RESUMO
Hereditary cancers derive from gene defects that often compromise DNA repair. Thus, BRCA-associated cancers are sensitive to DNA-damaging agents such as cisplatin. The efficacy of cisplatin is limited, however, by the development of resistance. One cisplatin resistance mechanism is restoration of homologous recombination (HR), which can result from BRCA reversion mutations. However, in BRCA2 mutant cancers, cisplatin resistance can occur independently of restored HR by a mechanism that remains unknown. Here we performed a genome-wide shRNA screen and found that loss of the nucleosome remodeling factor CHD4 confers cisplatin resistance. Restoration of cisplatin resistance is independent of HR but correlates with restored cell cycle progression, reduced chromosomal aberrations, and enhanced DNA damage tolerance. Suggesting clinical relevance, cisplatin-resistant clones lacking genetic reversion of BRCA2 show de novo loss of CHD4 expression in vitro. Moreover, BRCA2 mutant ovarian cancers with reduced CHD4 expression significantly correlate with shorter progression-free survival and shorter overall survival. Collectively, our findings indicate that CHD4 modulates therapeutic response in BRCA2 mutant cancer cells.
Assuntos
Autoantígenos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Genes BRCA2/fisiologia , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Neoplasias Ovarianas/genética , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Feminino , Humanos , Mutação/genética , Neoplasias Ovarianas/tratamento farmacológicoRESUMO
Homologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2 results in homologous recombination deficiency (HRD) and can be a target for therapeutic strategies including poly (ADP-ribose) polymerase inhibitors (PARPi). However, response is limited in patients who are not HRD, highlighting the need for reliable and robust HRD testing. This manuscript will review BRCA1/2 function and homologous recombination proficiency in respect to breast and ovarian cancer. The current standard testing methods for HRD will be discussed as well as trials leading to approval of PARPi's. Finally, standard of care treatment and synthetic lethality will be reviewed.
Assuntos
Neoplasias da Mama/genética , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Recombinação Homóloga/fisiologia , Neoplasias Ovarianas/genética , Reparo de DNA por Recombinação/fisiologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Variação Genética , Humanos , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/fisiologiaRESUMO
INTRODUCTION: It is estimated that up to 20% of ovarian cancers have an inherited genetic etiology with the most common being BRCA1/2 mutations. For women with these mutations risk-reducing bilateral salpingo-oophorectomy (RRBSO) to reduce the risk of primary ovarian cancer is often performed, however the surgery results in immediate onset of surgical menopause. AIM: The aim of this systematic review was to explore the psychosexual impacts of risk reducing bilateral salpingo oophorectomy in the published qualitative literature. METHODS: PubMed, Medline, Web of Science and PsycInfo were searched for qualitative papers that looked at the psychosexual impact of RRBSO on individuals who were pre-menopausal at the time of surgery. Studies were quality assessed using Mixed Method Appraisal Tool (MMAT) and Standard for Reporting Qualitative Research (SRQR) checklists and data were extracted. Thematic synthesis of the results was performed. RESULTS: Of 143 papers identified in searching, 5 qualitative papers were identified relating to interviews with 115 women after RRBSO published between 2000 and 2020. The quality of the papers was moderate. Five different themes were identified related to individual experiences with RRBSO: (1) information needs, (2) psychological impact, (3) psychosexual impact, (4) partner support and (5) hormone replacement therapy (HRT). CONCLUSION: Individual experiences of RRBSO were varied and influenced by multiple factors but psychosexual problems were common, often caused significant distress to the women and their partners and were often poorly explained before surgery. Women do not feel adequately prepared for the psychological and sexual side effects of RRBSO. The qualitative data provides invaluable insight into the individual experiences of women and can be used to better help women mitigate the effects of the surgery.
Assuntos
Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Salpingo-Ooforectomia/efeitos adversos , Feminino , Humanos , Mutação , Pesquisa Qualitativa , Estudos Retrospectivos , Salpingo-Ooforectomia/métodos , Disfunções Sexuais PsicogênicasRESUMO
OBJECTIVE: To study the possible association between uterine cancer and the BRCA1/2 associated cancer syndrome and discuss the implications of such an association on the clinical managment of patients with BRCA1/2 mutations. METHODS: A systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. Study protocol was prospectively registered at PROSPERO International prospective register of systematic reviews (registration number CRD42020193496). Considered for inclusion were studies providing the diagnosis rate of uterine cancer in patients with BRCA1/2 mutations by comparing observed and expected rate according to a known disease incidence. The results were measured by standardized incidence ratio (SIR). The primary outcome was defined as any uterine cancer diagnosis and subgroup analyses were conducted for uterine serous papillary cancer (USPC) specifically and for BRCA1 and BRCA2 mutations separately. RESULTS: 4591 records were identified through database search; eight studies were finally included, comprising 13,098 patients with BRCA1/2 mutations. BRCA1/2 mutated patients were found to have a significantly higher risk for uterine cancer compared to the general population (SIR = 2.22, 95% CI 1.76-2.8, p < 0.001). A higher incidence of USPC was also found in patients with BRCA1/2 mutations (SIR = 17.97, 95% CI 9.89-32.66, p < 0.001), as well as in a separate analysis for BRCA1 (SIR = 2.81, 95% CI 2.09-3.79, p < 0.001) and BRCA2 (SIR = 1.75, 95% CI 1.09-2.80, p < 0.001) mutations. CONCLUSION: Patients who carry a BRCA1/2 mutation are at a significantly higher risk of developing uterine cancer, specifically USPC, supporting that USPC may be a component of the BRCA1/2 syndrome. The decision to perform concurrent hysterectomy at the time of the risk reduction bilateral salpingo -oophorectomy surgery should be considered individually.
Assuntos
Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Histerectomia/métodos , Neoplasias Uterinas/cirurgia , Tomada de Decisões , Feminino , Humanos , Neoplasias Uterinas/patologiaRESUMO
OBJECTIVES: Mutations in the TP53 tumor suppressor gene are common in ovarian carcinoma (OC) but their impact on outcomes is controversial. We sought to define the relationship of TP53 mutations to cancer outcomes and their interactions with co-occurrent BRCA1 or BRCA2 (BRCA) mutations, comparing three different TP53 mutation classification schemes. METHODS: We performed next generation sequencing on 393 cases of OC prospectively followed for survival. TP53 mutations were classified according to three schemes termed Structural, Functional, and Hotspot. Mutation distribution was compared between cases with and without BRCA mutations. In a subset of 281 cases of high grade serous carcinoma (HGSC), overall survival was compared using Kaplan-Meier curves, logrank testing, and multivariate Cox regression analysis, both stratified and adjusted for BRCA mutation status. Multivariate logistic regression was used to analyze the effects of TP53 mutation type on platinum resistance. RESULTS: TP53 mutations were identified in 76.8% of the total cohort (n = 302/393) and 87.9% of HGSC (n = 247/281). Cases with BRCA mutations demonstrated significantly higher TP53 mutation frequency overall (n = 84/91, 92.3% vs. n = 218/302, 72.2%, p < 0.001). TP53 mutations were not associated with overall survival, even when stratified by BRCA mutation. TP53 mutations were associated with platinum sensitivity, even after adjusting for BRCA mutation status (OR 0.41, p = 0.048). The choice of TP53 mutation classification scheme was not found to alter any significant outcome. CONCLUSIONS: BRCA mutations significantly co-occur with TP53 mutations. After adjusting for BRCA mutations, TP53 mutations are associated with platinum sensitivity, and this effect is not dependent on TP53 mutation type.
Assuntos
Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Neoplasias Ovarianas/genética , Proteína Supressora de Tumor p53/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Proteína Supressora de Tumor p53/metabolismoRESUMO
Heritable breast cancers account for 5% to 10% of all breast cancers, and monogenic, highly penetrant genes cause them. Around 90% of pathogenic variants in BRCA1 and BRCA2 are observed using gene sequencing, with another 10% identified through gene duplication/deletion analysis, which differs across various communities. In this study, we performed a next-generation sequencing panel and MLPA on 1484 patients to explain the importance of recurrent germline duplications/deletions of BRCA1-2 and their clinical results and determine how often BRCA gene LGRs were seen in people suspected of hereditary breast and ovarian cancer syndrome. The large genomic rearrangements (LGRs) frequency was approximately 1% (14/1484). All 14 mutations were heterozygous and detected in patients with breast cancer. BRCA1 mutations were more predominant (n = 8, 57.1%) than BRCA2 mutations (6, 42.9%). The most common recurrent mutations were BRCA2 exon three and BRCA1 exon 24 (23) deletions. To the best of our knowledge, BRCA1 5'UTR-exon11 duplication has never been reported before. Testing with MLPA is essential to identify patients at high risk. Our data demonstrate that BRCA1-2 LGRs should be considered when ordering genetic testing for individuals with a personal or family history of cancer, particularly breast cancer. Further research could shed light on BRCA1-2 LGRs' unique carcinogenesis roles.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Rearranjo Gênico/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Neoplasias da Mama/genética , Éxons/genética , Feminino , Deleção de Genes , Duplicação Gênica/genética , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Genômica/métodos , Células Germinativas/metabolismo , Mutação em Linhagem Germinativa/genética , Humanos , Mutação/genética , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/genética , TurquiaRESUMO
Timely and faithful duplication of the entire genome depends on completion of replication. Replication forks frequently encounter obstacles that may cause genotoxic fork stalling. Nevertheless, failure to complete replication rarely occurs under normal conditions, which is attributed to an intricate network of proteins that serves to stabilize, repair and restart stalled forks. Indeed, many of the components in this network are encoded by tumour suppressor genes, and their loss of function by mutation or deletion generates genomic instability, a hallmark of cancer. Paradoxically, the same fork-protective network also confers resistance of cancer cells to chemotherapeutic drugs that induce high-level replication stress. Here, we review the mechanisms and major pathways rescuing stalled replication forks, with a focus on fork stabilization preventing fork collapse. A coherent understanding of how cells protect their replication forks will not only provide insight into how cells maintain genome stability, but also unravel potential therapeutic targets for cancers refractory to conventional chemotherapies.
Assuntos
Replicação do DNA , Instabilidade Genômica/fisiologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Genes BRCA2/fisiologia , Humanos , Redes e Vias Metabólicas , Modelos Teóricos , Terapia de Alvo Molecular , Mutação , Poli(ADP-Ribose) Polimerase-1/metabolismo , RecQ Helicases/metabolismoRESUMO
During the last decade, the genomics revolution has driven critical advances in molecular oncology and pathology, and a deeper appreciation of heterogeneity that is beginning to reshape our thinking around diagnostic classification. Recent developments have seen existing classification systems modified and improved where possible, gene-based diagnostics implemented and tumour-immune interactions modulated. We present a detailed discussion of this progress, including advances in the understanding of breast tumour classification, e.g. mixed ductal-lobular tumours and the spectrum of triple-negative breast cancer. The latest information on clinical trials and the implementation of gene-based diagnostics, including MammaPrint and Oncotype Dx and others, is synthesised, and emerging targeted therapies, as well as the burgeoning immuno-oncology field, and their relevance in breast cancer, are discussed. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Feminino , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Genes Neoplásicos/genética , Genômica , Humanos , Linfócitos do Interstício Tumoral/fisiologia , Terapia de Alvo Molecular/métodos , PrognósticoRESUMO
Breast cancer is currently the most common form of malignant tumour in womenboth in the Czech Republic and in most countries of the western world, and its incidence is constantly increasing. Many risk factors are known to play a major role in the development of this form of cancer. One of them is genetics, especially the BRCA1/2 genes. A higher risk of ovarian cancer is also associated with these genes. With the development of laboratory diagnostics massive parallel sequencing methods (NGS) are now routinely employed, enabling the detection of other pathogenic sequence variants, or variants of uncertain significance (VUS) not previously detected. Besides the high penetrance BRCA1/2 genes, medium and low penetrant genes also come to the fore. There were 2046 probands examined in the study, men and women, mainly from eastern part of the Czech Republic. These were selected for a genetic examination, after meeting indication criteria (probands from high-risk families or with breast or ovarian cancer). From this group only women, 2033 probands, were selected and were given a genetic examination for the possible presence of patogenic sequence variants in BRCA1/2 genes, or other candidate genes. Analyses were conducted in the laboratory using DHPLC or next generation sequencing. MLPA method is used for large rearrangements in genes. From all examined women 212 mutations were detected. The most mutations (128) were found in the BRCA1 gene (60%). In the BRCA2 gene 71 mutations (34%) were found and 13 more mutations (6%) were detected in another candidate genes (CHEK2, PALB2, ERCC4). The most frequent sequence variant was c.5266dupC in the BRCA1 gene. The results show that 72% of women with a confirmed mutation in the BRCA1 gene and 77.5% of women with the sequence variant BRCA2, already had breast cancer and 16.4% of women with BRCA1 and 7% of women with BRCA2 already had ovarian cancer. Only 21 high risk families used the possibility to be tested and had undergone targeted mutation testing. The study results suggest a reflection of the causes and needs for examination of patients and women predisposed to breast or ovarian cancer.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Taxa de Mutação , Adulto , Mama/patologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , República Tcheca/epidemiologia , Proteínas de Ligação a DNA/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Genes Supressores de Tumor/fisiologia , Predisposição Genética para Doença , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genéticaRESUMO
Resistance can be the result of secondary tissue variants (STVs), which restore the open reading frame of the germline BRCA allele, producing functional BRCA protein in germline BRCA1/2 (BRCA) pathogenic variant (PV) carriers, treated with platinum-based chemotherapy or poly-(ADP-ribose) polymerase inhibitors (PARP-1). We reported recently a BRCA2 mutant high grade serous ovarian cancer (HGSOC) patient with acquired resistance to the PARP-1 olaparib due to a STV detected by next generation tumor sequencing (NGTS). The aim of this study was to evaluate the versatility of the high-resolution melting analysis (HRMA) obtained by magnetic induction cycler (MIC) to monitor the BRCA2 status in formalin-fixed paraffin-embedded (FFPE) tissue samples of this patient and to compare the results obtained by NGTS. HRMA highlighted the BRCA2 STV previously detected in the IIIrd HGSOC recurrence following the tissue BRCA2 tissue status comparing the high resolution melting profiles (HRMPs). HRMPs differentiate not only BRCA2 alleles, but also their different allele abundance. We underline that (1) the MIC uses a latest generation technology guaranteeing temperature uniformity and maintenance in each well allowing high and accurate performance to obtain reported results and (2) the HRMA maintains a high sensitivity and specificity when it is performed on FFPE samples. Finally, this study represents an additional use of the HRMA, confirming its extreme versatility in the diagnostic environment.
Assuntos
Proteína BRCA2/genética , Recidiva Local de Neoplasia/diagnóstico , Desnaturação de Ácido Nucleico/genética , Adulto , Alelos , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Análise Mutacional de DNA/métodos , Feminino , Genes BRCA1 , Genes BRCA2/fisiologia , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Fenômenos Magnéticos , Mutação , Recidiva Local de Neoplasia/genética , Reação em Cadeia da Polimerase/métodosRESUMO
PURPOSE: Mutations in the genes BRCA1 and BRCA2 represent a significant risk factor for ovarian and breast cancer. With increasing number and success rates, fertility protection and treatment are gaining importance also for BRCA1/2 mutation carriers. However, the effect on primary cancer risk and risk for recurrence remains unclear. This review analyses the published data on fertility treatment and risk of ovarian and breast cancer in BRCA1/2 mutation carriers. METHODS: In this review, we included all relevant articles published in English from 1995 to 2018. Literature was identified through a search on PubMed and Cochrane Library. RESULTS: We identified one retrospective cohort and one case-control study regarding the association of fertility treatments and ovarian cancer risk in BRCA mutation carriers. The studies show no increase in ovarian cancer risk. Furthermore, one case-control study on the association between fertility treatment and breast cancer risk in BRCA mutation carriers and one prospective cohort study on the long-term safety of medication used for fertility preservation in women with a history of breast cancer were identified. One of the studies shows a possible adverse effect for gonadotropin-containing medication. CONCLUSION: Possible increases in cancer risk associated with fertility treatments in BRCA1/2 mutation carriers cannot be excluded at this time. Based on the existing studies, BRCA1/2 mutation carriers should not be generally excluded from fertility treatments. However, they have to be informed about limited data and possible increases in cancer risk.
Assuntos
Neoplasias da Mama/genética , Preservação da Fertilidade/métodos , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Neoplasias Ovarianas/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Fatores de RiscoRESUMO
OBJECTIVE: To investigate clinical factors associated with prolonged progression-free survival (PFS) and overall survival (OS) in relapsing epithelial ovarian cancer (EOC) patients with BRCA mutations and receiving olaparib as maintenance therapy in daily practice. METHODS: Multicenter (8 hospitals) European retrospective study of relapsing EOC patients having germline or somatic mutations of BRCA1/BRCA2 genes and treated with olaparib as maintenance therapy after platinum-based chemotherapy. RESULTS: One hundred and fifteen patients were included. Median age was 54â¯years. There were 90 BRCA1 carriers, 24 BRCA2 carriers and one patient had germline mutation of BRCA1 and BRCA2. Six patients had somatic mutations (all BRCA1) and 109 had germline mutations. Ninety percent had serous carcinomas and were platinum-sensitive. Following ultimate platinum-based chemotherapy, 69% of the patients had normalization of CA-125 levels and 87% had RECIST objective responses, either partial (53%) or complete (34%). After a median follow-up of 21â¯months, median PFS was 12.7â¯months and median OS was 35.4â¯months. In multivariate analysis, factors associated with prolonged PFS under olaparib were: platinum-free interval (PFI)â¯≥â¯12â¯months, RECIST complete response (CR) or partial response (PR) and normalization of CA-125 upon ultimate platinum-based chemotherapy. Factors associated with prolonged OS were PFIâ¯≥â¯12â¯months, CR and normalization of CA-125. CONCLUSIONS: Platinum-free intervalâ¯≥â¯12â¯months, complete response and normalized CA-125 levels after ultimate platinum-based chemotherapy are associated with prolonged PFS and OS in relapsing BRCA1/BRCA2 mutated ovarian cancer patients who received olaparib as maintenance therapy.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Antígeno Ca-125/metabolismo , Intervalo Livre de Doença , Feminino , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Mutação em Linhagem Germinativa/genética , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: Clinical genetic testing to diagnose germline mutations often requires blood sample or saliva smear from a cancer-affected individual. This rules out testing in families when cancer-affected individuals are deceased. We explored the use of a next-generation sequencing (NGS) platform to diagnose germline pathogenic mutations from tumors. METHODS: Archival tumors (ovarianâ¯=â¯26, breastâ¯=â¯25, othersâ¯=â¯9) were retrieved from 60 cancer patients who have undergone multi-gene panel blood testing. Genomic DNA was extracted and sequenced for BRCA1/2 using a NGS platform. 41/60 specimens were sequenced for 5 other genes (APC, ATM, PALB2, PTEN, TP53). Tumor testing and results interpretation were performed blinded to the blood test result. RESULTS: All 38 patients with no BRCA1/2 mutations on blood testing were correctly tested negative on tumor. Tumor testing correctly diagnosed BRCA1/2 pathogenic mutations in 15/22 (68%) patients while in 7/22 (32%) patients, the mutation was either detected but incorrectly classified as VUS (nâ¯=â¯3) or not detected at all (nâ¯=â¯4). Overall concordance rate for tumor and blood testing for BRCA1/2 mutations was 88%, with 0% false positive and 32% false negative rate for pathogenic mutations. Tumor testing correctly diagnosed 1/2 pathogenic germline ATM mutation, 1/1 pathogenic germline PALB2 mutation and 2/2 pathogenic germline TP53 mutations. False positive germline mutations were diagnosed in 4 genes at a rate of 2.4%-10.3% (APCâ¯=â¯2.4%, PALB2â¯=â¯2.4%, PTENâ¯=â¯4.9%, TP53â¯=â¯10.3%). CONCLUSION: Tumor testing for BRCA1/2 germline mutations using an NGS platform is fairly reliable with no false positive findings, and correctly diagnosed more than two-thirds of pathogenic germline BRCA1/2 mutations. However, it is not reliable to diagnose pathogenic germline mutations in genes frequently mutated in sporadic cancers, such as PTEN and TP53.
Assuntos
Neoplasias da Mama/genética , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Mutação em Linhagem Germinativa/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Neoplasias da Mama/diagnóstico , DNA de Neoplasias/genética , Reações Falso-Positivas , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Estudos Prospectivos , Análise de Sequência de DNA , Proteína Supressora de Tumor p53/metabolismoRESUMO
PURPOSE: To develop a decision support tool for young women with breast cancer considering genetic testing for BRCA1/2 mutations soon after cancer diagnosis. METHODS: A four-stage iterative development process was employed; stage 1, literature review exploring the availability and efficacy of empirically tested decision support tools; stage 2, in-depth interviews with 29 young women (< 50 years) recently diagnosed with breast cancer, exploring information requirements and experiences of genetic testing decision making; stage 3, three focus groups (N = 21) exploring preferences for information presentation and prioritisation of content; stage 4, think-aloud interviews to refine the prototype (N = 16). RESULTS: Participants wanted information regarding the pros and cons of testing, the testing process and implications for their family, presented in a way that allowed them to choose the level of detail they required. They preferred the term 'altered gene', valued a medical word definition function and warnings before accessing sensitive information. CONCLUSION: Participants valued the decision support tool, the accessibility of the information and its clinical endorsement. The decision support tool has considerable clinical utility as an adjunct to genetic counselling or for use in busy oncology clinics where formal genetic counselling may be unavailable.
Assuntos
Neoplasias da Mama/genética , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Aconselhamento Genético/métodos , Testes Genéticos/métodos , Adulto , Neoplasias da Mama/patologia , Tomada de Decisões , Feminino , Humanos , MutaçãoRESUMO
OBJECTIVE: Estimate the prevalence of cardiovascular disease risk factors and endpoints in women with BRCA mutations. METHODS: Women, age 40 and older, with BRCA mutations identified in Kaiser Permanente Northern California completed a questionnaire and underwent a lipid and fasting glucose panel. Bivariable analysis of clinical and demographic factors was performed. The Atherosclerotic Cardiovascular Disease (ASCVD) calculator was used to predict 10-year risk of a cardiovascular event. RESULTS: Of the 233 women, 19 women had intact ovaries (median age 56.0) and 214 had undergone risk-reducing salpingo-oophorectomy (RRSO). Among the 108 women with RRSO under age 50 (median age 51.0), compared to the 106 women who had RRSO at or over age 50 (median age 63.5) 6.5% vs 10.4% reported diabetes (pâ¯=â¯0.30), 23.2% versus 28.3% had elevated fasting blood glucose (pâ¯=â¯0.39), 21.3% versus 34.0% reported hypertension (pâ¯=â¯0.04) with median systolic blood pressure of 118â¯mmHg versus 125.5â¯mmHg (pâ¯<â¯0.009), 25% versus 32% reported hyperlipidemia (pâ¯=â¯0.40), and 42% versus 49% had any abnormal lipid test (pâ¯=â¯0.28). An elevated 10-year ASCVD risk of over 10% was seen in 6.1% versus 24.8% respectively (pâ¯=â¯0.0001). CONCLUSION: Women who underwent RRSO at age of 50 and over, had higher ASCVD 10-year risk than women who underwent RRSO at younger ages most likely owing to older age at study entry. The ASCVD risks for women with BRCA mutation who had RRSO did not suggest increased risk associated with being a BRCA mutation carrier.
Assuntos
Doenças Cardiovasculares/genética , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Predisposição Genética para Doença/genética , Doenças Cardiovasculares/patologia , Feminino , Humanos , Pessoa de Meia-Idade , MutaçãoRESUMO
OBJECTIVES: To compare the outcomes after intraperitoneal (IP) chemotherapy in patients with and without pathogenic BRCA mutations. METHODS: Patients with high grade ovarian cancer who were treated with adjuvant IP chemotherapy in the initial setting between 2005 and 2016 were identified. Outcomes were compared between patients with pathogenic mutations in BRCA (BRCA+) and those who tested negative or were unknown (BRCA-). RESULTS: A total of 100 eligible patients were identified. The median follow-up was 47.0â¯months (range, 6.6-144.1â¯months). Of these 100 patients, 77 patients underwent BRCA testing; 25 patients (32%) were BRCA+ (23 germline, 2 somatic). No differences were noted between groups with respect to number of IP cycles, stage, or residual disease after surgery. The median progression-free survival (PFS) was longer in the BRCA+ group; median PFS was not reached in the BRCA+ group compared to 17.3â¯months in the BRCA- group (HRâ¯=â¯0.38; 95% CI 0.20-0.73, Pâ¯=â¯0.003). Median overall survival (OS) was longer in the BRCA+ group at 110.4â¯months versus 67.1â¯months (HRâ¯=â¯0.28, 95% CI 0.11-0.73, Pâ¯=â¯0.009). CONCLUSIONS: Pathogenic BRCA mutations are more common than expected in optimally resected ovarian cancer patients selected for IP therapy. IP therapy was associated with a dramatic improvement in PFS and OS in BRCA+ patients compared with BRCA- patients. This improvement is greater than has been reported for BRCA+ patients with IV chemotherapy. The magnitude of this benefit suggests that patients with pathogenic mutations in BRCA may benefit from IP therapy.
Assuntos
Quimioterapia Adjuvante/métodos , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Neoplasias Ovarianas/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/patologia , Resultado do TratamentoRESUMO
Risk-reducing salpingo-oophorectomy (RRSO) is a procedure to reduce the risk of adnexal cancer in BRCA mutation carriers and for hormonal manipulation in women with breast cancer (BC). The goal of the study is to report the frequency of subsequent BC and high-grade serous carcinoma (HGSC) following RRSO in BRCA1 and BRCA2 mutation carriers and in patients with personal history of BC with or without BRCA mutation. A series of 147 consecutive patients who received a RRSO were reviewed. Patient's age, clinical history, BC histotype, gene mutation data, incidence of post-RRSO BC and HGSC and time intervals were analyzed. The cases were followed for a mean of 49â¯months. Group 1 consists of 97 cases with pathogenic or likely pathogenic "deleterious" mutation BRCA1 (nâ¯=â¯49) or BRCA2 (nâ¯=â¯48). Group 2 consists of 50 cases with history of BC and no documented BRCA gene mutation. Prior to RRSO, 42 (43%) cases in group 1 had a history of BC and all cases in group 2 had a history of BC. There was no difference between the groups in the age at diagnosis for BC (Mean of 44â¯years). Following RRSO, 2/49 cases (4%) with BRCA1 mutation were found to have occult HGSC and none in BRCA2 cases. There were also 1 BC recurrence and 1 primary BC with BRCA1 mutation compared to 5 recurrent BC in Group 2 (10%). In conclusion, the risk of subsequent recurrent BC after RRSO appears to be higher (10%) in patients with history of BC with no BRCA mutation when compared to (2%) in BRCA mutation carriers.
Assuntos
Neoplasias da Mama/genética , Genes BRCA2/fisiologia , Predisposição Genética para Doença , Mutação/genética , Recidiva Local de Neoplasia/genética , Adulto , Idoso , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Ovariectomia/métodosRESUMO
BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. RESULTS: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. CONCLUSIONS: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.
Assuntos
Reparo do DNA/genética , DNA/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Proteína BRCA1/genética , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Genes BRCA2/fisiologia , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Estudos Prospectivos , RiscoRESUMO
Germline mutations in the tumour suppressor BRCA2 predispose to breast, ovarian and a number of other human cancers. Brca2-deficient mouse models are used for preclinical studies but the pattern of genomic alterations in these tumours has not yet been described in detail. We have performed whole-exome DNA sequencing analysis of mouse mammary tumours from Blg-Cre Brca2(f/f) Trp53(f/f) animals, a model of BRCA2-deficient human cancer. We also used the sequencing data to estimate DNA copy number alterations in these tumours and identified a recurrent copy number gain in Met, which has been found amplified in other mouse mammary cancer models. Through a comparative genomic analysis, we identified several mouse Blg-Cre Brca2(f/f) Trp53(f/f) mammary tumour somatic mutations in genes that are also mutated in human cancer, but few of these genes have been found frequently mutated in human breast cancer. A more detailed analysis of these somatic mutations revealed a set of genes that are mutated in human BRCA2 mutant breast and ovarian tumours and that are also mutated in mouse Brca2-null, Trp53-null mammary tumours. Finally, a DNA deletion surrounded by microhomology signature found in human BRCA1/2-deficient cancers was not common in the genome of these mouse tumours. Although a useful model, there are some differences in the genomic landscape of tumours arising in Blg-Cre Brca2(f/f) Trp53(f/f) mice compared to human BRCA-mutated breast cancers. Therefore, this needs to be taken into account in the use of this model.
Assuntos
Genes BRCA2/fisiologia , Neoplasias Mamárias Experimentais/genética , Proteína Supressora de Tumor p53/deficiência , Animais , Antígenos CD/genética , Neoplasias da Mama/genética , Proteínas Cromossômicas não Histona/genética , Variações do Número de Cópias de DNA/genética , DNA de Neoplasias/genética , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Mutação em Linhagem Germinativa/genética , Humanos , Camundongos Transgênicos , Mutação de Sentido Incorreto/genética , Neoplasias Ovarianas/genética , Proteínas Serina-Treonina Quinases/genética , Receptores Imunológicos/genética , Análise de Sequência de DNA , Família de Moléculas de Sinalização da Ativação LinfocitáriaRESUMO
PURPOSE: To use localized correlated spectroscopy (COSY) to assess for an altered biochemical state or states in breast tissue of women with BRCA gene mutations that potentially constitute preinvasive conditions. MATERIALS AND METHODS: Institutional review board approval was obtained. Participants provided written informed consent. In vivo localized COSY images were recorded at 3 T in the breast tissue of women carrying BRCA1 (n = 9) or BRCA2 (n = 14) gene mutations and were compared with images in healthy control subjects with no family history of breast cancer (n = 10). All participants underwent contrast material-enhanced MR imaging and ultrasonography (US). Statistical significance was calculated with the Mann-Whitney two-sided nonparametric test. RESULTS: No abnormality was recorded with MR imaging or US. Metabolite levels in the BRCA1 cohort were reduced by 79% (P = .014) when compared with triglycerides level, and there was a 19% increase in lipid unsaturation and triglyceride levels (P = .027 and P = .086, respectively) when compared with cellular cholesterol level. Cholesterol level was reduced by 47% (P = .027) when compared with diallylic lipid level. Metabolite levels in the BRCA2 cohort showed increased unsaturation of 21% (P = .030) relative to triglycerides level. Comparison of the BRCA1 and BRCA2 cohorts showed a 47% (P = .002) increase in cholesterol level in the BRCA2 cohort when compared with diallylic lipid level and a 52% (P = .003) increase when compared with triglycerides level. Levels of diallylic lipid, unsaturated lipid, triglycerides, and terminal methyl on the acyl chain are reduced by 46% (P = .002), 57% (P = .003), 66% (P = .003), and 29% (P = .010), respectively, when compared with cholesterol level. CONCLUSION: Localized COSY recorded significant changes in women with BRCA1 and BRCA2 gene mutations when compared with control subjects. If these changes are ultimately proven to be a premalignant stage, this method may prove useful in screening.