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ABSTRACT A total of 1.67 million breast cancer cases per year are reported worldwide. Of these, 5%-10% are caused by inherited mutations. Phenocopy is a rare phenomenon, with only a few cases reported in the literature. In phenocopies, phenotypes identical to those with genetic origin occur because of environmental factors rather than familial mutations. We describe a case of phenocopy in a 44-year-old female patient with triple-negative breast cancer. The mother and sister wee heterozygous for c.1813delA, p.Ile605TyrfsTer9 in BRCA2 . The patient underwent genetic testing for BRCA1 and BRCA2 and exome sequencing. Familial or other cancer variants were not detected. The most accepted phenocopy theory is that patients without genetic variants but who are carriers of these mutations undergo cellular changes due to environmental factors, increasing the risk of breast cancer. Therefore, the detection of phenocopy in patients with breast cancer is important in clinical practice.

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Introducción: la predisposición hereditaria causada por mutaciones patogénicas de la línea germinal (MPG) explica hasta el 10% de los cánceres de mama. Para reducir su impacto en mujeres mutadas se han propuesto diferentes estrategias, tales como las cirugías reductoras de riesgo o el screening con resonancia magnética (RM) de mamas. Métodos: en este estudio observacional retrospectivo se analizaron los registros de mujeres portadoras de MPG para evaluar las diferentes acciones tomadas luego del test genético. A las pacientes no mastectomizadas se les recomendó ingresar a un programa anual de cribado con RM y se evaluó el porcentaje de adherencia al plan, el número de biopsias efectuadas y el número de cánceres de mama detectados. Resultados: se incluyeron 134 mujeres con MPG, con una distribución en tercios iguales de los genes BRCA1, BRCA2 y genes no-BRCA. Entre las mutadas con indicación de seguimiento, 64% ingresaron al programa de cribado con RM. Las razones que llevaron a las mujeres a no ingresar al programa de seguimiento fueron: la oposición del médico tratante (53%), oposición de la paciente (38%), y falta de recursos (9%). Se realizaron seis biopsias por hallazgos en la RM entre las cuales se detectó un cáncer de mama. La incidencia de cáncer fue de 11 cada 1.000 mujeres-años de riesgo. Conclusiones: nuestro programa de seguimiento con RM de pacientes mutadas logró captar un porcentaje alto de candidatas. Una proporción significativa de las mujeres no ingresó debido la desaprobación del médico tratante o de la propia paciente. La evidencia obtenida revela una necesidad imperiosa de reforzar los programas educativos que destaquen la importancia del seguimiento con RM de las pacientes de alto riesgo en nuestro país.

Summary: Introduction: genetic propensity caused by germline pathogenic mutations explain up to 10% of breast cancer cases. Different strategies have been proposed to reduce its impact on women who are carriers of mutations, such as risk-reducing surgeries or breast magnetic resonance screening. Method: observational, retrospective study analyzing the medical records of women who are carriers of germline pathogenic mutations to assess the different measures taken after the genetic test. Non-mastectomized patients were advised to join an annual MRI screening program and the percentage of adherence to plan was evaluated, along with biopsies performed and the number of breast cancer cases detected. Results: 134 women carriers of germline pathogenic mutations were included in the study, with equal distributions in thirds for BRCA1, BRCA2 and non-BRCA genes. 64% of carriers of mutations who were subject to follow-up checkups joined the RMI screening program. The reasons why women failed to join the follow-up program were: the treating physician objected to the program (53%), the patients opposed to program (38%) and lack of resources (9%). Six biopsies were performed as a consequence of findings in the RMI, and one case of breast cancer was detected. Cancer incidence was 11 out of 1000 women - risk years. Conclusions: our RMI follow-up program for women who are carriers of mutations managed to attract a high percentage of candidates. A significant amount of women failed to join the program because of their treating physician's or their own disapproval. Evidence obtained reveals the dramatic need to reinforce educational programs that emphasize on the importance of RMI follow-up of high risk patients in our country.

Introdução: a predisposição hereditária causada por mutações germinativas patogênicas (GMP) explica até 10% dos cânceres de mama. Para reduzir seu impacto em mulheres com mutações, diferentes estratégias têm sido propostas, como cirurgias de redução de risco ou ressonância magnética (RM) das mamas. Métodos: neste estudo observacional retrospectivo, os registros de mulheres portadoras de MPG foram analisados para avaliar as diferentes ações tomadas após o teste genético. Pacientes não mastectomizadas foram recomendadas a entrar em um programa anual de triagem por ressonância magnética e foram avaliados o percentual de adesão ao plano, o número de biópsias realizadas e o número de cânceres de mama detectados. Resultados: foram incluídas 134 mulheres com MPG, com uma distribuição de terços iguais dos genes BRCA1, BRCA2 e não-BRCA. Entre as mulheres com mutações com indicação de acompanhamento, 64% entraram no programa de triagem por ressonância magnética. Os motivos que levaram as mulheres a não ingressarem ao programa de acompanhamento foram: oposição do médico assistente (53%), oposição da paciente (38%) e falta de recursos (9%). Seis biópsias foram realizadas devido a achados de ressonância magnética, entre os quais foi detectado um câncer de mama. A incidência de câncer foi de 11 por 1.000 mulheres-ano de risco. Conclusões: nosso programa de acompanhamento de ressonância magnética para pacientes com mutação conseguiu capturar uma alta porcentagem de candidatas. Uma proporção significativa de mulheres não entrou devido à falta de aprovação do médico assistente ou da própria paciente. As evidências obtidas revelam a necessidade urgente de reforçar programas educacionais que destaquem a importância do acompanhamento por RM de pacientes de alto risco no Uruguai.

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Introduction: Hereditary predisposition syndromes to cancer represent 5-10% of cancer cases, the most studied being HBOC produced by mutations in the BRCA1/2 genes. Objectives: To describe clinical, histopathological and PV characteristics in patients with HBOC in Córdoba, Argentina and compare it with those without BRCA1/2 mutations. Methods: Cross-sectional, correlational and observational analysis of patients from Córdoba. The ANOVA, Student's t test contingency tables and Fisher exact test were used the significance level was α = 0.05. Results: 155 women with BC, OC and BC/OC were studied. 40 BRCA1 / 2 mutations were identified. No differences were found in the age of diagnosis between patients with and without BRCA1/2 mutations. A significant association was found between VP in BRCA1/2 and the type of cancer (p = 0.003); all cases with BC/OC presented mutations in BRCA1/2. No significant association was found between mutated/non-mutated and personal history, family background, and ER-PR-HER2. 23.1% and 38.1% of BC cases were TN in individuals with VP in BRCA 1 and 2, respectively. The prevalence of mutations was 25.8% and the prevalence of novel PV was 10.0%. Conclusions: Patients with BC-VP BRCA1/2 are associated with ductal histology, and younger age of presentation with VP BRCA1. We did not find significant differences in the age at diagnosis of BC between patients with BRCA1 and BRCA2 mutations, a higher proportion of BC TN is observed than in the general population. In our sample, the prevalence of BRCA1/2 mutations among patients who meet criteria for HBOC is 25.8%, with 10% new pathogenic variant.

Introducción: Los síndromes de predisposición hereditaria al cáncer representan un 5-10% de los casos de cáncer, el más estudiado es HBOC producido por mutaciones en los genes BRCA1/2. Objetivos: Describir características clínicas, histopatológicas y VP en pacientes con HBOC en Córdoba, Argentina y compararla con aquellas sin mutaciones en BRCA1/2. Métodos: Análisis transversal, correlacional y observacional de pacientes de Córdoba. Se utilizó la prueba ANOVA, t de Student, tablas de contingencia y prueba exacta de Fisher, el nivel de significancia fue α=0,05. Resultados: Se estudiaron 155 mujeres con CM, CO y CM/CO. Se identificaron 40 mutaciones en BRCA1/2. No se encontraron diferencias en edad de diagnóstico entre pacientes con y sin mutaciones en BRCA1/2. Se encontró asociación significativa entre VP en BRCA1/2 y el tipo de cáncer (p=0,003); todos los casos con CM/CO presentaron mutaciones en BRCA1/2. No se encontró asociación significativa entre mutados/no mutados y AP, AF, RE-RP-HER2. El 23.1% y 38.1% de los casos de CM fueron TN en individuos con VP en BRCA 1 y 2 respectivamente. La prevalencia de mutaciones fue 25,8% y la prevalencia de VP noveles del 10,0%. Conclusiones: Las pacientes con CM-VP BRCA1/2 están asociadas con histología ductal, y menor edad de presentación con VP BRCA1. No encontramos diferencias significativas en edad de diagnóstico del CM entre pacientes con mutaciones BRCA1 y BRCA2, se observa una mayor proporción CM TN que en la población en general. En nuestra muestra, la prevalencia de mutaciones en BRCA1/2 entre los pacientes que reúnen criterios para HBOC es del 25,8%, con 10% de VP noveles.

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Resumo O câncer de mama representa um problema de saúde pública por ser a neoplasia maligna de maior incidência em mulheres no mundo. A forma hereditária corresponde a cerca de 5% a 10% de todos os casos e está diretamente relacionada à herança de mutações genéticas, sendo as principais nos genes supressores de tumor BRCA1 e BRCA2. A identificação dessas mutações é de extrema importância pelo elevado risco de desenvolvimento de câncer de mama nessa população, permitindo estratégias de rastreamento diferenciado e adoção de medidas de redução de risco. Entretanto, é importante e necessário refletir sobre os aspectos éticos relacionados ao uso indiscriminado de testes genéticos. O objetivo deste trabalho foi avaliar o conhecimento e a opinião de médicos de um centro de referência oncológico sobre a indicação dos testes genéticos de suscetibilidade ao câncer de mama mediante dilemas éticos aos quais são submetidos na prática médica.

Abstract Breast cancer is a public health problem because it is the malignant neoplasm with the highest incidence in women worldwide. The hereditary form corresponds to about 5% to 10% of all cases and is directly related to the inheritance of genetic mutations. The main ones occur in the BRCA1 and BRCA2 tumor suppressor genes. The identification of these mutations is extremely important because of the high risk of breast cancer development in this population, allowing differentiated screening strategies and the adoption of risk reduction measures. However, reflections on the ethical aspects related to the indiscriminate use of genetic testing are important and necessary. The objective of this study was to evaluate the knowledge and opinion of physicians of an oncology reference center on the indication of genetic tests for susceptibility to breast cancer given the ethical dilemmas to which they are submitted in medical practice.

Resumen El cáncer de mama representa un problema de salud pública, ya que es la neoplasia maligna con mayor incidencia en las mujeres de todo el mundo. La forma hereditaria corresponde a entre el 5% y el 10% de todos los casos y está directamente relacionada con la herencia de mutaciones genéticas, y las principales se dan en los genes supresores de tumores BRCA1 y BRCA2. La identificación de estas mutaciones es extremadamente importante debido al elevado riesgo de esta población de desarrollar cáncer de mama, además de permitir estrategias de rastreo diferenciadas y la adopción de medidas de reducción del riesgo. Sin embargo, es importante y necesario reflexionar sobre los aspectos éticos relacionados con el uso indiscriminado de las pruebas genéticas. El objetivo de este estudio fue evaluar el conocimiento y la opinión de los médicos de un centro oncológico de referencia sobre la indicación de las pruebas genéticas de susceptibilidad al cáncer de mama mediante los dilemas éticos a los que se ven sometidos en la práctica médica.

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INTRODUCTION: Breast Cancer (BC) is a neoplasm with the highest prevalence in women in Brazil and worldwide. Pregnancy-associated with BC is defined as that which occurs during pregnancy or within 1 to 2 years postpartum. The objective is to present a clinical case of a young patient with a history of familial BC who had cancer during pregnancy. The patient had cardiotoxicity after using doxorubicin and trastuzumab. CASE REPORT: She was a young patient within infiltrating ductal carcinoma in the right breast She was diagnosed within nine weeks of gestation and submitted to neoadjuvant chemotherapy with AC protocol (doxorubicina and cyclophosphamide) and mastectomy. Developed left atrial overload after treatment and still responding to hypersensitivity to trastuzumab. MANAGEMENT AND OUTCOME: The patient presented an alteration in the electrocardiogram (ECG) after the use of doxorubicin. The exam was repeated and the ECG was normal. Trastuzumab was started after delivery and the patient had a hypersensitivity reaction. Administration of trastuzumab was stopped and hydrocortisone was administered. The patient showed improvement in symptoms with cessation of trastuzumab. DISCUSSION: Although anthracycline-induced cardiotoxicity and hypersensitivity reactions to trastuzumab are common reactions, there are few studies on the effects of these drugs in patients with Gestational breast cancer (GBC). Monitoring cardiotoxicity in breast cancer treatment in pregnant patients is essential to avoid two complications: for the pregnant woman and the fetus.

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Abstract | Introduction: Next Generation Sequencing (NGS) is cost-effective and a faster method to study genes, but its protocol is challenging. Objective: To analyze different adjustments to the protocol for screening the BRCA genes using Ion Torrent PGM sequencing and correlate the results with the number of false positive (FP) variants. Materials and methods: We conducted a library preparation process and analyzed the number of FP InDels, the library concentration, the number of cycles in the target amplification step, the purity of the nucleic acid, the input, and the number of samples/Ion 314 chips in association with the results obtained by NGS. Results: We carried out 51 reactions and nine adjustments of protocols and observed eight FP InDels in homopolymer regions. No FP Single-Nucleotide Polymorphism variant was observed; 67.5% of protocol variables were jointly associated with the quality of the results obtained (p<0.05). The number of FP InDels decreased when the quality of results increased. Conclusion: The Ion AmpliSeq BRCA1/BRCA2 Community Panel had a better performance using four samples per Ion-314 chip instead of eight and the optimum number of cycles in the amplification step, even when using high-quality DNA, was 23. We observed better results with the manual equalization process and not using the Ion Library Equalizer kit. These adjustments provided a higher coverage of the variants and fewer artifacts (6.7-fold). Laboratories must perform internal validation because FP InDel variants can vary according to the quality of results while the NGS assay should be validated with Sanger.

Resumen | Introducción. La secuenciación de nueva generación es un método rentable y rápido para el estudio de los genes, pero su protocolo entraña desafíos. Objetivo. Investigar diferentes ajustes del protocolo de selección de los genes BRCAmediante secuenciación de Ion Torrent PGM™ y correlacionar los resultados con el número de variantes de falso positivo. Materiales y métodos. El proceso de preparación de la biblioteca, el número de falsos positivos InDels, la concentración de la biblioteca, el número de ciclos en el paso de amplificación de objetivos, la pureza del ácido nucleico, la entrada y el número de muestras por chip del Ion-314 se analizaron en asociación con los resultados obtenidos por secuenciación de nueva generación secuenciación de nueva generación. Resultados. Se hicieron 51 reacciones y nueve ajustes de los protocolos, y se observaron ocho falsos positivos InDels en las regiones de homopolímeros. No se observó ninguna variante de polimorfismo de nucleótido simple falso positivo. En 67,5 % de los casos, las variables de protocolo en su conjunto se asociaron con la calidad de los resultados obtenidos (p<0,05). El número de falsos positivos InDels disminuyó al aumentar la calidad de los resultados. Conclusiones. El panel comunitario Ion AmpliSeq BRCA1/BRCA2 tuvo un mejor rendimiento, con cuatro muestras por chip Ion-314 en lugar de ocho, y el número de ciclos en el paso de amplificación, incluso con ADN de alta calidad, fue mejor con 23. Se observaron mejores resultados con el proceso de ecualización manual y sin el uso del kit Ion Library Equalizer. Estos ajustes proporcionaron una mayor cobertura de las variantes y menos artefactos. Los laboratorios deben realizar la validación interna porque las variantes de falsos positivos InDel pueden variar según la calidad de los resultados. La secuenciación de próxima generación debe validarse con Sanger.

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Introdução e contexto: O câncer de mama do subtipo triplo-negativo (TN) representa cerca de 15% de todos os cânceres de mama e é negativo para expressão dos receptores de estrógeno e progesterona e superexpressão/amplificação de HER2. É mais prevalente em mulheres jovens e negras, apresenta maior risco de desenvolvimento de metástases e pior prognóstico. Parte significativa de tumores TN apresentam deficiência na via de reparo de recombinação homóloga (DRH), resultado de mecanismos genéticos, como variantes P/PP germinativas em BRCA1/2, sendo mutação em BRCA1 a mais frequente, e/ou silenciamento epigenético de BRCA1 e RAD51C no tumor. Não há dados sobre o status de mutação germinativa em BRCA1/2 em relação ao padrão metastático dos TN e nem em relação a mecanismos envolvidos na DRH em mulheres brasileiras. Objetivos: Avaliar o status de mutação germinativa nos genes BRCA1 e BRCA2 em mulheres com tumores TN e sua associação com padrão metastático, mecanismos de DRH e ancestralidade. Metodologia: Estudo retrospectivo unicêntrico. A avaliação de BRCA1/2 foi realizada a partir do DNA de leucócito/tecido não tumoral, e quando não disponíveis, tecido tumoral fresco ou emblocado em parafina. O status de metilação de BRCA1 e RAD51C foi determinado por sequenciamento de próxima geração (NGS) de amplicon usando DNA tumoral tratado com bissulfito de sódio; o critério de classificação foi >40% hipermetilado; entre ≥20% à <40% intermediário. A análise de ancestralidade foi realizada por eletroforese capilar com análise de fragmentos ou por genotipagem usando o array PMDA, utilizando DNA de leucócito. Informações clínicas de toda a casuística foram obtidas dos prontuários eletrônicos disponíveis na Instituição. Resultados: Foram incluídos 400 casos de tumores TN, 132 com diagnóstico de metástase e 268 sem metástase. A caracterização genética de BRCA1/2 foi obtida para 399 casos, sendo que 21,6% (86/399) apresentaram variantes patogênicas (P) ou provavelmente patogênicas (PP), onde 81,4% (70/86) das portadoras de variantes P/PP eram portadoras de variante P/PP em BRCA1, correspondento a 17,5% dos casos avaliados (70/399), e 18,6% (16/86) portadoras de variante P/PP em BRCA2, correspondendo a 4,0% dos casos (16/399). A média de idade ao diagnóstico foi menor para portadoras de variantes P/PP em BRCA1 que apresentaram idade de 41,7 anos, sendo que a idade das portadoras de variantes P/PP em BRCA2 e mulheres sem variantes P/PP ou VUS (do inglês, variant of uncertain significance) foi de 47,1 e 47,9 anos, respectivamente. Dos casos metastáticos, 131 tiveram BRCA1/2 testados, sendo 12,2% (16/131) BRCA1-P/PP e 6,1% (8/131) BRCA2-P/PP. Em relação ao padrão metastático dos tumores TN, os sítios mais acometidos em BRCA1-P/PP e sem variantes P/PP foram pulmão (50% e 37%, respectivamente) e SNC (31% e 23%, respectivamente), enquanto que para BRCA2-P/PP, os sítios mais acometidos foram SNC (62%) e ossos (37%). Em análise com modelos de regressão logística multivariada, observou-se que o risco para desenvolver metástase no grupo BRCA2-P/PP foi significativamente maior, chegando a quase 4 vezes mais para desenvolver em SNC (p=0,035) quando comparado com o grupo sem variantes P/PP e perto da significância (p=0,067) para desenvolver em ossos. O grupo BRCA1-P/PP não apresentou risco aumentado quando comparado com o grupo sem variantes P/PP. A análise de metilação nos genes BRCA1/RAD51C foi realizada no tumor primário para 177 casos, apresentando hipermetilação de 55,4% em um dos dois genes, sendo 43,5% (77/177) hipermetilados em BRCA1; e para RAD51C, 11,9% (21/177) hipermetilados. Já a análise de metilação nos tumores metastáticos foi realizada para 25 casos, sendo 32% hipermetilados em um dos dois genes, sendo 20% (5/25) hipermetilados em BRCA1 e 12% (3/25) em RAD51C. A análise de ancestralidade foi realizada para 216 casos, onde a maioria (68%) foi classificada como ancestralidade predominantemente europeia; foi investigada se havia associação entre as ancestralidades e o evento genético ou epigenético subjacente a DRH, porém não ficou evidente nenhuma associação. Conclusões: BRCA1 confirmou ser o gene que mais frequentemente apresenta variantes P/PP em mulheres com CMTN, principalmente em mulheres diagnosticadas em idade jovem. A maioria dos casos cujo DNA tumoral apresentou hipermetilação em um dos dois genes investigados (BRCA1 e RAD51C) foram em mulheres jovens, sendo o gene BRCA1 mais frequentemente metilado. Observou-se que há um risco elevado de até 4 vezes para desenvolver metástase no SNC no grupo de mulheres com BRCA2-PP. Não foi possível estabelecer associação significativa entre os mecanismos genéticos e epigenéticos subjacentes a DRH com ancestralidades europeias ou africanas na população estudada.

Introduction: Triple-negative (TN) subtype breast cancer accounts for about 15% of all breast cancers and is negative for estrogen and progesterone receptor expression and HER2 overexpression/amplification. It is more prevalent in young, black women, has a higher risk of developing metastases and a worse prognosis. A significant part of TN tumors have a deficiency in the homologous recombination repair (HRD) pathway, resulting from genetic mechanisms, such as germline pathogenic mutations in BRCA1/2, with BRCA1 being the most frequent mutation, and/or epigenetic silencing of BRCA1 and RAD51C in the tumor. There are no data regarding BRCA1/2 germline mutation status in relation to the metastatic pattern of TN tumors or about the mechanisms involved in HRD in Brazilian women. Objectives: To evaluate the germline mutation status in BRCA1 and BRCA2 genes in women with TNBC and its association with metastatic pattern, HRD mechanisms and ancestry. Methodology: Single-center retrospective study. BRCA1/2 evaluation was performed from leukocyte/non-tumor tissue DNA, and when not available, fresh tumor tissue or embedded in paraffin. The methylation status of BRCA1 and RAD51C was determined by next-generation amplicon sequencing (NGS) using tumor DNA treated with sodium bisulfite; the classification criteria was >40% hypermethylated; between 20% to <39% intermediate. Ancestry analysis was performed by capillary electrophoresis with fragment analysis using the PMDA array using leukocyte DNA. Clinical information from the entire sample was obtained from electronic medical records available at the institution. Results: 400 cases of TNBC were included, 132 diagnosed with metastasis and 268 without metastasis. The genetic characterization of BRCA1/2 was obtained for 399 cases, and 21.6% (86/399) presented pathogenic (P) or probably pathogenic (PP) variants, where 81.4% (70/86) of the carriers of P/PP variants carried a pathogenic variant in BRCA1, corresponding to 17.5% of the evaluated cases (70/399), and 18.6% (16/86) carried P/PP variants in BRCA2, corresponding to 4, 0% of cases (16/399). The mean age at diagnosis was lower for carriers of P/PP variants in BRCA1, who were 41.7 years old, and the age of carriers of P/PP variants in BRCA2 and women without P/PP or VUS (Variant of Uncertain Significance) was 47.1 and 47.9 years, respectively. In regarding to metastatic cases, 131 had BRCA1/2 tested, with 12.2% (16/131) BRCA1-P/PP and 6.1% (8/131) BRCA2-P/PP. Regarding the metastatic pattern of TN tumors, the most affected sites in BRCA1-P/PP and without P/PP variants were lung (50% and 37%, respectively) and CNS (31% and 23%, respectively), while for BRCA2-P/PP, the most affected sites were the CNS (62%) and bones (37%). In analysis with multivariate logistic regression models, it was observed that the risk of developing metastasis in the BRCA2-P/PP group was significantly higher, reaching almost 4 times more to develop in the CNS (p=0.035) when compared to the group without P/PP variants and close to significance (p=0.067) to develop in bone. The BRCA1-P/PP group was not at increased risk when compared to the group without P/PP variants. The analysis of methylation in the BRCA1/RAD51C genes was performed in the primary tumor for 177 cases, showing 55.4% hypermethylation in one of the two genes, with 43.5% (77/177) being hypermethylated in BRCA1; and for RAD51C, 11.9% (21/177) hypermethylated. The analysis of methylation in metastatic tumors was performed for 25 cases, 32% of which were hypermethylated in one of the two genes, 20% (5/25) hypermethylated in BRCA1 and 12% (3/25) in RAD51C. Ancestry analysis was performed for 216 cases, where the majority (68%) were classified as predominantly European ancestry; it was investigated whether there was an association between ancestry and the genetic or epigenetic event underlying the HRD, but no association was evident. Conclusions: BRCA1 confirmed to be the gene that most frequently presents P/PP variants in women with TNBC, mainly in women diagnosed at a young age. Most cases whose tumor DNA showed hypermethylation in one of the two genes investigated (BRCA1 and RAD51C) were in young women, with the BRCA1 gene being more frequently methylated. It was observed that there is an up to 4-fold increased risk of developing CNS metastasis in the group of women with BRCA2-PP. It was not possible to establish a significant association between the genetic and epigenetic mechanisms underlying HRD with European or African ancestry in the population studied

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Triple-negative breast cancer (TNBC) is an uncommon molecular subtype (representing 15%­20% of breast cancers) characterized by the non-expression of estrogen receptor, progesterone receptor, and human epidermal growth receptor factor 2. More aggressive and lethal, TNBC is often associated with pathogenic variants in BRCA1/2 genes. This study aimed to describe a series of seven cases of patients with TNBC and pathogenic variants in BRCA1/2 genes. All patients were female and under 50 years of age at diagnosis. Four of them presented a family history of breast cancer and/or other neoplasms. The predominant clinical stage was IIB, and the main anatomopathological stage was pT2pN0M0. The mean tumor size in the series was 2.5 cm (1.0 to 3.2 cm). Ki-67 was > 30% in all patients. Three cases (43%) had pathological complete response, and only one presented extensive residual disease after neoadjuvant chemotherapy. Six patients showed pathogenic variants in BRCA1 (86%) and one in BRCA2+ (14%). After a mean follow-up of 38 months (19 to 68 months), five patients were alive and without neoplastic disease, and two progressed to metastasis.

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Resumen: Las mutaciones de BRCA1 son raras en el cáncer de mama (CM) esporádico; sin embargo, su expresión a nivel tumoral se encuentra disminuida o ausente en 30%-50% de los casos. Objetivo: valorar la expresión tumoral de BRCA1 por inmunohistoquímica (IHQ) en mujeres uruguayas diagnosticadas de CM antes de los 40 años. Material y método: se incluyeron pacientes diagnosticadas de CM antes de los 40 años. Se utilizaron los anticuerpos monoclonales anti-BRCA1 MS110 contra el extremo N-terminal y GLK-2 contra el extremo C-terminal. Se calculó la sobrevida global (SVG) y la sobrevida libre de enfermedad (SVLE), para la construcción de las curvas se utilizó el método de Kaplan-Meier y la diferencia de sobrevida se evaluó mediante el test de log rank. Resultados: se incluyeron 40 pacientes, la SVG y la SVLE a cinco años fueron de 73% y 60% respectivamente. La expresión de BRCA1 mediante GLK-2 fue <10% en 16 de las 40 pacientes (40%). La SVG y la SVLE a cinco años para las pacientes con expresión <10% fue de 56% vs 85% para las pacientes con expresión >10% (p=0,015) y de 40% vs 72% (p=0,034) respectivamente. La expresión de BRCA1 mediante MS110 fue <10% en 11 de las 40 pacientes (27,5%). No se encontraron diferencias en la SVG ni en la SVLE a cinco años con este marcador. Conclusión: la pérdida de la expresión tumoral de BRCA1 determinada mediante GLK-2 se encontró en el 40% de las pacientes incluidas y se asoció a una menor SVG y SVLE, por lo que podría tener un valor pronóstico desfavorable en estas pacientes.

Summary: BRCA1 mutations are rare in sporadic breast cancer (CM), however their expression at the tumor level is diminished or absent in 30-50% of cases. Objective: to assess the tumor expression of BRCA1 using immunohistochemistry (IHC) in Uruguayan women diagnosed with BC before the age of 40 years. Material and methods: patients diagnosed with BC before the age of 40 between. The antibodies used were anti BRCA1 MS110 monoclonal antibodies against the N-terminal end and GLK-2 against the C-terminal. Overall survival (OS) and disease free survival (DFS) were calculated; the curves were developed using the Kaplan-Meier method and the difference in survival was evaluated through the log rank test. Results: the average age of the 40 patients included was 36 years. The 5-year OS and DFS were 73% and 60% respectively. The expression of BRCA1 with GLK-2 was <10% in 16 of the 40 patients included (40%). The 5-year OS and DFS for patients with <10% expression was 56% vs. 85% for patients with >10% (p=0.015) and 40% vs. 72% (p = 0.034) respectively. The expression of BRCA1 by MS110 was <10% in 11 of the 40 patients included (27.5%). No differences were found in the 5-year OS or DFS based on the expression of this marker. Conclusion: The loss of BRCA1 expression using GLK-2, which suggests the presence of a truncated protein, was associated with a statistically significantly lower OS and DFS, that the decrease in the BRCA1 protein as determined by GLK2 has an unfavorable prognostic value for young patients with BC.

Resumo: As mutações de BRCA1 são raras no câncer de mama (CM) esporádico; no entanto sua expressão no nível tumoral está diminuída ou ausente em 30-50% dos casos. Objetivo: avaliar a expressão tumoral de BRCA1 por imuno-histoquímica (IHQ) em mulheres uruguaias com diagnóstico de CM antes dos 40 anos. Material e métodos: foram incluídas pacientes com diagnóstico de CM antes dos 40 anos. Foram utilizados anticorpos monoclonais anti BRCA1 MS110 contra o extremo N-terminal e GLK-2 contra o extremo C-terminal. A sobrevida global (SVG) e a sobrevida livre de enfermidade (SVLE) foram calculadas; o método de Kaplan-Meier foi utilizado para a construção das curvas e a diferença de sobrevida foi avaliada usando o teste de log-rank. Resultados: foram incluídas 40 pacientes; a SVG e a SVLE aos 5 anos foram 73% e 60% respectivamente. A expressão de BRCA1 mediante GLK-2 foi <10% em 16 das 40 pacientes (40 %). A SVG e a SVLE aos 5 anos para as pacientes com expressão £10% foi 56% vs. 85% para as pacientes com expressão >10% (p=0,015) e 40% vs. 72% (p=0,034) respectivamente. A expressão de BRCA1 mediante MS110 foi =10% em 11 das 40 pacientes (27,5%). Não foram encontradas diferenças na SVG nem na SVLE aos 5 anos com este marcador. Conclusão: foi encontrada perda da expressão tumoral de BRCA1 determinada por GLK-2 em 40% das pacientes incluídas e foi associada a uma menor SVG e SVLE, o que poderia ter um valor prognóstico desfavorável nestas pacientes.

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Introducción. El cáncer de mama es un problema mundial de salud pública; entre el 5 y el 10 % de los casos presentan agregación familiar, lo que se explicaría por la presencia de mutaciones en genes de alto riesgo como el BRCA1 y el BRCA2. El origen fundador de la deleción BRCA1 3450del4 en Colombia ya fue reportado. Objetivo. Hacer un análisis descriptivo de seis familias del del Tolima y del Huila con la deleción BRCA1 3450del4 de la asociación de la mutación germinal, con el cáncer de mama y la agregación familiar. Materiales y métodos. Se hizo un estudio descriptivo y transversal de seis casos índice con cáncer de mama positivos para BRCA1 3450del4, que cumplían tres de los criterios establecidos por Jalkh, et al. A partir de la información de las entrevistas, se realizaron los árboles genealógicos (GenoPro™, versión 2016). Se tipificó la mutación en familiares sanos y afectados que aceptaron participar. Resultados. De los 78 individuos seleccionados por conveniencia en las seis familias, 30 presentaron la mutación BRCA1 3450del4; de ellos, seis tenían cáncer de mama, uno, cáncer de ovario, uno, cáncer de mama y ovario, y otro, cáncer de próstata; 21 no presentaban neoplasias. De los 30 individuos portadores de la variante patogénica, seis eran hombres y 24 mujeres, 13 de ellas menores de 30 años. Conclusiones. En este estudio se confirmó la asociación de la deleción BRCA1 3450del4 con el cáncer de mama de agregación familiar.

Introduction: Breast cancer is a worldwide public health problem; between 5% and 10% of the cases present familial aggregation explained by genes of high risk such as BRCA1and BRCA2. The founding origin of the deletion BRCA1 3450del4 in Colombia has been previously reported. Objective: To carry out in six families from Tolima and Huila departments a descriptive analysis of the presence of the BRCA1 3450del4 mutation associated with breast cancer and familial aggregation. Materials and methods: We conducted a descriptive and cross-sectional study of six index cases with breast cancer positive for BRCA1 3450del4 that fulfilled three of the criteria established by Jalkh, et al. The genealogical trees were made using the information of the interview data (GenoPro™, version 2016). The mutation was typified in healthy and affected relatives who agreed to participate. Results: Thirty of the 78 individuals selected by convenience in the six families presented the mutation BRCA1 3450del4 six of whom developed breast cancer, one, ovarian cancer, one ovarian and breast cancer, and one prostate cancer; 21 did not present any type of neoplasm at the time of the study. Of the 30 individuals carrying the pathogenic variant, six were men, 24 were women, and 13 of these were under 30. Conclusions: In this study of families with the deletion BRCA1 3450del4 in Tolima and Huila we confirmed its association with familial aggregation of breast cancer.

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Resumen OBJETIVO: Determinar las mutaciones genéticas en el cáncer de mama de patrón hereditario y demostrar si existe alguna asociación significativa entre las más comunes en población mexicana y el riesgo de padecerlo. MATERIALES Y MÉTODOS: Estudio transversal y observacional efectuado en el Hospital Ángeles México en coordinación con el Instituto Nacional de Medicina Genómica. Criterios de inclusión: pacientes con cáncer de mama y uno o más familiares de primer grado afectados por esta enfermedad y pacientes con cáncer de ovario. Criterios de exclusión: pacientes sin antecedentes de cáncer de mama ni ovario, o con algún familiar en el protocolo. Se empleó la técnica de rearreglos en placas RT2 Profiler para Master-Mix Quantinova probe PCR kit. Para el análisis estadístico se utilizó el programa SPSS versión 22 y Epi Info versión 7. RESULTADOS: Se estudiaron 39 pacientes con edad promedio de 53.2 ± 12.1 años. Los receptores de progesterona y estrógeno no mostraron diferencia entre grupos. Hubo mayor tendencia para BRCA1. Al estudiar las mutaciones con significación estadística, en las que sobresalieron los casos de BRCA2 versus sin significación y los casos negativos, no hubo diferencia estadística significativa, pero con una tendencia a mayor frecuencia de BCRA1. Al evaluar las estirpes de cáncer de mama y los grados nucleares comparados por edad, los tres grupos de grado nuclear comparados por edad mostraron diferencias. CONCLUSIÓN: Los datos obtenidos muestran que en la población mexicana el gen BRCA2 es el de mayor incidencia de cáncer hereditario, en edad de aparición más temprana y mayor grado nuclear al momento del diagnóstico.

Abstract OBJECTIVE: To determine the genetic mutations in hereditary pattern breast cancer and demonstrate whether there is a significant association between the most common in the Mexican population and the risk of suffering it. MATERIALS AND METHODS: Cross-sectional and observational study conducted at the Hospital Angeles México in coordination with the National Institute of Genomic Medicine. Inclusion criteria: patients with breast cancer and one or more first-degree relatives affected by this disease and patients with ovarian cancer. Exclusion criteria: patients without a history of breast or ovarian cancer, or with a family member in the protocol. The RT2 Profiler plate rearrangement technique was used for Master-Mix Quantinova probe PCR kit. The SPSS version 22 program and Epi Info version 7 were used for the statistical analysis. RESULTS: 39 patients with an average age of 53.2 ± 12.1 years were studied. Progesterone and estrogen receptors showed no difference between groups. There was a greater trend for BRCA1. When studying the mutations with statistical significance, in which the cases of BRCA2 versus without significance and the negative cases stood out, there was no significant statistical difference, but with a tendency to higher frequency of BCRA1. When evaluating breast cancer lines and nuclear grades compared by age, the three nuclear grade groups compared by age showed differences. CONCLUSION: The data obtained show that in the Mexican population the BRCA2 gene has a higher incidence in hereditary cancer, at an age of earlier onset and greater nuclear grade at the time of diagnosis.

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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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Background: Male breast cancer is a rare entity, with an approximate rate of 1.1 / 100 000 in the US, with an average age of 67 years. In all cases a genetic study must be performed, in order to find mutations in known genes, and after the resolution of the disease, based on the results, a contralateral prophylactic mastectomy should be considered. Clinical case: 53 -year-old male diagnosed with right breast cancer, infiltrating ductal adenocarcinoma type, clinical stage IIB, breast cancer on 2 immediate family history, mutations of the BRCA1 gene and positive hormone receptors and Her2/Neu. He was treated with modified radical mastectomy in diseased side with subsequent neoadjuvant chemotherapy/radiotherapy. After a year of follow-up and a free behavior of disease, contralateral prophylactic mastectomy was performed. The patient progressed satisfactorily, following up to 18 months since the beginning, with no tumor activity data. Conclusions: Breast cancer in male patient has a worse prognosis than female patients, due to lower amount of tissue in breast exposed to an earlier chest spread and a different biological behavior, also a higher risk of prostate and pancreatic cancer is associated. Studies of adequate methodological quality are scarce, so that decisions are based on guidelines for breast cancer in women.

Introducción: el cáncer de mama en varones es una entidad poco frecuente, con una tasa aproximada de 1.1/100 000 habitantes en los Estados Unidos de América, con una edad media de presentación de 67 años. En todos los casos se aconseja realizar un estudio genético al paciente en búsqueda de mutaciones conocidas y después de la resolución de la enfermedad, con base en los resultados, considerar realizar una mastectomía profiláctica contralateral. Caso clínico: paciente masculino de 53 años de edad, con diagnóstico de cáncer de mama derecha, tipo adenocarcinoma canalicular infiltrante, estadio clínico IIB, con antecedentes de cáncer de mama en 2 familiares directos, mutaciones del gen BRCA1 y positivo tanto a receptores hormonales como para el gen Her2/Neu. Fue tratado con mastectomía radical modificada en lado enfermo con neoadyuvancia subsecuente a base de quimio/radioterapia, tras un año de seguimiento y con un comportamiento libre de enfermedad se realizó mastectomía profiláctica contralateral. El paciente evolucionó satisfactoriamente, en seguimiento a 18 meses sin datos de actividad tumoral. Conclusiones: el cáncer de mama en el paciente varón tiene un pronóstico peor respecto al paciente de sexo femenino, esto por la menor cantidad de tejido en mama que lo expone a una diseminación torácica más temprana y por su comportamiento más agresivo, además de asociarse a un mayor riesgo de desarrollar cáncer de próstata y páncreas, respecto a la población general. Los estudios de adecuada calidad metodológica son escasos, por lo que la toma decisiones se fundamenta en las directrices para el cáncer de mama en mujeres.

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Objective: Genetic-related breast cancer has a tendency to manifest earlier and to be more aggressive than sporadic cancer. There are few studies evaluating the prevalence and incidence of hereditary breast and ovarian cancer (HBOC) among Brazilians. In order to improve assistance, efforts to characterize the population at risk of HBOC could help to formulate locally designed guidelines. Methodology: Descriptive retrospective study in Hospital Erasto Gaertner's service of Oncogenetics, in Curitiba, state of Paraná, Brazil. We included individuals at-risk for HBOC, according to the National Comprehensive Cancer Network (NCCN) criteria, who had performed genetic tests for HBOC. We collected complete family history, presented as heredograms. We excluded families with inappropriate family history. Results: Of the 27 patients analyzed (total of 25 families), 7% were asymptomatic, 8% had ovarian cancer and 85% had breast cancer. Mutations were found in 29.6%, 6 cases of BRCA1, 1 of BRCA2 and 1 of TP53. Triple negative was the most common reported subtype, representing 60% of breast cancers; among patients with identified pathogenic variants, 2 were BRCA2 mutated and 1 TP53 mutated. The mean age of diagnosis was 40 years for those identified as probands on heredograms; in the generation above, it was 52,5, and in the below, 33, suggesting the antecipation phenomena Two new mutations were identified in Brazilian population, both in BRCA1: c.4258 G>A and c.5345 G>A. The most frequent NCCN criteria were number 2, 9, 8 and 4. Estimated penetrance was 22%. Conclusion: This is the first descriptive study in the population at-risk for HBOC in the state of Paraná. We could identify two new pathogenic variants of BRCA1 in Brazilian population. A comprehensive family history was included in the study, depicted as heredograms of each family. Despite the low number of patients, the main results are in agreement with previous studies

Objetivo: Os carcinomas de mama hereditários têm a tendência de se manifestar precocemente e serem mais agressivos do que os esporádicos. São poucos os estudos que avaliam a prevalência e a incidência da síndrome de câncer de mama e ovário hereditário (SCMOH) na população brasileira. No intuito de melhorar a assistência prestada, a análise das características encontradas na população em risco para SCMOH ajudaria a formulação de protocolos regionais para a abordagem desses pacientes. Metodologia: Estudo descritivo retrospectivo realizado no serviço de Oncogenética do Hospital Erasto Gaertner em Curitiba, Paraná. Incluímos indivíduos em risco para SCMOH pelos critérios estabelecidos pela National Comprehensive Cancer Network (NCCN) e que realizaram testes genéticos para SCMOH. Coletamos o histórico familiar completo, apresentado na forma de heredograma. Foram excluídas famílias com histórico familiar inapropriado. Resultados: Das 27 pacientes analisadas (total de 25 famílias), 7% eram assintomáticas, 8% tiveram câncer de ovário e 85%, câncer de mama. Mutações foram encontradas em 29,6%, sendo 6 casos de BRCA1, 1 de BRCA2 e 1 de TP53. Tumores triplo negativos foram os mais encontrados entre os subtipos, representando 60% dos carcinomas de mama; dentre os pacientes com variantes patogênicas, 2 eram de mutações em BRCA2 e 1 em TP53. A média de idade entre as pacientes foi de 40 anos entre probandas dos heredogramas; na geração superior, foi de 52,5 anos e na inferior, de 33, sugerindo o fenômeno de antecipação. Duas novas mutações foram descritas na população brasileira, as duas sendo em BRCA1: c.4258 G>A e c.5345 G>A. Os critérios NCCN mais encontrados foram os de número 2, 9, 8 e 4. A penetrância estimada foi de 22%. Conclusão: Este foi o primeiro estudo descritivo de uma população em risco para SCMOH no estado do Paraná. Encontramos duas novas mutações que não haviam sido descritas na população brasileira até então. Foi realizada a análise detalhada do histórico familiar das pacientes, sendo descrita e detalhada em heredogramas para cada família. Apesar do baixo número de indivíduos analisados, os resultados principais foram de acordo com o encontrado em estudos prévios

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O câncer de mama é o principal câncer que atinge a população feminina no mundo, com maior taxa de incidência e mortalidade, sendo que de 5% a 10% de todos os casos são relacionados à herança de mutações genéticas. A identificação precoce dos casos de câncer de mama e ovário é importante, pois um indivíduo afetado pode herdar propriedade de antecedentes familiares que indicam uma predisposição hereditária. O efeito cancerígeno pode ocorrer quando dois genes supressores de maior importância, como BRCA1 e BRCA2, perdem suas funções nos dois alelos decorrentes de mutações na linhagem germinativa. Desta forma, foi realizada uma revisão da literatura sobre câncer de mama hereditário e suas correlações com mutações germinativas nos genes BRCA1 e BRCA2 que aumentam o risco para o desenvolvimento de câncer de mama.

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ABSTRACT OBJECTIVE: To analyze the cost effectiveness of the diagnostic program for the germline mutation in BRCA1/2 genes and of preventative strategies for the relatives of patients diagnosed with ovarian cancer associated with this mutation. METHODS: The study analyzed the cost effectiveness by developing an analysis of the Markov decision process from the perspective of the National Health System. The strategies compared reflect upon the adoption of genetic testing and preventative strategies for relatives or the usual care currently proposed. The incremental cost-effectiveness ratio was expressed in terms of cost per case avoided. The sensitivity analysis was performed in a univariate and deterministic manner. RESULTS: The study showed increments for effectiveness and for costs when performing genetic testing and adopting prophylactic measures for family members. The incremental cost-effectiveness ratio was estimated at R$908.58 per case of cancer avoided, a figure considered lower than the study's cost-effectiveness threshold (R$7,543.50). CONCLUSIONS: The program analyzed should be considered a cost-effective strategy for the national situation. Studies in various other countries have reached similar conclusions. One possible ramification of this research might the need to perform a budgetary-impact analysis of making the program one of the country's health policies.

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Introducción: el cáncer de mama representa la primera causa de muerte por cáncer en mujeres de Uruguay. Se estima que cerca de 7% son causados por mutaciones en el ácido desoxirribonucleico germinal. Los costos de la secuenciación genética han descendido dramáticamente gracias a la aparición de la secuenciación de nueva generación (NGS). El cambio tecnológico abrió una nueva etapa en el estudio del cáncer hereditario en nuestro país. Objetivo: comunicar los resultados de la utilización de tecnología NGS y paneles multigénicos en familias uruguayas con alto riesgo de cáncer de mama hereditario. Pacientes y método: se secuenciaron 135 familias de alto riesgo que provenían de la consulta de consejería genética que funciona en el Grupo Colaborativo Uruguayo: Investigación de afecciones oncológicas hereditarias. Cuando la historia familiar sugería claramente un síndrome de cáncer de mama y ovario hereditario se efectuó secuenciación NGS exclusiva de los genes BRCA1 y 2; cuando el patrón familiar no configuraba claramente se utilizó un panel multigénico. Resultados: se efectuó NGS exclusiva de genes BRCA1 y 2 en 62 familias y un panel multigénico en 73 familias. Se identificaron en total 29 mutaciones patógenas (21 en genes BRCA y 8 en otros genes). Dos de ellas fueron noveles y tres pueden considerarse recurrentes en la población uruguaya. Conclusiones: este trabajo es el primero en Uruguay en reportar el resultado de esta nueva tecnología en el cáncer de mama hereditario. El hallazgo de 29 mutaciones patógenas nos ayuda a delinear el perfil mutacional de nuestro país.

Introduction: breast cancer is women's first cause of death in Uruguay. According to estimations, around 7% of cases result from germinal mutations by deoxyribonucleic acid. The cost of genetic sequencing has dramatically dropped thanks to the arrival of next-generation sequencing (NGS). This technological change opened a new era in the study of hereditary cancer in our country. Objective:to communicate the results of using NGS technology and multigenic panels in Uruguayan families with high risk of hereditary breast cancer. Method: 135 high risk families referred by the genetic counselling consultation that is provided at the Uruguayan Collaborative Group (Hereditary Oncological Conditions Research) were sequenced. When the family history clearly suggested hereditary breast and ovary cancer was a possibility, exclusive NGS sequencing was done for BRCA1 and BRCA2 genes; when the family pattern was not clear to this respect, multigenic panels were used. Results: exclusive NGS sequencing for BRCA1 and BRCA2 genes was done in 62 families, and multigenic panels were used in 73 families. 29 pathogenic mutations were identified (21 in BRCA genes and 8 in other genes). Two of them were new to the disease and three could be considered recurrent in the Uruguayan population. Conclusions:this study is the first one in Uruguay to report the results of this new technology in hereditary breast cancer. The finding of 29 pathogenic mutations contributes to outlining the mutational profile of our country.

Introdução: o câncer de mama é a primeira causa de morte por câncer em mulheres no Uruguai. Estima-se que aproximadamente 7% sejam causados por mutações no ácido desoxirribonucleico germinal. Os custos da sequenciação genética diminuíram dramaticamente graças ao aparecimento da sequenciação de nova geração (NGS). Esta nova tecnologia deu inicio a uma nueva etapa no estudo do câncer hereditário no nosso país. Objetivo: comunicar os resultados da utilização de tecnologia NGS e painéis mutagênicos em famílias uruguaias com alto risco de câncer de mama hereditário. Pacientes e método: 135 famílias de alto risco originárias do aconselhamento genético que funciona no Grupo Colaborativo Uruguaio: Pesquisa de afecções oncológicas hereditárias foram sequenciadas. Quando a história familiar sugeria uma síndrome de câncer de mama e ovário hereditários fez-se a secuenciacao NGS exclusivamente dos genes BRCA1 e 2; quando o padrão familiar não era claro foi utilizado um painel multigênico. Resultados: realizou-se NGS exclusivamente de genes BRCA1 e 2 em 62 famílias e um painel multigênico em 73 famílias. Foram identificadas 29 mutações patogênicas (21 em genes BRCA e 8 em outros genes). Duas eram novas e três podem ser consideradas como recorrentes na população uruguaia. Conclusões: este trabalho é o primeiro que apresenta os resultados desta nova tecnologia aplicada ao câncer de mama hereditário no Uruguai. O achado de 29 mutações patogênicas ajuda a definir o perfil mutacional do nosso país.

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Aportar al ginecólogo herramientas para la identificación de pacientes con riesgo de síndrome de cáncer hereditario de mama y ovario (SCHMO), y brindar consejería en el manejo preventivo de pacientes con este síndrome.Materiales y métodos: a partir de un caso hipotético se formulan preguntas relacionadas con el riesgo de desarrollar cáncer de mama y ovario en pacientes con SCHMO. Para responder estas preguntas se realizó una revisión de la literatura pertinente en las bases de datos Medline vía PubMed, ScienceDirect y SciELO. Se utilizaron los términos MESH "Síndrome de cáncer de mama y ovario hereditario", "Neoplasias ováricas", "Neoplasias de la mama", "Genes BRCA1", "Genes BRCA2" y su equivalente en inglés. Los resultados se restringieron a artículos publicados entre el 2005 y 2015.Resultados: a través de la búsqueda en PubMed se obtuvieron 56 artículos, de los cuales se seleccionaron 45. En ScienceDirect y SciELO se encontraron 7 artículos. Además, se incluyeron 4 artículos de fuentes no ligadas a estas bases de datos.Conclusiones: el ginecoobstetra debe identificar pacientes con riesgo de presentar el síndrome de cáncer hereditario de mama y ovario, y explicar a los pacientes la importancia de la realización de las pruebas moleculares de los genes BRCA1 y BRCA2 y de participar en equipos multidisciplinarios que además deben incluir al genetista, cirujano, los oncólogos y al paciente para la toma de decisiones médicas de acuerdo con los resultados moleculares...

To provide gynaecologists with tools for the identification of patients at risk of hereditary breast and ovarian cancer syndrome (HBOC) and present advise regarding the preventive management of patients with this syndrome.Materials and methods: Questions were asked in relation to the risk of patients with HBOC developing breast and ovarian cancer. To answer those questions, a review of the relevant literature was conducted in the Medline database via PubMed, and in ScienceDirect and SciELO. The MESH terms used were Breast and Ovarian Cancer Syndrome, Ovarian Neoplasms, Breast Neoplasms, BRCA1 Genes, BRCA2 Genes, and their equivalent in English. Results were limited to articles published between 2005 and 2015.Results: Overall, 56 articles were found in PubMed, of which 45 were selected. The search in ScienceDirect and SciELO resulted in 7 articles. Additionally, 4 articles from other sources not linked to these data bases were also included.Conclusions: Obstetric gynaecologists must identify patients at risk of presenting Hereditary Breast and Ovarian Cancer Syndrome, and explain to the patients the importance of performing molecular testing for BRCA1 and BRCA2 genes; and they must participate in multi-disciplinary teams consisting also of geneticists, surgeons, oncologists and patients for medical decision-making in accordance with the molecular results...

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O presente artigo discute aspectos éticos, científicos e jurídicos sobre o patenteamento de genes humanos,partindo de um contexto histórico sobre propriedade intelectual de seres vivos e passando pela decisão da Suprema Corte dos EUA relativa ao caso Myriad Genetics, conflito em torno da patente dos genes BRCA1e BRCA2, relacionados ao câncer de mama e de ovário. Além disso, o artigo aborda diplomas normativos sobre o assunto, considerando tanto a legislação brasileira quanto a internacional. Por fim, contrapõe posições distintas sobre patente de genes humanos, adotando posicionamento crítico que o assunto merece...

This article discusses ethical, scientific and legal aspects of the patenting of human genes, startingfrom a historical context of intellectual property of living beings and passing through the decision ofthe US Supreme Court in Myriad Genetics case, conflict over patent of the genes BRCA1 and BRCA2,related to breast cancer and ovarian cancer. Moreover, the article discusses regulatory instrumentson the subject, considering both the Brazilian and international legislation. Finally, it contrastsdifferent positions on patent of human genes, adopting critical position that this matter deserves...

Este artículo aborda los aspectos éticos, científicos y legales de las patentes de genes humanos, a partir de uncontexto histórico de la propiedad intelectual de los seres vivos y pasando por la decisión de la Corte Suprema deEstados Unidos en el caso Myriad Genetics, el conflicto sobre patentes de los genes BRCA1 y BRCA2 relacionadoscon el cáncer de mama y cáncer de ovario. Además, el artículo analiza los instrumentos normativos sobre eltema, teniendo en cuenta tanto la legislación brasileña como internacional. Por último, contrasta diferentesposiciones sobre las patentes de los genes humanos, y adopta una posición crítica que este asunto merece...

Assuntos

RESUMO

A Sindrome de Câncer de Mama e Ovário Hereditários é a principal causa hereditária de câncer de mama. Nesse artigo, abordamos os principais fatos relevantes à epidemiologia, rastreamento, medidas de redução de risco e características patologicas que podem nos ajudar a estabelecer nossa atuação em relação a essa patologia em 2015.

Hereditary breast?ovarian cancer syndrome is the main cause of hereditary breast cancer. In this paper we discuss the main facts relevant to the epidemiology, screening, risk reduction measures and pathological caractheristics that can help us in our practice in 2015.