Menopausia quirúrgica en pacientes con mutación BRCA, el papel de la terapia hormonal / Surgical Menopause in Patients with BRCA Mutation, the Role of Hormone Therapy

Introducción: las mujeres con mutación BRCA1/2 (mBRCA) tienen un riesgo aumentado de desarrollar cáncer de mama (CM) y ovario (CO). La salpingo-oforectomía bilateral (SOB) se asocia con la reducción del riesgo del 80% para CO y un 50% para CM. Se recomienda realizarla entre los 35 y 40 años. Como consecuencia se produce una menopausia prematura, con un impacto negativo sobre la calidad de vida por la presencia de síntomas climatéricos, aumento del riesgo de enfermedad cardiovascular, osteoporosis y riesgo de alteración cognitiva. La terapia hormonal (THM) es el tratamiento más eficaz para la prevención de estos síntomas. Estado del arte: distintos estudios han demostrado un mayor riesgo de CM en mujeres posmenopáusicas que reciben THM en particular con terapia combinada, estrógeno + progesterona (E+P). Según el metanálisis de Marchetti y cols., en las mujeres portadoras de mBRCA que recibieron THM, no hubo diferencias en el riesgo de CM comparando E solo con E+P. En el estudio de Kotsopoulos, incluso se encontró un posible efecto protector en aquellas que usaron E solo. Otro estudio en portadoras sanas demostró que, en las mujeres menores de 45 años al momento de la SOB, la THM no afectó las tasas de CM. Sin embargo, en las mujeres mayores de 45 años, las tasas de CM fueron más altas. Como el esquema de E+P se asocia con un mayor riesgo relativo (RR) de CM, las dosis de progestágenos utilizados se deberían limitar, eligiendo derivados naturales de progesterona, de uso intermitente para disminuir la exposición sistémica. Según diferentes guías internacionales, a las portadoras de mBRCA sanas que se someten a una SOB se les debe ofrecer THM hasta la edad promedio de la menopausia. Conclusión: la menopausia prematura disminuye la expectativa de vida; es por ello que una de las herramientas para mejorar y prevenir el deterioro de la calidad de vida es la THM. El uso de THM a corto plazo parece seguro para las mujeres portadoras de mBRCA que se someten a una SOB antes de los 45 años, al no contrarrestar la reducción del riesgo de CM obtenida gracias a la cirugía. (AU)

Introduction: women with BRCA1/2 (mBRCA) mutation have an increased risk of developing breast (BC) and ovarian (OC) cancer. Bilateral salpingo-oophorectomy (BSO) is associated with an 80% risk reduction for OC and 50% for BC. The recommended age for this procedure is 35 to 40 years. The consequence is premature menopause, which hurts the quality of life due to the presence of climacteric symptoms, increased risk of cardiovascular disease, osteoporosis, and a higher risk of cognitive impairment. Hormone therapy (MHT) is the most effective treatment for preventing these symptoms. State of the art: different studies have shown an increased risk of BC in postmenopausal women receiving MHT, particularly with combined therapy, estrogen + progesterone (E+P). According to the meta-analysis by Marchetti et al., in women carrying mBRCA who received MHT, there was no difference in the risk of BC compared to E alone with E+P. In the Kostopoulos study, there was also a possible protective effect in those who used E alone. Another study in healthy carriers showed that in women younger than 45 years at the time of BSO, MHT did not affect BC rates. However, in women older than 45 years, BC rates were higher. As the E+P scheme is associated with a higher RR of BC, the doses of progestogens should be limited, choosing natural progesterone byproducts of intermittent use to decrease systemic exposure. According to various international guidelines, healthy mBRCA carriers undergoing BSO should be offered MHT until the average age of menopause. Conclusion: premature menopause decreases life expectancy, which is why one of the tools to improve and prevent deterioration of quality of life is MHT. Short-term use of MHT appears safe for women with mBRCA who undergo BSO before age 45 as it does not counteract the reduction in the risk of MC obtained by surgery. (AU)

Application of next-generation sequencing in detection of BRCA1/2 and homologous recombination repair pathway multi-genes germline mutation and correlation analysis / 中华预防医学杂志

Objective: To investigate the germline mutation status of related genes in breast cancer patients and high-risk individuals by next-generation sequencing. To analyze the correlations between homologous recombination repair (HR) pathway gene mutation status and clinicopathological characteristics of breast cancer patients. To supplement the database of breast cancer related gene mutations in Chinese population. Methods: This study is a cross-sectional study. From October 2020 to September 2021, whole blood samples were collected from 350 breast cancer patients and 49 high-risk individuals, admitted to Peking University People's Hospital and accepted genetic testing voluntarily. Germline mutations in 32 breast cancer related genes were detected by NGS. The clinicopathological characteristics, including age at the onset, family history, unilateral/bilateral tumor, Luminal typing (Luminal A subtype, Luminal B subtype, HER2-enriched subtype and triple negative breast cancer), tumor size and metastasis, were analyzed, and the correlations between HR pathway gene mutation status and clinicopathological characteristics were analyzed by Chi-squared test and Fisher's exact probability test. Results: Among 350 breast cancer patients, 64 (18.3%) cases carried gene pathogenic mutations (including pathogenic and likely pathogenic mutations), including 47 (13.4%) in BRCA1/2, 16 (4.6%) in non-BRCA1/2 genes, 1 (0.3%) in BRCA2 and FANCL. Among 49 high-risk individuals, 7 (14.3%) cases carried gene pathogenic mutations, including 6 (12.3%) in BRCA1/2 and 1 (2%) in ATM genes. BRCA1/2 pathogenic mutations were associated with age at the onset (18%, 8.7%, χ²=6.346, P=0.012), and the BRCA1/2 pathogenic mutation frequency was higher in patients diagnosed at age ≤45 years. HR pathway gene mutations (including pathogenic, likely pathogenic and uncertain significance mutations) were correlated with unilateral/bilateral tumor (49.5%, 68.4%, χ²=4.841, P=0.028) and Luminal typing (45.7%, 62.2%, 32%, 60%, χ²=12.004, P=0.007), and the HR mutation frequencies were higher in patients with bilateral tumor, Luminal B breast cancer and triple negative breast cancer (TNBC). Conclusion: The BRCA1/2 pathogenic mutation frequency in high-risk individuals is similar to that in breast cancer patients, and BRCA1/2 testing is helpful to guide breast cancer screening and prevention in high-risk individuals. Patients with early onset breast cancer, bilateral breast cancer, Luminal B breast cancer and TNBC have higher mutation frequencies of HR pathway genes, and HR pathway genes testing should be conducted as soon as possible to provide laboratory evidence for diagnosis, treatment, prognosis and risk evaluation of breast cancer.

Identification of a novel germline BRCA2 variant in a male with breast cancer / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a male with breast cancer and a sister who had deceased of the disease.@*METHODS@#Medical and family history of the proband was collected. Next-generation sequencing was carried out to detect potential variant associated with breast cancer, and Sanger sequencing was used to verify the result.@*RESULTS@#The proband was found to harbor a novel heterozygous c.6018dupT variant of the BRCA2 gene which may cause premature termination of mRNA translation, resulting in a truncated protein. Combined with the family history, the variant was deduced to be a germline mutation. Based on the American College of Medical Genetics and Genomics standards and guidelines, c.6018dupT variant of BRCA2 gene was predicted to be pathogenic (PVS1+PM1/2+PP4).@*CONCLUSION@#The germline variant of the BRCA2 gene probably underlay the breast cancer in this pedigree.

BRCA1 and BRCA2 mutations in a sample of breast and ovarian cancer families from the Colombian pacific / Mutaciones en los genes BRCA1 y BRCA2 en una muestra de familias con cáncer de mama y/u ovario del pacífico colombiano

Abstract Introduction: Breast cancer is the most common neoplasia of women from all over the world especially women from Colombia. 5%­10% of all cases are caused by hereditary factors, 25% of those cases have mutations in the BRCA1/BRCA2 genes. Objective: The purpose of this study was to identify the mutations associated with the risk of familial breast and/or ovarian cancer in a population of Colombian pacific. Methods: 58 high-risk breast and/or ovarian cancer families and 20 controls were screened for germline mutations in BRCA1 and BRCA2, by Single Strand Conformation Polymorphism (SSCP) and sequencing. Results: Four families (6.9%) were found to carry BRCA1 mutations and eight families (13.8%) had mutations in BRCA2. In BRCA1, we found three Variants of Uncertain Significance (VUS), of which we concluded, using in silico tools, that c.81­12C>G and c.3119G>A (p.Ser1040Asn) are probably deleterious, and c.3083G>A (p.Arg1028His) is probably neutral. In BRCA2, we found three variants of uncertain significance: two were previously described and one novel mutation. Using in silico analysis, we concluded that c.865A>G (p.Asn289Asp) and c.6427T>C (p.Ser2143Pro) are probably deleterious and c.125A>G (p.Tyr42Cys) is probably neutral. Only one of them has previously been reported in Colombia. We also identified 13 polymorphisms (4 in BRCA1 and 9 in BRCA2), two of them are associated with a moderate increase in breast cancer risk (BRCA2 c.1114A>C and c.8755­66T>C). Conclusion: According to our results, the Colombian pacific population presents diverse mutational spectrum for BRCA genes that differs from the findings in other regions in the country.

Resumen Introducción: El cáncer de mama es la neoplasia más común en mujeres de todo el mundo, y, también de Colombia. 5% a 10% de todos los casos son causados por factores hereditarios; 25% de estos casos tienen mutaciones en los genes BRCA1/BRCA2. Objetivo: El propósito de este estudio fue el de identificar mutaciones asociadas con riesgo de cáncer de mama y/u ovario familiar en pacientes del pacífico colombiano. Métodos: Fueron revisados para mutaciones en BRCA1 y BRCA2 de línea germinal mediante SSCP y secuenciación 58 familias de alto riesgo para cáncer de mama y/u ovario y 20 controles Resultados: cuatro familias (6.9%) presentaron mutaciones en BRCA1 y ocho familias (13.8%) en BRCA2. En BRCA1, encontramos tres variantes de significado clínico desconocido (VUS), de las cuales concluimos, usando herramientas bioinformáticas, que c.81­12C>G y c.3119G>A (p.Ser1040Asn) son probablemente deletéreas, y c.3083G>A (p.Arg1028His) es probablemente neutral. En BRCA2, encontramos tres VUS: una mutación nueva y dos previamente descritas, usando análisis bioinformáticos, concluimos que c.865A>G (p.Asn289Asp) y c.6427T>C (p.Ser2143Pro) son probablemente deletéreas y c.125A>G (p.Tyr42Cys) es probablemente neutral. Solo una de ellas ha sido reportada previamente en Colombia. También identificamos 13 polimorfismos (4 en BRCA1 y 9 en BRCA2), dos de ellos asociados con un moderado incremento del riesgo para cáncer de mama (BRCA2 c.1114A>C and c.8755­66T>C). Conclusión: de acuerdo con nuestros resultados, la población del suroccidente colombiano presenta un espectro mutacional diverso para los genes BRCA que difiere de lo encontrado en otras regiones del país.

Mastectomía profiláctica versus vigilancia en la prevención de cáncer de mama en mujeres BRCA positivo / Prophylactic mastectomy versus surveillance for the prevention of breast cancer in women's BRCA carriers

INTRODUCCIÓN: Las mujeres que poseen mutaciones en genes BRCA tienen un alto riesgo de desarrollar cáncer de mama. Por lo anterior, se han planteado múltiples estrategias preventivas dentro de las cuales se encuentra la mastectomía profiláctica. Existe controversia sobre si los beneficios de esta intervención superan al de una vigilancia activa, en especial considerando el impacto físico y psicológico asociado. MÉTODOS: Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos 13 revisiones sistemáticas que en conjunto incluyen 50 estudios primarios. Concluímos que si bien la mastectomía profiláctica se asocia a efectos adversos frecuentes, reduce la incidencia de cáncer de mama y la mortalidad, y podría asociarse a altos niveles de satisfacción.

INTRODUCTION: Women who have mutations in BRCA genes have a high risk of developing breast cancer. Therefore, multiple preventive strategies have been proposed, within which is prophylactic mastectomy. Considering physical and psychological effects of surgery, the controversy is established as to whether the preventive effect exceeds that of active vigilance. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified 13 systematic reviews including 50 studies overall. We concluded prophylactic mastectomy is associated with frequent adverse effects, but probably reduces the incidence of breast cancer and decreases mortality, in addition to being associated with high levels of satisfaction.

Mutational spectrum in breast cancer associated BRCA1 and BRCA2 genes in Colombia / Espectro de mutaciones en los genes BRCA1 y BRCA2 asociados a cáncer de mama en Colombia

Abstract Introduction: The risk of developing breast and ovarian cancer is higher in families that carry mutations in BRCA1 or BRCA2 genes, and timely mutation detection is critical. Objective: To identify the presence of mutations in the Colombian population and evaluate two testing strategies. Methods: From a total universe of 853 individual blood samples referred for BRCA1 and BRCA2 typing, 256 cases were analyzed by complete direct sequencing of both genes in Myriad Genetics, and the remaining 597 cases were studied by partial sequencing based on founder mutations in a PCR test designed by ourselves ("Profile Colombia"). Results: We found 107 patients carrying deleterious mutations in this group of patients, 69 (64.5%) located in BRCA1, and 38 (35.5%) in BRCA2. Overall, we detected 39 previously unreported mutations in Colombia (22 in BRCA1 and 17 in BRCA2) and only 4 out of the 6 previously reported founder mutations. Sixty four out of 597 patients (10.7%) studied by "Profile Colombia" showed mutations in BRCA1 or BRCA2, and 41/256 patients (16%) showed mutations by complete BRCA1-BRCA2 sequencing. Conclusions: The spectrum of 44 different mutations in Colombia as detected in our study is broader than the one previously reported for this country. "Profile Colombia" is a useful screening test to establish both founder and new mutations (detection rate of 10.7%) in cases with family history of breast cancer. Complete sequencing shows a detection rate of 16.0%, and should complement the study of the genetic basis of this disease.

Resumen Introducción: El riesgo de desarrollar cáncer de mama y cáncer de ovario puede transmitirse en familias que porten mutaciones en los genes BRCA1 o BRCA2. La detección de estas mutaciones permite tomar decisiones oportunas en el ámbito de la medicina preventiva. Objetivo: Estudiar el espectro de mutaciones en la población colombiana y evaluar dos estrategias de detección. Metodos: Se incluyeron en total 853 pacientes con diagnóstico de cáncer de mama y con solicitud de análisis de los genes BRCA1 y BRCA2. Un total de 256 pruebas se analizaron mediante secuencia directa completa de estos genes en Myriad Genetics, y las restantes 597 se estudiaron mediante secuencia parcial basada en mutaciones fundadoras a través de la prueba "Perfil Colombia", implementada por nosotros. Resultados: Se detectaron 107 pacientes portadores de mutaciones en pacientes colombianos, 69 de las cuales estaban localizadas en BRCA1 y 38 en BRCA2. De estas 39 mutaciones son nuevas (22 en BRCA1 y 17 en BRCA2) y solo se hallaron 4 de las 6 mutaciones reportadas previamente como fundadoras en Colombia. En 64/597 pacientes analizados mediante el "Perfil Colombia" se detectaron mutaciones en BRCA1 o BRCA2, así como en 41/256 pacientes que solicitaron la secuenciación completa de los genes BRCA1 y BRCA2. Conclusiones: El espectro de mutaciones fundadoras en Colombia es más amplio que el reportado anteriormente para este país. El "Perfil Colombia" es una prueba que revela a la vez mutaciones fundadoras y mutaciones nuevas, con una tasa de detección del 10.7%. La secuenciación completa presenta una tasa de detección del 16.0% y puede complementar el diagnóstico de la base genética de esta enfermedad.

Comparison of Targeted Next-Generation and Sanger Sequencing for the BRCA1 and BRCA2 Mutation Screening

No abstract available.

Conditional knockout of brca1/2 and p53 in mouse ovarian surface epithelium: Do they play a role in ovarian carcinogenesis?

Alterations of genes are known to be critical for the induction of tumorigenesis, but the mechanism of ovarian carcinogenesis is little understood and remains to be elucidated. In this study, we investigated the roles of brca1, brca2 and p53 genes in the development of ovarian cancer using conditional knockout mice generated by a Cre-loxP recombinant system. Following the application of recombinant adenovirus expressing Cre in vitro, the proliferation of ovarian surface epithelium (OSE) was increased. For instance, a significant increase in cell growth was observed in OSE cells in vitro by conditional knockout isolated from the mice bearing concurrent floxed copies of brca1 and brca2/p53. However, the proliferative effect of the ovarian cells was not observed in concurrent brca1/brca2 or p53 knockout mice in vivo, indicating that we could not observe the direct evidence of the involvement of brca1, brca2, and p53 in ovarian carcinogenesis. Since morphological changes including tumor formation were not observed in mice bearing floxed copies of concurrent brca1/brca2 or p53, the inactivation of brca1/2 or p53 is not sufficient for the induction of tumor formation. Taken together, these results suggest that the deficiency of these genes may not be involved directly in the mechanism of ovarian carcinogenesis.

Identificação e acompanhamento de mulheres com risco aumentado para câncer de mama / Identification and screening of women with increased risk for breast cancer

A identificação de mulheres com aumento da probabilidade de desenvolverem câncer de mama é fundamental para se tentar definir grupos de risco e, dessa forma, oferecer modelos preventivos que possam ser particularizados e opções de manejo harmoniosamente decididas entre médicos e pacientes. Este artigo visa a sugerir rotinas e fornecer orientações a médicos generalistas, ginecologistas e mastologistas sobre o tema (AU)

The identification of women with an increased risk of developing breast cancer is essential to guide which patients would benefit from specific preventive interventions and strict breast cancer screening strategies. In this article we discuss how high risk patients can be identified and discuss general guidelines that clinicians, gynecologists and mastologists may use to direct at-risk patients to intervention programs (AU)

Prevalence of BRCA1 and BRCA2 Mutations in Korean Breast Cancer Patients

The incidence of breast cancer in Korea has been increasing in recent years, such that it is now the most common female cancer. Breast cancer in Korea is characterized by an earlier age of onset than in Western countries, suggesting that it would be related with genetic background. We assayed germline mutations in the BRCA genes to evaluate their genetic pathology in Korean breast cancer patients. The study subjects consisted of 173 patients at clinically higher risk and 109 unselected patients. Germline mutations in the entire coding sequences of the BRCA1 and BRCA2 genes were analyzed by Conformation-Sensitive Gel Electrophoresis (CSGE), and any aberrantly-sized band was sequenced. BRCA mutations were present in 12.7% of the high risk patients, compared with 2.8% of the unselected patients. Among high risk patients, mutations were most prevalent in patients with a family history of breast or first-degree ovarian cancer (22.1%), followed by those with male breast cancer (20%), bilateral breast cancer (20%), multiple organ cancer including breast (13%) and younger breast cancer patients (aged<35 yr) (8.1%). Moreover, BRCA mutations were detected in 34.8% of patients having two highrisk factors. These findings suggest that BRCA gene mutation analysis should be performed on Korean patients with high-risk factors for breast cancer.

Impaired phosphorylation and mis-localization of Bub1 and BubR1 are responsible for the defective mitotic checkpoint function in Brca2-mutant thymic lymphomas

Breast cancer susceptibility gene, BRCA2, is a tumor suppressor and individuals who inherit one defected copy of BRCA2 allele experience early onset breast cancer or ovarian cancer accompanied by the loss of the wild type allele. Mouse model for Brca2 mutation shows growth retardation and paradoxical occurrence of thymic lymphomas. Thymic lymphomas from Brca2-mutant mice harbor mutations in p53, Bub1, and BubR1, which function as mitotic checkpoint proteins. Therefore, interplay between Brca2 and mitotic checkpoint has been suggested in the maintenance of genetic fidelity, although it has not been assessed whether the unique mutations in Bub1 and BubR1 found in Brca2-mutant mice are responsible for the abolishment of mitotic checkpoint function. This report demonstrates that Bub1 and BubR1 mutant proteins from Brca2(-/-)thymic lymphomas have defects in the phosphorylation and kinetochore localization after spindle damage. Thus, the mutations of Bub1 and BubR1 found in Brca2- mutant mice indeed are responsible for the chromosome instability in Brca2-mutated tumors.