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Homologous recombination deficiency (HRD) has become an important prognostic and predictive biomarker for patients with high-grade serous ovarian cancer who may benefit from poly-ADP ribose polymerase inhibitors (PARPi) and platinum-based therapies. HRD testing provides relevant information to personalize patients' treatment options and has been progressively incorporated into diagnostic laboratories. Here, we assessed the performance of an in-house HRD testing system deployable in a diagnostic clinical setting, comparing results from two commercially available next-generation sequencing (NGS)-based tumor tests (SOPHiA DDMTM HRD Solution and AmoyDx® (HRD Focus Panel)) with the reference assay from Myriad MyChoice® (CDx). A total of 85 ovarian cancer samples were subject to HRD testing. An overall strong correlation was observed across the three assays evaluated, regardless of the different underlying methods employed to assess genomic instability, with the highest pairwise correlation between Myriad and SOPHiA (R = 0.87, p-value = 3.39 × 10-19). The comparison of the assigned HRD status to the reference Myriad's test revealed a positive predictive value (PPV) and negative predictive value (NPV) of 90.9% and 96.3% for SOPHiA's test, while AmoyDx's test achieved 75% PPV and 100% NPV. This is the largest HRD testing evaluation using different methodologies and provides a clear picture of the robustness of NGS-based tests currently offered in the market. Our data shows that the implementation of in-house HRD testing in diagnostic laboratories is technically feasible and can be reliably performed with commercial assays. Also, the turnaround time is compatible with clinical needs, making it an ideal alternative to offer to a broader number of patients while maintaining high-quality standards at more accessible price tiers.
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Purpose: There is a significant lack of epidemiological data on hereditary cancer in Northeast Brazil. This is the largest study on the prevalence and mutational spectrum of cancer predisposition genes conducted in this region and the first in the State of Ceará. Methods: Patients ≥18 years of age that were referred to CHANCE (Grupo de Câncer Hereditário do Ceará) from March 2014 to December 2020 with testing criteria for breast cancer susceptibility genes according to NCCN v.1.2021 were eligible to participate. The inclusion of patients was limited to one individual per family and to those born in the State of Ceará. All patients underwent a hereditary cancer panel testing with at least 30 genes. Results: A total of 355 patients were included, and 97 (27.3%) carried a P/LP germline variant in 18 different genes. Among the 97 P/LP carriers, BRCA1 (31, 31.9%) and BRCA2 (25, 25.7%) were the most frequently mutated genes, followed by PALB2 (10, 10.3%), CHEK2 (7, 7.2%) and ATM (4, 4.1%). A small number of recurrent variants (detected in three or more individuals) in BRCA1, BRCA2, CHEK2 and ATM represented the majority of the P/LP variants described in this cohort. Conclusion: In this cohort, the prevalence of L/PL was high, particularly involving the BRCA1, BRCA2, PALB2, CHEK2 and ATM genes and, to a lesser extent than expected, the TP53 gene. A high frequency of recurrent variants was also observed, for which further and larger analyses should clarify the presence of any possible founder effect. Characterizing the mutational profile of cancer predisposition genes in diverse populations may contribute to cancer prevention and therapeutic management.
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BACKGROUND: Pathogenic germline mutations in the BRCA1 and BRCA2 (BRCA1/2) genes contribute to hereditary breast/ovarian cancer (OC) in White/mestizo Colombian women. As there is virtually no genetic data on breast cancer (BC) in Colombians of African descent, we conducted a comprehensive BRCA1/2 mutational analysis of 60 Afro-Colombian families affected by breast/OC. MATERIALS AND METHODS: Mutation screening of the complete BRCA1/2 genes for small-scale mutations and large genomic alterations was performed in these families using next-generation sequencing and multiplex ligation-dependent probe amplification analysis. RESULTS: Four pathogenic germline mutations, including one novel mutation, were identified, comprising 3 in BRCA1 and one in BRCA2. The prevalence of BRCA1/2 mutations, including one BRCA1 founder mutation (c.5123C>A) previously identified in this sample set, was 3.9% (2/51) in female BC-affected families and 33.3% (3/9) in those affected by both breast and OC. Haplotype analysis of 2 BRCA2_c.2701delC carriers (one Afro-Colombian and one previously identified White/mestizo Colombian patient with BC) suggested that the mutation arose in a common ancestor. CONCLUSION: Our data showed that 2/5 (40%) mutations (including the one previously identified in this sample set) are shared by White/mestizo Colombian and Afro-Colombian populations. This suggests that these 2 populations are closely related. Nevertheless, variations in the BRCA1/2 mutational spectrum among Afro-Colombian subgroups from different regions of the country were observed, suggesting that specific genetic risk assessment strategies need to be developed.
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Proteína BRCA1 , Proteína BRCA2 , Neoplasias de la Mama , Mutación de Línea Germinal , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Colombia/epidemiología , Femenino , Humanos , PrevalenciaRESUMEN
Introducción: Las guías de la National Comprehensive Cancer Network (NCCN) establecen criterios para solicitud de estudios BRCA1/2. La identificación de pacientes portadores de variantes patogénicas, constituye una oportunidad para dirigirlos hacia programas de cuidado específicos. Objetivo: Analizar si los criterios para la solicitud de estudio genético BRCA1 y 2, cumplen con los criterios indicados en las guías de la NCCN 2019. Describir las características de los pacientes con mutaciones patogénicas para BRCA 1/2; estrategias de prevención y reducción de riesgo llevadas a cabo. Resultados: Se solicitó el estudio a 103 pacientes, de las cuales 101 (98%) cumplían con al menos 1 criterio acorde a NCCN 2019 y realizaron el estudio 77 pacientes (76%). Obtuvimos 15 resultados positivos para una mutación patogénica en BRCA 1y 2 (19.4%), 61 resultados negativos (79.22%) y 1 variante de significado incierto (VUS) en BRCA1 (1.29%). El 46.66 % de las pacientes con mutación patogénica (PMP) eligió al menos una estrategia quirúrgica de disminución de riesgo. Conclusiones: El 98% de los pacientes a quienes se les solicito el estudio cumplían con al menos un Criterio de las Guías NCCN 2019.El hallazgo de 19.4% de mutaciones, probablemente se deba a la correcta selección de pacientes.
Introduction: National Comprehensive Cancer Network Guidelines (NCCN) establish BRCA 1/2 testing criteria. Identification of mutations carriers gives an opportunity to direct them towards specific care programs. Objective: Analyze whether the BRCA 1/2 testing criteria met the NCCN 2019 guidelines criteria. To describe the characteristics of BRCA 1/2 pathogenic mutations carriers, risk reduction and prevention strategies carried out. Results: The study was requested to 103 patients, 101 patients (98%) met at least one NCCN 2019 testing criteria and 77 patients (76%) did the test. We obtained 15 positive results for a BRCA 1/2 pathogenic mutation (19.4%), 61 negative results (79.22%) and 1 BRCA 1 variant of uncer- tain significance (VUS) (1.29%). The 46.66% of patients with a pathogenic mutation chose at least one surgical risk reducing strategy. Conclusions: Al least one NCCN 2019 testing criteria was fulfilled by the 98 % of the patients to whom the test was requested. Probably due to the correct patient selection we found 19.4% mutations in our study.
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Neoplasias , Pacientes , Estrategias de Salud , GenéticaRESUMEN
Mammary tumours are the first and third most incident neoplasm in women and cats, respectively. Approximately 85% of feline mammary gland tumours are malignant and aggressive, especially the triple-negative and HER-2+ molecular subtypes. Triple-negative basal-like feline mammary carcinomas (FMCs) are considered suitable models due to the clinical and morphological similarities with human basal-like triple-negative breast cancer (TNBC). In women, TNBC has a poor prognosis and is often associated with mutations in the tumour suppressor genes BRCA1 and BRCA2. In light of this, the aim of the present investigation was to screen somatic and germline variants of BRCA1 and BRCA2 in nine female cats bearing FMCs. Matched whole blood and FMC samples were obtained for genetic analysis. Additional tumour samples were obtained for histopathological and immunohistochemical evaluation. Genomic DNA was isolated and 27 exonic regions of BRCA1 and BRCA2 genes were amplified and screened by next-generation sequencing. A somatic variant with high functional impact was found in exon 11 of BRCA2 at a frequency of 4.34% in one FMC-bearing cat. Four germline variants with moderate impact were detected in three of the nine FMC-bearing cats and were restricted to exon 9 of BRCA1. It is concluded that the germline genetic variants found in one-third of FMC-bearing animals might be associated with a higher risk of hereditary mammary carcinogenesis.
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Neoplasias de la Mama , Carcinoma , Enfermedades de los Gatos , Neoplasias Mamarias Animales , Neoplasias de la Mama Triple Negativas , Animales , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/veterinaria , Carcinoma/veterinaria , Enfermedades de los Gatos/genética , Gatos , Femenino , Genes BRCA2 , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Mamarias Animales/genética , Mutación , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/veterinariaRESUMEN
The aim of this study was to evaluate the association of single-nucleotide variant n.60G>C (rs2910164) of microRNA (miR)-146a, related to suppressing of BRCA1/2 DNA repair protein, with the risk and survival of colorectal cancer patients, as well as miR-146a and BRCA1/2 levels and miR binding efficiency. The genotypes were identified in 125 colorectal cancer patients and 276 controls using TaqMan polymerase chain reaction assay. The miR-146a and BRCA1/2 levels were assessed by quantitative-polymerase chain reaction protocols. Primary precursor of miR-146a containing G (wild-type) and C (variant) allele were cloned into pcDNA.3.3 vector and co-transfected in HT-29 colorectal cancer cell line. Luciferase reporter assay was performed to assess miR-146a binding to BRCA2 3'-untranslated region in HT-29. The differences between groups were calculated using chi-square or Fisher's exact test, logistic regression, and Mann-Whitney test. The prognostic impact of single-nucleotide variant genotypes on overall survival was evaluated by Kaplan-Meier estimate and Cox regression. The GC or CC genotypes prevalence was similar in patients and controls (50.4% vs 50.7%, p = 0.74). However, patients with tumors in advanced stage with miR-146a GG genotype had 2.41 more chance of dying than GC or CC genotypes. In addition, tumor tissues of patients with GG genotype presented higher miR-146a (p = 0.02) and lower BRCA1 (p = 0.01) and BRCA2 (p < 0.0001) levels when compared to those with GC or CC genotypes. In fact, pcDNA.3.3-miR-146a-G presented increased binding capacity to the 3'-untranslated region of BRCA2 (p = 0.001) compared to pcDNA.3.3-miR-146a-C. In addition, the G allele altered the binding affinity between miR-146a and its BRCA2 3'-untranslated region target (p < 0.001), thus enhancing suppression of BRCA2 expression. Our results suggest that single-nucleotide variant rs2910164 does not influence the colorectal cancer risk in Brazilian patients; however, the GG genotype could act as a factor of worse prognosis in patients with advanced disease due to suppression of BRCA1/2 modulated by miR-146a.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Colorrectales/genética , MicroARNs/genética , Regiones no Traducidas 3'/genética , Adulto , Alelos , Brasil/epidemiología , Neoplasias Colorrectales/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Células HT29 , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Polimorfismo de Nucleótido Simple/genética , Pronóstico , Unión ProteicaRESUMEN
Resumen: ANTECEDENTES: El carcinoma intraepitelial tubárico seroso es una lesión precursora del carcinoma invasivo de las trompas de Falopio que con frecuencia se diagnostica en el contexto de una salpingooforectomía bilateral profiláctica por patología ginecológica benigna. CASO CLÍNICO: Paciente nulípara, de 51 años, con cuadro clínico de dolor abdominal y elevación de marcadores tumorales CA-125 y CA-19.9, diagnosticada con útero polimiomatoso y sospecha de endometrioma en el ovario derecho. Después de la histerectomía subtotal con anexectomía bilateral, el estudio histológico de la pieza tubárica extirpada reportó focos microscópicos de carcinoma intraepitelial tubárico seroso, sin signos de invasión estromal. Por los hallazgos se solicitaron pruebas de imagen mamarias y el estudio genético de mutación BRCA 1 y 2. CONCLUSIÓN: La salpingooforectomía bilateral profiláctica es un procedimiento que reduce el riesgo de carcinomas peritoneales, tubáricos y serosos de ovario. Las pacientes con carcinoma intraepitelial tubárico seroso deben tener seguimiento basado en controles ecográficos, pruebas de imagen mamarias, determinación de marcadores tumorales y estudios genéticos, debido a su asociación con mutaciones en los genes BRCA 1 y 2.
Abstract: BACKGROUND: Serous tubal intraepithelial carcinoma (STIC) is a precursor lesion of invasive high-grade tubal and serous carcinoma of the ovary, frequently diagnosed in the context of prophylactic bilateral salpingoophorectomy for benign gynecological pathology. The objective of this work is to carry out a literature review on the most relevant aspects of the follow-up of this injury, after its incidental diagnosis in gynecological surgery. CLINICAL CASE: A 51-year-old nulliparous patient who, in the context of a clinical situation of abdominal pain with elevation of tumor markers CA125 and CA19.9, was diagnosed with polymomatous uterus and suspected endometrioma in the right ovary. After a subtotal hysterectomy with bilateral adnexectomy, the histological study of the excised tubal specimen found microscopic foci of STIC without signs of stromal invasion. Given this finding, breast imaging tests and a genetic study of the BRCA 1/2 mutation was requested. CONCLUSION: Prophylactic bilateral salpingoophorectomy in gynecological surgery is a procedure that can reduce the risk of developing peritoneal, tubal, and serous ovarian carcinomas. Patients diagnosed with STIC should be subsidiaries of follow-up based on ultrasound controls, mammary imaging tests, tumor markers, and genetic studies, due to their association in many cases with mutations in the BRCA 1/2 genes. It is necessary to establish a series of standardized clinical protocols for the management of patients with STIC and to continue advancing our understanding of this pathology and its subsequent evolution to high-grade serous carcinoma.
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Introducción Si bien el cáncer de mama hereditario representa entre el 5-10% del total de los cánceres de mama, es importante la detección de pacientes portadoras de mutaciones patogénicas en genes brca1/2 y otros genes relacionados con el cáncer de mama ya que esta información permitirá tomar conductas adecuadas de prevención y/o tratamiento tanto en la paciente portadora como en sus familiares. Objetivo Llevar a cabo un análisis retrospectivo de 106 pacientes que realizaron estudios genéticos para genes brca1/2 y otros genes relacionados con el cáncer de mama. Resultados Del total de 106 pacientes, encontramos: 17 (16,03%) con mutación patogénica; 38 (35,85%) con vus (Variantes de significado incierto) informadas en el reporte original; y 51 (48,11%) con estudios negativos. De los 38 informes con vus, 7 (6,6%) fueron reclasificadas como vus verdaderas a junio de 2018. De las 17 mutaciones patogénicas encontradas, 16 correspondieron a mutaciones en los genes brca1/2 (15,09%) y 1 a mutación en el chek2 (3,77%). Conclusiones Los estudios genéticos de predisposición en cáncer de mama son, en la actualidad, una herramienta fundamental para la atención multidisciplinaria de la paciente de alto riesgo en un consultorio de patología mamaria. Es un deber del mastólogo pensar en la indicación de un estudio genético de predisposición al cáncer de mama y derivar al genetista para identificar correctamente al paciente que se va a beneficiar de esta información
Introduction Although hereditary breast cáncer represents 5-10% of all breast cancers, it is important to detect patients carrying pathogenic mutations in brca1/2 genes and other genes related to breast cáncer as this information will allow take appropriate prevention and / or treatment behaviors in both the patient carrier and their family members. Objective To make a retrospective analysis of 106 patients who carried out genetic studies for brca1/2 genes and other genes related to breast cancer. Results From 106 patients we found 17 (16.03%) with pathogenic mutations, 38 (35.85%) with vus (variant of unknown significance) in the original report, and 51 (48.11%) negatives. From 35 vus, we reclasified as true vus only 7 (6,6%) in June 2018. From 17 pathogenic mutations in 106 patients studied (16.03%), we found 16 in the brca1/2 genes (15.09%) and 1 mutation in chek2 (3.77%). Conclusions Genetic predisposition tests in breast cáncer are a fundamental tool for multidisciplinary care of the high-risk patient in a breast center query. The mastologist has to think in the first place about the indication of a genetic testing ofbreast cancer predisposition, and refer to the geneticist for a prompt consultation for patients benefit
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Neoplasias de la Mama , Predisposición Genética a la Enfermedad , GenesRESUMEN
BACKGROUND: Inherited mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2) confer high risks of breast and ovarian cancer. In Colombian Hispanic families, four common BRCA1/2 founder mutations have previously been identified. Because nothing is known about the contribution of BRCA1/2 germline mutations to early-onset and hereditary breast and/or ovarian cancer in Afro-Colombians, we conducted the first study on 60 patients with early-onset and familial breast cancer in this population. MATERIALS AND METHODS: Screening for the four Colombian founder mutations BRCA1/c.3331_3334delCAAG, BRCA1/c.5123C>A, BRCA2/c.2806_2809delAAAC, and BRCA2/c.1763_1766delATAA was performed using mismatch polymerase chain reaction (PCR) analysis, PCR-based restriction fragment length polymorphism analysis, and qualitative real-time PCR. Mutations were confirmed by direct DNA sequencing. RESULTS: The BRCA1 founder mutation c.5123C>A was identified in one family with breast and ovarian cancer (1/60, 1.7%). Three women were diagnosed with breast cancer, including one with bilateral disease, at the ages of 30, 30/33, and 52 years, and one woman was diagnosed with ovarian cancer at the age of 60 years. CONCLUSION: Our data showed a low prevalence of the BRCA1/2 founder mutations in Colombians of African descent, implying that these mutations should not be recommended for genetic screening programs in the Afro-Colombian population. IMPLICATIONS FOR PRACTICE: Risk reduction intervention programs are needed for women who are found to carry a BRCA1/2 mutation, as is the implementation of prevention programs for patients with inherited breast cancer, to reduce the burden of inherited diseases. With the aim of reducing racial disparities in breast cancer prevention, this study focused on genetic testing and treatment for patients in a minority population with BRCA1/2 mutations.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Adulto , Colombia , Femenino , Humanos , Tamizaje Masivo , Persona de Mediana Edad , Mutación , PrevalenciaRESUMEN
In Ashkenazi Jewish (AJ) high risk families 3 mutations [2 in BRCA1 (c. 68_69del and c.5266dup) and 1 in BRCA2 (c.5946del)] account for the majority of high risk breast and ovarian cancer cases in that ethnic group. Few studies with limited number of genotyped individuals have expanded the spectrum of mutations in both BRCA genes beyond the 3 mutation panel. In this study, 279 high risk individual AJ were counseled at CEMIC (Centro de Educación Médica e Investigaciones Clínicas), and were genotyped first for the 3 recurrent mutation panel followed by Next Generation Sequencing (NGS) of BRCA1 BRCA2 in 76 individuals who tested negative for the first genotyping step. Of 279 probands (259 women), 55 (50 women) harbored one of the 3 mutations (19.7%); Of 76 fully sequenced cases (73 women), 6 (5 women) (7.9%) carried a pathogenic mutation: in BRCA1, c.2728C>T - p.(Gln910*); c.5407-?_(*1_?)del and c.5445G>A - p.(Trp1815*); in BRCA2, c.5351dup - p.(Asn1784Lysfs*3); c.7308del - p.(Asn2436Lysfs*33) and c.9026_9030del - p.(Tyr3009Serfs*7). Of 61 mutation carriers the distribution was as follows: 11 cancer free at the time of genotyping, 34 female breast cancer cases with age range 28-72 years (41.6 ± 9.3), 3 male breast cancer cases with age range 59-75 years (65 ± 7.3), 6 breast and ovarian cancer cases with age range 35-60 years (breast 40.4 ± 5.2; ovary 47.8 ± 7.2) and 7 ovarian cancer cases with age range 41-77 years (60.6 ± 13.3). This information proved highly useful for counseling, treatment, and prevention for the patient and the family. In conclusion comprehensive BRCA1/2 testing in AJ high risk breast ovarian cancer cases adds valuable clinically relevant information in a subset of cases estimated up to 7% and is therefore recommended.
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Hereditary breast and ovarian cancer syndrome (HBOC) represents 5â»10% of all patients with breast cancer and is associated with high-risk pathogenic alleles in BRCA1/2 genes, but only for 25% of cases. We aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 27 high-risk patients with a severe family history of cancer, using massive parallel sequencing. We found pathogenic variants in 23 genes, including BRCA1/2. In the group of cancer patients 15% (46/300) had a pathogenic variant; 11% (33/300) harbored variants with unknown clinical significance (VUS) and 74% (221/300) were negative. The high-risk group had 22% (6/27) of patients with pathogenic variants, 4% (1/27) had VUS and 74% (20/27) were negative. The most recurrent mutations were the Mexican founder deletion of exons 9-12 and the variant p.G228fs in BRCA1, each found in 5 of 17 patients with alterations in this gene. Rare VUS with potential impact at the protein level were found in 21 genes. Our results show for the first time in the Mexican population a higher contribution of pathogenic alleles in other susceptibility cancer genes (54%) than in BRCA1/2 (46%), highlighting the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to include broader gene panels.
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BACKGROUND: Ovarian cancer is the leading cause of death worldwide among gynecologic malignancies. The recent approval of inhibitors of poly (ADP-ribose) polymerase (iPARP) in the treatment of ovarian cancer in the presence of a BRCA1/2 mutation has sparked the analysis of women with such diagnosis, which can further benefit from the detection of carriers in the family. Germline sequence and large rearrangements for BRCA1/2 were tested in 398 consecutive epithelial ovarian cancer (EOC) patients. The aim of this study was to identify the frequency and spectrum of germline BRCA1/2 pathogenic alterations in a cohort of patients with ovarian serous carcinoma, with a view to adequately selecting patients for prevention through family counseling and correlating this frequency with platinum sensitivity as a guidance to identify patients eligible for iPARP in our population. RESULTS: A total of 96 patients carried a pathogenic germline mutation, accounting for an overall 24.1% mutation incidence. Among mutation carriers, BRCA1 showed 62.5% incidence, BRCA2 rendered 36.5%, and one patient exhibited a mutation in both genes. Three pathogenic mutations were recurrent mutations detected five, three, and four times and represented 12.5% of the mutated samples. Worth highlighting, a 50% mutation incidence was detected when breast and ovarian cancer coexisted in the same patient. Novel mutations amounted to 9.4% of the total mutations, as compared to 4.7% in breast cancer. Forty out of 60 BRCA1 mutations were beyond the ovarian cancer cluster region (OCCR), in stark contrast with 22 out of 36 BRCA2 mutations being inside the OCCR. Taken together, germline BRCA1/2 mutations in EOC patients showed a distinct mutational spectrum compared to our previously published data on breast cancer patients. CONCLUSIONS: In sum, our study provides novel data on ovarian BRCA1/2 mutation prevalence worldwide, enhances adequate patient selection for family counseling and prevention, and sheds light on the benefits of iPARP treatment.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Neoplasias Ováricas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Mutación de Línea Germinal/genética , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Adulto JovenRESUMEN
Deleterious mutations in BRCA1 or BRCA2 genes increase a woman's lifetime risk of breast and ovarian cancer. Risk management guidelines endorse early detection and prevention behaviors. Despite expressed intent, uptake of these measures remains low. This longitudinal, qualitative study integrated retrospective and prospective data to distinguish factors shaping intent to act from those that are catalysts to taking action to reduce cancer risk. Twelve BRCA1/2 mutation-positive women participating in the National Cancer Institute's Breast Imaging Study aged 18-35 completed two semi-structured interviews three years apart. Researchers completed focused coding to identify points of behavioral intent and action and contextual factors acting as catalysts upon participant narratives. All women shared only two action steps: seeking information about cancer risk and completing genetic testing. The constellation of action steps created a unique action trajectory that was defined, with precise ideas about risk perception and clear behavioral response, or iterative, in which unanticipated life events shifted the speed, accessibility, or order in which risk management and family planning goals were prioritized, planned, or executed. Factors shifting action steps included salient, unanticipated life events, such as infertility, insurance/financial constraints, birth of the last child, or a relative's cancer diagnosis. Focus on cancer morbidity may obfuscate how women prioritize actions, and ignore varied pragmatic, relational, and social factors affecting how intended actions are completed, particularly during the reproductive years. We recommend providers update patients' risk management plans at each visit to assess readiness for next steps and reduce reluctance to discuss, or guilt associated with, change.
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Neoplasias de la Mama/prevención & control , Genes BRCA1 , Genes BRCA2 , Mutación , Neoplasias Ováricas/prevención & control , Adolescente , Adulto , Neoplasias de la Mama/genética , Femenino , Pruebas Genéticas , Humanos , Estudios Longitudinales , Neoplasias Ováricas/genética , Estudios Prospectivos , Investigación Cualitativa , Estudios Retrospectivos , Conducta de Reducción del Riesgo , Adulto JovenRESUMEN
PURPOSE: The molecular mechanism of breast and/or ovarian cancer susceptibility remains unclear in the majority of patients. While germline mutations in the regulatory non-coding regions of BRCA1 and BRCA2 genes have been described, screening has generally been limited to coding regions. The aim of this study was to evaluate the contribution of BRCA1/2 non-coding variants. METHODS: Four BRCA1/2 non-coding regions were screened using high-resolution melting analysis/Sanger sequencing or next-generation sequencing on DNA extracted from index cases with breast and ovarian cancer predisposition (3926 for BRCA1 and 3910 for BRCA2). The impact of a set of variants on BRCA1/2 gene regulation was evaluated by site-directed mutagenesis, transfection, followed by Luciferase gene reporter assay. RESULTS: We identified a total of 117 variants and tested twelve BRCA1 and 8 BRCA2 variants mapping to promoter and intronic regions. We highlighted two neighboring BRCA1 promoter variants (c.-130del; c.-125C > T) and one BRCA2 promoter variants (c.-296C > T) inhibiting significantly the promoter activity. In the functional assays, a regulating region within the intron 12 was found with the same enhancing impact as within the intron 2. Furthermore, the variants c.81-3980A > G and c.4186-2022C > T suppress the positive effect of the introns 2 and 12, respectively, on the BRCA1 promoter activity. We also found some variants inducing the promoter activities. CONCLUSION: In this study, we highlighted some variants among many, modulating negatively the promoter activity of BRCA1 or 2 and thus having a potential impact on the risk of developing cancer. This selection makes it possible to conduct future validation studies on a limited number of variants.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Genes BRCA1 , Genes BRCA2 , Síndrome de Cáncer de Mama y Ovario Hereditario/genética , Adulto , Anciano , Estudios de Cohortes , Biología Computacional , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Intrones/genética , Persona de Mediana Edad , Linaje , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Regiones no Traducidas/genéticaRESUMEN
BRCA1/2 mutations in Latin America are scarcely documented and in serious need of knowledge about the spectrum of BRCA pathogenic variants, information which may alter clinical practice and subsequently improve patient outcome. In addition, the search for data on testing policies in different regions constitutes a fundamental strength for the present study, which analyzes BRCA1/2 gene sequences and large rearrangements in 940 probands with familial and/or personal history of breast/ovary cancer (BOC). In non-mutated DNA samples, Multiplex Ligation-dependent Probe Amplification assays (MLPA) were used for the analysis of large rearrangements. Our studies detected 179 deleterious mutations out of 940 (19.04%) probands, including 5 large rearrangements and 22 novel mutations. The recurrent mutations accounted for 15.08% of the total and only 2.87% of the probands analyzed, very different from a Hispanic panel previously described. IN CONCLUSION: a) this first comprehensive description of the spectrum in BRCA1/2 sheds light on the low frequency of recurrent mutations; b) this information is key in clinical practice to select adequate sequencing studies in our population, subsequently improve patient outcome and prevent damage associated to false normal reports resulting from the use of invalid population panels; c) panels of mutations from other populations should be cautiously validated before imported, even those of apparently similar origin, a concept to be considered beyond significance in Argentina.
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Patients with triple-negative breast cancer (TNBC), defined as lacking expression of the estrogen and progesterone receptors (ER/PR) and amplification of the HER2 oncogene, often have a more aggressive disease course than do patients with hormone receptor-positive breast cancer, including higher rates of visceral and central nervous system metastases, early cancer recurrences and deaths. Triple-negative breast cancer is associated with a young age at diagnosis and both African and Ashkenazi Jewish ancestry, the latter due to three common founder mutations in the highly penetrant cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2). In the past decade, there has been a surge both in genetic testing technology and in patient access to such testing. Advances in genetic testing have enabled more rapid and less expensive commercial sequencing than could be imagined only a few years ago. Massively parallel, next-generation sequencing allows the simultaneous analysis of many different genes. Studies of TNBC patients in the current era have revealed associations of TNBC with mutations in several moderate penetrance breast cancer susceptibility genes, including PALB2, BARD1, BRIP1, RAD51C and RAD51D. Interestingly, many of these genes, like BRCA1/2, are involved in homologous recombination DNA double-stranded repair. In this review, we summarize the current understanding of pathogenic germline gene mutations associated with TNBC and the early detection and prevention strategies for women at risk of developing this high-risk breast cancer subtype. Furthermore, we discuss recent the advances in targeted therapies for TNBC patients with a hereditary predisposition, including the role of poly (ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2 mutation-associated breast cancers.