previously detected in the same patients. In particular, all single-nucleotide variants and small indels were correctly identified. Moreover, two copy number variants, included to assess the software’s performance in detecting this kind of gene alteration, were also detected. Even if copy number variant estimation still requires confirmation by a molecular technique to avoid false positive results, it is able to reduce the number of patients requiring multiplex ligation probe amplification analysis, positively impacting the test’s turnaround time. Finally, since the time and costs of the analysis are similar to those required just for BRCA genes, this strategy may be affordable for providing a more comprehensive test for hereditary cancer risk assessment.
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Oktay, K., J. Kim, D. Barad, N. Gleicher i S. Babayev. "Association of BRCA1 mutations with diminished ovarian reserve: A common genetic mechanism for breast/ovarian cancer, and infertility?" Journal of Clinical Oncology 27, nr 15_suppl (20.05.2009): 11039. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.11039.
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11039 Background: 25% of all breast cancers (BC) occur prior to menopause and preservation of fertility is an important quality of life issue for these women. We recently reported an ovarian stimulation (OS) protocol utilizing letrozole for women with BC who wish to preserve their fertility by embryo freezing. Because BRCA+ young women are highly represented among those undergoing fertility preservation, and because knock out models showed a relationship between DNA repair genes and germ cell development, we hypothesized that women with BRCA mutations have diminished oocyte reserve (DOR). Methods: We analyzed the letrozole-OS data to assess the association between BRCA mutations and number of oocytes retrieved, which is the most direct non-invasive method of assessing ovarian reserve. Women with infertility history and age>37 were excluded. Results: Of 125 BC patients who underwent OS between 5/03 and 11/08, 82 met the criteria, of which 47 (57%) had BRCA testing. Of those, 14 (30%) were BRCA+; 9 BRCA1+, 4 BRCA2+, and 1 + for both. Mean ages of those untested, BRCA-, and + women were similar (33.0±2.9 vs 32.8±2.9 vs 33.0±2.8; p=0.97)). Age-adjusted poor response (PR) rate (<4 oocytes retrieved) was significantly higher in BRCA+ (28.6%; 4/14) compared to BRCA- (3%;1/33, p=0.009) and untested (2.9%; 1/35, p=0.007). All poor responders were BRCA1+ with one also having a mutation in BRCA2. A BRCA mutation was associated with 17.7 times the relative risk (RR) of PR (95% CI 1.4–214; p=0.024). The mean number of oocytes was significantly lower in BRCA1+ but not BRCA2+ compared to BRCA- and untested (p=0.05). BRCA1 but not BRCA2 mutations were associated with PR with a RR of 24.0 (95% CI 1.9–298; p=0.013). When only mutations of known clinical significance were included, the RR for PR further increased (RR=36, 95% CI 2.5–503; p=0.008) suggesting a common mechanism between BRCA-induced cancer and premature diminishment of oocyte reserve. Conclusions: Because women with BRCA1 mutations may have DOR prematurely, they should be counseled for possible higher risk of ovarian failure and infertility after chemotherapy, and referred for fertility preservation. Diminished ovarian reserve may be a new component of the Hereditary Breast Ovarian Cancer Syndrome. No significant financial relationships to disclose.
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Wesolowski, R., A. G. Shealy, J. Tao i H. C. Moore. "Differential outcomes in patients treated with endocrine therapy for early or locally advanced breast cancer based on BRCA mutation status". Journal of Clinical Oncology 27, nr 15_suppl (20.05.2009): e22065-e22065. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22065.
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e22065 Background: Mutations in BRCA1 and BRCA2 genes lead to defects in DNA repair. Estrogen receptor modulates transcription of genes responsible for cell division, which depends on cell's ability to repair DNA for genomic integrity. Differential efficacy of endocrine therapy for breast cancer, therefore, may be possible depending on the tumor's BRCA mutation status. Methods: Through an IRB approved registry, breast cancer patients tested for BRCA1 and BRCA2 mutations and treated with endocrine therapy for hormone-receptor positive non-metastatic disease were identified. Primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS) respectively. Fisher's exact test or Wilcoxon rank sum test were used to assess differences among subgroups with respect to their characteristics. Cox proportional hazard analysis was used to identify univariate and multivariate risk factors for OS and PFS. Results: Of 115 breast cancer patients tested for BRCA mutations, 63 met the inclusion criteria of whom 16 patients were BRCA 1 or 2 mutation positive and 47 were negative. In the BRCA(+) group, 14 patients (87.5%) had stage I-III disease at diagnosis. In the BRCA(-) group, 5 patients (10.6%) had stage 0 disease while 41 patients (87.2%) had stage I-III disease at diagnosis. Stage at diagnosis was unavailable for 2 BRCA(+) and 1 BRCA(-) patients. Both groups were similar with respect to Her-2 expression status, history of ovarian suppression, age of diagnosis, and age of menopause. Median age was 48 yo in BRCA(+) group, 42 yo in BRCA(-), (p=0.12). Median follow up was 76.1 mos in BRCA(+) and 62.9 mos in BRCA(-) group. OS was worse in BRCA(+) group (HR 7.38, 95% [CI] 1.49–36.4 p=0.014). After adjustment for stage and history of ovarian suppression, the difference remained significant (HR 16.6, 95% [CI] 1.95–142, p=0.010). There was no difference in PFS (HR 2.02, 95% [CI] 0.82–4.96, p=0.13). Conclusions: Patients with BRCA mutation, hormone-receptor positive hereditary breast cancer treated with endocrine therapy had inferior survival compared with similar patients who are BRCA mutation negative. Prospective studies to evaluate the differential effects of endocrine therapy in these populations are warranted. No significant financial relationships to disclose.
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Goindani, Piryanka, Ghulam Haider, Ammara ., Faiza Mahar, Ahra Sami, Perah Manzoor i Monika Bai. "Positivity of BRCA 1 & 2 Mutations in Ovarian Cancer". Pakistan Journal of Medical and Health Sciences 17, nr 5 (23.05.2024): 681–83. http://dx.doi.org/10.53350/pjmhs2023175681.
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Aim: Ovarian cancer is a significant gynecological malignancy, with mutations in BRCA1 and BRCA2 genes contributing to its development and progression. Methods: This descriptive cross-sectional study was conducted at JPMC Hospital, Karachi, over six months. It involved 159 women aged 18 to 75 years with histopathologically confirmed ovarian cancer. The study employed non-probability consecutive sampling and next-generation sequencing to identify BRCA mutations. Results: The study found a low percentage of participants with a family history of ovarian cancer, a few identified with BRCA1 mutations, none with BRCA2 alone, and a minor proportion with mutations in both genes, suggesting a higher incidence of non-mutation- associated ovarian cancer. Conclusion: The findings indicate a relatively low rate of BRCA1 and BRCA2 variations within those suffering from ovarian cancer in Pakistan, pointing to the need for further research to understand the genetic underpinning of ovarian carcinoma in this population and to develop targeted prevention and treatment strategies. Keywords: BRCA mutations, ovarian cancer, genetic testing, Pakistan, prevalence, cross- sectional study.
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Tian, Jiangfang, Du He, Zhixi Huang, Bole Tian i Dan Cao. "Main driver genes and BRCA mutation in Chinese patients with pancreatic adenocarcinoma." Journal of Clinical Oncology 37, nr 15_suppl (20.05.2019): e15741-e15741. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15741.
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e15741 Background: Data on pathogenic genetic alterations in Chinese patients with pancreatic adenocarcinoma (PAC) are limited. Especially, as BRCA mutations may become potential biomarkers guiding therapy for PAC patients, the prevalence of BRCA mutations in Chinese patients remains largely unknown.We performed the study to analyze genes mutational landscape and determine the prevalence of BRCA mutations in Chinese PAC patients. Methods: We reviewed clinical characteristics and genes mutations of 134 patients with a pathologically confirmed PAC from West China Hospital of Sichuan University between May 2016 and November 2018. All of them underwent gene-testing and genes variant evaluation with a panel of 381 genes by next-generation sequencing (NGS). The test samples were mainly from primary pancreatic lesions, other were from peripheral blood and metastatic sites. All main driver gene mutations and clinical stages were measured to determine associations of driver gene mutations, the number of altered genes, the level of CA199 with clinical stage. Results: Of the 134 patients, 73 (54.5%) were men with a median age of 58 (range from 34 to 82) years. The major driver mutations were KRAS (89.6%), TP53 (71.6%), CDKN2A (26.9%), SMAD4 (18.7%) and ARID1A (10.4%). The majority of patients (76.9%) had 2 genes or more genes mutations, KRAS/TP53 and KRAS/TP53/CDKN2A were the most frequently combinate types. Stages of PAC was relevant to numbers of altered genes (p = 0.040) and the level of CA199 (p = 0.002). Five (3.7%) patients with BRCA mutations were identified, two patients had somatic BRCA2 variants, one patient had somatic BRCA1 mutation and the other two patients had germline BRCA2 mutation. Two patients with germline BRCA2 mutations received olaparib and keep stable disease for 4 months and more than 8 months. Our finding revealed patients with PAC had a low TMB (median 3.81 per Mb (range 0.81-9 per Mb)) and PD-L1 expression (16/36, 44.4%), nearly all of them were MSS (50/51,98.0%), just three patients with dMMR (3/134,2.2%). Conclusions: The PAC patient commonly harbored two or more number of five major driver mutations including KRAS, TP53, CDKN2A, SMAD4 and ARID1A. The frequency of BRCA1/2 mutations in Chinese patients with PAC was 3.7%. Olaparib may be effective for PAC patients with BRCA mutations. The PAC may be poor response to immunotherapy.
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Caleca, Laura, Mara Colombo, Thomas van Overeem Hansen, Conxi Lázaro, Siranoush Manoukian, Michael T. Parsons, Amanda B. Spurdle i Paolo Radice. "GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the BRCA1 and BRCA2 Genes". Cancers 11, nr 2 (28.01.2019): 151. http://dx.doi.org/10.3390/cancers11020151.
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Genetic testing for BRCA1 and BRCA2 genes has led to the identification of many unique variants of uncertain significance (VUS). Multifactorial likelihood models that predict the odds ratio for VUS in favor or against cancer causality, have been developed, but their use is conditioned by the amount of necessary data, which are difficult to obtain if a variant is rare. As an alternative, variants mapping to the coding regions can be examined using in vitro functional assays. BRCA1 and BRCA2 proteins promote genome protection by interacting with different proteins. In this study, we assessed the functional effect of two sets of variants in BRCA genes by exploiting the green fluorescent protein (GFP)-reassembly in vitro assay, which was set-up to test the BRCA1/BARD1, BRCA1/UbcH5a, and BRCA2/DSS1 interactions. Based on the findings observed for the validation panels of previously classified variants, BRCA1/UbcH5a and BRCA2/DSS1 binding assays showed 100% sensitivity and specificity in identifying pathogenic and non-pathogenic variants. While the actual efficiency of these assays in assessing the clinical significance of BRCA VUS has to be verified using larger validation panels, our results suggest that the GFP-reassembly assay is a robust method to identify variants affecting normal protein functioning and contributes to the classification of VUS.
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Madariaga, Ainhoa, Stephanie Lheureux i Amit Oza. "Tailoring Ovarian Cancer Treatment: Implications of BRCA1/2 Mutations". Cancers 11, nr 3 (23.03.2019): 416. http://dx.doi.org/10.3390/cancers11030416.
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High grade serous ovarian cancer (HGSOC) is the most common epithelial ovarian cancer, harbouring more than 20% germline or somatic mutations in the tumour suppressor genes BRCA1 and BRCA2. These genes are involved in both DNA damage repair process via homologous recombination (HR) and transcriptional regulation. BRCA mutation confers distinct characteristics, including an increased response to DNA-damaging agents, such us platinum chemotherapy and poly-ADP ribose polymerase inhibitors (PARPi). However, several mechanisms of resistance to these agents have been described, including increased HR capacity through reverse BRCA mutations, non-homologous end-joint (NHEJ) repair alterations and drug efflux pumps. Current treatments of ovarian cancer including surgery, chemotherapy, targeted treatment and maintenance strategies, as well as resistance mechanisms will be reviewed, focusing on future trends with respect to BRCA mutation carriers.
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Bayrakli, Fatih, Bekir Akgun, Burcak Soylemez, Metin Kaplan i Mustafa Gurelik. "Variation in the BRCA2 gene in a child with medulloblastoma and a family history of breast cancer". Journal of Neurosurgery: Pediatrics 8, nr 5 (listopad 2011): 476–78. http://dx.doi.org/10.3171/2011.8.peds11210.
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The fact that BRCA genes operate as tumor suppressors is evident from the genetics of the different human disorders caused by inherited mutations. Germline mutations affecting 1 allele of either BRCA1 or BRCA2 confer susceptibility to different types of cancers such as breast cancer and medulloblastoma. A family with a history of cancer was identified in Eastern Turkey in which one of the family members (a 13-year-old boy) had medulloblastoma. Venous blood was collected from available family members. The BRCA1 and BRCA2 genes were sequenced in the patient with medulloblastoma and the healthy father. An Asn372His homozygous variation was noted in the BRCA2 gene in the patient with medulloblastoma whereas the variation was heterozygous in the healthy father. A biallelic homozygous variation was demonstrated in the BRCA2 gene, which is important in medulloblastoma suppression, and may have caused medulloblastoma formation in the 13-year-old boy. Further investigations in large human populations with medulloblastoma are necessary for further delineation of BRCA gene malfunctions and their relationship to medulloblastoma formation, and to clarify the therapeutic implications of these malfunctions.
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Kapoor, Nimmi S., Lisa D. Curcio, Carlee A. Blakemore, Amy K. Bremner, Rachel E. McFarland, John G. West i Kimberly C. Banks. "Benefits and safety of multigene panel testing in patients at risk for hereditary breast cancer." Journal of Clinical Oncology 33, nr 28_suppl (1.10.2015): 16. http://dx.doi.org/10.1200/jco.2015.33.28_suppl.16.
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16 Background: Recently introduced multi-gene panel testing including BRCA1 and BRCA2 genes (BRCA1/2) for hereditary cancer risk has raised concerns with the ability to detect all deleterious BRCA1/2 mutations compared to older methods of sequentially testing BRCA1/2 separately. The purpose of this study is to evaluate rates of pathogenic BRCA1/2mutations and variants of uncertain significance (VUS) between previous restricted algorithms of genetic testing and newer approaches of multi-gene testing. Methods: Data was collected retrospectively from 966 patients who underwent genetic testing at one of three sites from a single institution. Test results were compared between patients who underwent BRCA1/2testing only (limited group, n = 629) to those who underwent multi-gene testing with 5-43 cancer-related genes (panel group, n = 337). Results: Deleterious BRCA1/2 mutations were identified in 37 patients, with equivalent rates between limited and panel groups (4.0% vs 3.6%, respectively, p = 0.86). Thirty-nine patients had a BRCA1/2 VUS, with similar rates between limited and panel groups (4.5% vs 3.3%, respectively, p = 0.49). On multivariate analysis, there was no difference in detection of either BRCA1/2 mutations or VUS between both groups. Of patients undergoing panel testing, an additional 3.9% (n = 13) had non-BRCA pathogenic mutations and 13.4% (n = 45) had non-BRCA VUSs. Mutations in PALB2, CHEK2, and ATM were the most common non-BRCA mutations identified. Conclusions: Multi-gene panel testing detects pathogenic BRCA1/2 mutations at equivalent rates as limited testing and increases the diagnostic yield. Panel testing increases the VUS rate, mainly due to non-BRCA genes. Patients at risk for hereditary breast cancer can safely benefit from upfront, more efficient, multi-gene panel testing.
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Abdrakhmanova, Aliya, Nazgul Omarbayeva, Dilyara Kaidarova, Gulnur Zhunussova, Saltanat Abdikerim, Saule Yessenkulova, Aizhan Jakipbayeva, Zhanna Chingissova i Leila Djansugurova. "Next generation sequencing analysis of key genes in breast cancer patients from Kazakh population." Journal of Clinical Oncology 38, nr 15_suppl (20.05.2020): e13548-e13548. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13548.
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e13548 Background: Breast cancer (BC) shows a high incidence both in Kazakhstan and worldwide. Approximately 20-30% of cases of hereditary breast cancer are caused by presence of BRCA1/2 genes defects. Also, there are additional genes, which can increase the risk of BC and they are still under study. In our study we identify new, detectable and objective markers of key cancer genes by next-generation sequencing (NGS) of young BC patients in Kazakh population. Methods: The study enrolled 235 unrelated patients from Kazakh population(the average age 34.25 ± 4.56) with BC. Genomic DNA was obtained from peripheral blood and sequencing was performed using TruSight Cancer Kit on the MiSeq platform. Studio Variant was used to annotate and interpret genetic variants. 26(11.1%) patients had a maternal family history of BC, 21 (80.8%) of them had first- degree relatives diagnosed with BC at different age. Results: Bioinformatics analysis of NGS data identified 23,915 variants in 83 genes. 64 pathogenic variants in the heterozygous state were found in 62 (26.4%) patients, 8 (12.5%) variants were not previously described in databases (LOVD, ClinVar, 1000 Genomes, ESP6500 and ExAC). The most frequent pathogenic mutations were in the genes BRCA1 (24 variants (37.5%) and BRCA2 (18 (28.1%)). Additional pathogenic variants were identified in the non-BRCA genes (APC, ATM, BLM, CHEK2, PALB2, TP53, ERCC2, FANCA, FANCM, NBN, PMS1, PMS2, SDHB and XPA). A hereditary history was recorded in 29.1% and 27.8% of representatives of the group with pathogenic mutations in the BRCA1 and BRCA2, respectively, higher compared to the group of patients without pathogenic mutations and to the group of patients with non-BRCA genes. Conclusions: The frequent and novel germline mutations in BRCA1/2 and non-BRCA genes were identified by NGS. Diagnostic and prevention tools for key genes are considered to be developed and included in the National guidelines of Republic of Kazakhstan after final statistic data processing.
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Wang, Xinfeng, Tomi Jun, Nan Sun, Jie He i Kuan-lin Huang. "Abstract 5692: Tissue specificity of chromosome aneuploidy correlates with BRCA-associated cancer risk". Cancer Research 82, nr 12_Supplement (15.06.2022): 5692. http://dx.doi.org/10.1158/1538-7445.am2022-5692.
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Abstract Pathogenic germline variants of BRCA1 and BRCA2 disproportionally elevated the risk of specific cancer types (ex. breast [BRCA] and ovarian [OV] cancer) compared to tumors arising from other tissues. The reason underlying the strong tissue-specificity for BRCA-associated cancer risk remains largely unknown. Under the two-hit hypothesis, BRCA-mediated oncogenesis is thought to originate from a cell where the germline BRCA1/2 variant underwent loss of heterozygosity (LOH) of the wildtype BRCA allele, resulting in homologous recombination DNA repair deficiencies. Notably, tumor aneuploidy and loss of chromosome arms also show strong tissue specificity across cancer types. The apparent tissue specificities of BRCA-associated cancer risk and chromosome aneuploidy, together with deletion-induced LOH underlying the two-hit hypothesis, pose an intriguing possibility that they may be linked. Using genomic data from the TCGA PanCanAtlas and ICGC PCAWG projects, we calculated the frequencies of deletions of the chromosomal arms where the BRCA1/2 genes are located (17q for BRCA1; 13q for BRCA2) across different cancer types in tumors with no whole-genome doublings (WGD). Among TCGA cases, OV and BRCA showed significantly higher frequencies of 17q deletion (32.75% and 8.05%, respectively) than other cancer types (ranked 2/30 and 5/30, permutation p-value = 0.030 and 0.024), and relatively higher frequencies of 13q deletion (32.75% and 21.92%, respectively) compared to other cancers (ranked 5/32 and 8/32, p-value = 0.101 and 0.078). As expected, cancer types showing high fractions of BRCA1/2 deletions overlap with those showing 17q/13q deletions and often include BRCA and OV. Subsequently, we determined how often BRCA1/2 deletion co-occurred and thus may be caused by the corresponding 17q/13q deletions, showing that BRCA1 deletion carriers who also had chr17q deletion accounted for 40.76% in OV and 25.93% in BRCA patients, compared to 33.33% in all other cancer types while BRCA2 deletion carriers who also had chr13q deletion accounted for OV (53.97%) and BRCA (58.60%) patients, compared to 49.83% in all other cancer types. In addition, we validated our findings in non-overlapping cases of the ICGC PCAWG projects. Consistent with TCGA results, OV and BRCA showed higher frequencies of 17q and 13q deletion compared to other cancer types. To conclude, we identified a correlation between cross-cancer difference in arm-level and focal chromosome aneuploidy affecting BRCA1/2 and BRCA-associated cancer risk, and how chromosome aneuploid may give rise to tissue-specific risks of cancer remain to be investigated. Citation Format: Xinfeng Wang, Tomi Jun, Nan Sun, Jie He, Kuan-lin Huang. Tissue specificity of chromosome aneuploidy correlates with BRCA-associated cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5692.