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Background and purpose:BRCA1/2 plays an important role in maintaining the genome stability.Whether BRCA1/2 germline mutation could increase the tumor sensitivity to radiotherapy,thereby inducing secondary primary cancer after radiotherapy is unclear.This study aimed to investigate whether postoperative radiotherapy is a risk factor for the development of second primary cancer in triple-negative breast cancer(TNBC)patients with BRCA1/2 germline mutation.Methods:This research was based on a previously reported retrospective cohort,i.e.,the Fudan University Shanghai Cancer Center TNBC cohort.Between January 1,2007 and December 31,2014,a total of 292 female TNBC patients with BRCA1/2 mutation were enrolled.We performed logistic regression analysis in patients without BRCA1/2 germline mutation(n=261)and BRCA1/2 germline mutation patients(n=31),respectively,to assess the risk factors affecting the incidence of second primary cancer.We then performed interactive analysis on the above two analyses to evaluate the interactive effect between BRCA1/2 germline mutation and postoperative radiotherapy.P<0.05 indicates a statistically significant difference.The research was approved by Fudan University Shanghai Cancer Center TNBC Ethics Committee(050432-4-2108),and each patient provided written informed consent.Results:Logistic regression analysis in patients with BRCA1/2 germline mutations showed that postoperative radiotherapy significantly increased the risk of secondary primary disease compared to non-radiotherapy[odds ratio(OR)=2.475,95%confidence interval(CI):1.933-3.167,P<0.001].In patients without BRCA1/2 germline mutation,the effect of radiotherapy on the incidence of second primary tumor was not significant.There was a significant interaction between BRCA1/2 germline mutation and postoperative radiotherapy for the incidence of secondary primary cancer(OR=9.710,95%CI:0.320-295.250,P=0.193).Conclusion:Although statistical analysis results show that patients with BRCA1/2 germline mutations have an increased risk of developing a second primary tumor after postoperative radiotherapy compared to patients who have not received radiotherapy,there is no significant correlation between BRCA1/2 germline mutations and radiotherapy for the development of a second primary tumor.Therefore,patients with BRCA1/2 germline mutations who receive radiotherapy after surgery may not increase the risk of developing a second primary tumor.
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Objective To investigate the potential significance of FOXP3 expression in BRCA1/2-mutant breast cancer. Methods A total of 48 BRCA mutation carriers (16 with BRCA1 and 32 with BRCA2) and 78 age-matched non-carriers were included in this study. Immunohistochemistry was used to detect the expression of FOXP3 in breast cancer tissues. The FOXP3 RNA expression in 39 BRCA1, 36 BRCA2, and 948 non-carrier breast cancer patients from TCGA-BRCA and the correlation with homologous recombination deficiency scores were evaluated to validate the immunohistochemistry results. Results The FOXP3 positive rate was 43.8% (7/16) in BRCA1 mutation carriers, 59.4% (19/32) in BRCA2 mutation carriers, and 9.0% (7/78) in non-carriers. The FOXP3 positive rates in patients with BRCA1/2 mutant breast cancer were significantly higher than those in non-carriers (P=0.002; P<0.001). TCGA-BRCA results showed that the FOXP3 RNA level in BRCA1/2 mutant breast cancer was significantly higher than that in non-carriers (P=0.02, P=0.004). The FOXP3 RNA level was positively correlated with the homologous recombination deficiency score (Spearman R=0.30, P<2.2e-16). Conclusion Patients with BRCA1/2 mutant breast cancers have higher FOXP3 expression than non-carriers, and may be more sensitive to immunotherapy.
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Background & objectives: Studies have shown that apart from hereditary breast carcinomas, breast cancer susceptibility gene 1 (BRCA1) mutations conferring to its loss are seen in sporadic breast carcinomas (SBC) as well. The aim of the present study was to assess BRCA1 methylation in females presenting at King George’s Medical University, Lucknow, with SBC by both immunohistochemistry (IHC) and methylation PCR with respect to hormonal profile and various morphological prognostic parameters. The primary objective was to look for the association between BRCA1 protein expression and DNA promoter methylation. Methods: 81 mastectomy specimens from SBC of invasive breast carcinoma (no special type) were included in this study. After a detailed morphological assessment, formalin fixed paraffin embedded tissue from a representative tumour area was selected for BRCA1 IHC by heat-mediated antigen retrieval under high pH and DNA extraction and further bisulphate treatment. BRCA1 was studied for methylation by methylated and unmethylated PCR-specific primers. Results: BRCA1 promoter methylation was present in 42/81 (51.9%) participants, with significant BRCA1 protein loss (72.7%; P=0.002). A significant association between BRCA1 loss and hormonal profile was found (P=0.001); maximum in triple negative breast carcinoma (TNBC) (72%; 18/25). Most of the TNBC also harboured methylation (68%). Although not significant grade II and III tumours, lymph vascular invasion, ductal carcinoma in situ, and nodal metastasis (?3) were seen in a higher percentage in methylated tumours. Mortality in SBC was significantly associated with BRCA1 loss (30.3%; P=0.024). Interpretation & conclusions: Study results highlight the concept of “BRCAness” in SBC as well. Hence, we can confer that identification of BRCA1 loss in SBC can make it a perfect candidate for poly ADP- ribose polymerase inhibitors or cisplatin-based therapy like hereditary ones.
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Objective:To investigate the radiosensitizing effect of silencing breast cancer susceptibility gene 1 (shBRCA1) expression on MDA-MB-231 breast cancer bearing nude mice by 3′-deoxy-3′- 18F-fluorothymidine ( 18F-FLT) microPET/CT imaging. Methods:Twenty-four BALB/c nude mice were divided into 4 groups ( n=6 in each group) according to the random number table method, namely negative control (NC) group, NC+ radiotherapy group, shBRCA1 group and shBRCA1+ radiotherapy group. 18F-FLT microPET/CT imaging was performed before and 24 h after radiotherapy. The changes of SUV max before and after radiotherapy were compared among 4 groups, and the total proliferative volume (TPV) of tumors in each group after treatment was also analyzed. The expression of Ki-67 in tumor tissues was analyzed by immunohistochemistry. Data were analyzed by paired t test, one-way analysis of variance, least significant difference t test and Pearson correlation analysis. Results:Breast cancer cells targeting the BRCA1 were constructed. Before radiotherapy, the differences of SUV max among the NC group, NC+ radiotherapy group, shBRCA1 group and shBRCA1+ radiotherapy group were not statistically significant (1.034±0.137, 1.031±0.152, 1.028±0.169 and 1.026±0.156; F=0.00, P=0.999). Twenty-four hours after the end of the four times of radiotherapy, the differences of SUV max among the 4 groups were statistically significant (1.367±0.100, 0.781±0.079, 1.306±0.213 and 0.597±0.129; F=44.77, P<0.001), with lower SUV max in the shBRCA1+ radiotherapy group compared with the NC+ radiotherapy group ( t=2.98, P=0.014). The SUV max of the NC+ radiotherapy group and shBRCA1+ radiotherapy group were reduced compared with those before radiotherapy ( t values: 5.82, 5.44, P values: 0.002, 0.003), while SUV max of the NC group and shBRCA1 group increased compared with those before radiotherapy ( t values: -4.47, -3.98, P values: 0.007, 0.011). TPV was smaller in the shBRCA1+ radiotherapy group compared with that in the NC+ radiotherapy group (0.48±0.03 vs 0.61±0.07; F=25.36, t=3.82, P=0.003). Immunohistochemical assays showed that Ki-67 was less expressed in the shBRCA1+ radiotherapy group than that in the NC+ radiotherapy group (0.286±0.072 vs 0.476±0.093; F=15.73, t=3.61, P=0.007). Correlation analysis showed a positive correlation between Ki-67 expression and SUV max ( r=0.83, P<0.001). Conclusion:18F-FLT microPET/CT imaging can evaluate the radiosensitizing effect of shBRCA1 expression on MDA-MB-231 breast cancer bearing nude mice.
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INTRODUCTION@#Ovarian cancer is one of the leading causes of mortality in women. In 2020, 5,395 (6.2%) of diagnosed malignancies in females were ovarian in origin. It also ranked second among gynecologic malignancies after cervical cancer. The prevalence in Asian /Pacific women is 9.2 per 100,000 population. Increased mortality and poor prognosis in ovarian cancer are caused by asymptomatic growth and delayed or absent symptoms for which about 70% of women have an advanced stage (III/IV) by the time of diagnosis. The most associated gene mutations are Breast Cancer gene 1 (BRCA1) which is identified in chromosome 17q21 and Breast Cancer gene 2 (BRCA2) identified in chromosome 13. Both proteins function in the double-strand DNA break repair pathway especially in the large framework repair molecules. Olaparib is a first-line drug used in the management of ovarian cancer. It targets affected cells by inhibition of poly (ADP-ribose) polymerase (PARP) activity which induces synthetic lethality in mutated BRCA1/2 cancers by selectively targeting tumor cells that fail to repair DNA double-strand breaks (DSBs).@*OBJECTIVE@#The study aims to determine the prevalence of pathogenic somatic mutations in BRCA1 and BRCA2 among patients diagnosed of having ovarian cancer, to characterize the identified variants into benign/ no pathogenic variant identified, variant of uncertain significance (VUS), and pathogenic, and to determine the relationship of specific mutations detected with histomorphologic findings and clinical attributes.@*METHODOLOGY@#Ovarian cancer tissues available at the St. Luke’s Medical Center Human Cancer Biobank and formalin-fixed paraffin-embedded (FFPE) tissue blocks diagnosed as ovarian cancer from the year 2016 to 2020 were included. Determination of the prevalence of somatic BRCA1 and BRCA2 mutations using Next Generation Sequencing (NGS).@*RESULTS@#A total of 60 samples were processed, and three samples were excluded from the analysis due to an inadequate number of cells. In the remaining 57 samples diagnosed ovarian tumors, pathogenic BRCA1/2 variants were identified in 10 (17.5%) samples. Among the BRCA1/2 positive samples, 3 (5.3%) BRCA1 and 7 (12.3%) BRCA2 somatic mutations were identified.@*CONCLUSION@#Identification of specific BRCA1/2 mutations in FFPE samples with NGS plays a big role in the management of ovarian cancer, particularly with the use of targeted therapies such as Olaparib. The use of this drug could provide a longer disease-free survival for these patients. Furthermore, we recommend that women diagnosed with ovarian cancer should be subjected to genetic testing regardless of the histologic subtypes or clinical features. Lastly, genetic testing should be done along with proper genetic counseling, especially for patients who are susceptible to these mutations.
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Tumeurs de l'ovaireRésumé
Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.
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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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@#[摘 要] 目的:采用基于中国人群单核苷酸多态性位点开发的同源重组缺陷(HRD)检测工具评估云南地区卵巢癌患者的HRD状态和BRCA1/2基因突变频率并探讨其临床意义。方法:共纳入2021年1月至2023年5月间在云南省肿瘤医院收治的卵巢癌患者248例,HRD状态采用基因组瘢痕评分法(GSS)(主要依据拷贝数的长度、类型、位置及基因组断片)或HRD评分法(杂合性缺失、端粒等位基因失衡及大片段移位等基因组不稳定事件的总和)进行评估,当组织样本的GSS≥50分或HRD评分≥42分者或检测到有害的BRCA1/2基因突变时HRD被定义为阳性。分析患者HRD状态与临床病理特征的关系。结果:248名卵巢癌患者中70.97%的患者HRD呈阳性,其中BRCA1/2基因突变率为30.65%。Ⅲ~Ⅵ期、高级别浆液腺癌的卵巢癌患者具有更高的HRD阳性率(均P<0.01),HRD评分更高的患者其合并其他基因突变的频率也越高(P<0.05)。HRD状态与卵巢癌的病理类型、临床分期和其他基因突变均有关联(均P<0.01)。结论:云南地区卵巢癌患者HRD阳性率较高,HRD阳性的卵巢癌患者可以从聚ADP核糖聚合酶(PARP)抑制剂治疗中获得更大的收益。
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Objective:To explore the relationship between the occurrence and development of colorectal cancer and the risk of BRCA1 and BRCA2 gene mutations. Methods:Sixty-one patients with colorectal adenocarcinoma admitted to Beijing Friendship Hospital Affiliated to Capital Medical University from January 2022 to March 2022 were tested by second-generation sequencing. Information such as age of onset, gender, histological grade and TNM stage were collected. According to whether the BRCA1 and BRCA2 gene had systemic mutation, the patients were divided into BRCA1 and BRCA2 gene system mutation group and unmutated group. There were 8 cases in the BRCA1 and BRCA2 gene system mutant group and 53 cases in the non-mutant group. The main outcome measures were the relationship between pathogenic or likely pathogenic germline mutations in colorectal cancer and clinicopathological data of patients, including age of onset, gender, tumor location, TNM stage, histological differentiation, and family history. The secondary outcome was the relationship between BRCA1 and BRCA2 gene system mutations and clinicopathological data. Measurement data with normal distribution were expressed as mean±standard deviation ( ± s), and comparison between groups was analyzed using the t-test. Measurement data with non-normal distribution were represented as M ( Q1, Q3), and comparison between groups was analyzed using the Mann-Whitney U test. Measurement data were expressed as the number of cases or percentage (%), and Chi-square test was used for comparison between groups. Results:Among 61 colorectal adenocarcinoma patients, the frequency of pathogenic or potentially pathogenic germ line mutations in colorectal cancer was 13.1% (8/61), and the frequency of BRCA1 and BRCA2 mutations was 3.3% (2/61). The frequency of BRCA1 and BRCA2 mutations was 13.1% (8/61). Women with BRCA1 and BRCA2 mutations (75.0% vs 37.7%, χ2=3.947, P=0.047) and right colon cancer (75.0% vs 26.4%, χ2=7.889, P=0.019) were significantly higher than those without mutation. Conclusions:The frequency of BRCA1 and BRCA2 gene mutation is higher in colorectal cancer patients. BRCA1 and BRCA2 gene mutations are recommended for colorectal cancer patients with a family history of breast or ovarian cancer.
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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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Humains , Femelle , Tumeurs du sein , Dépistage génétique , Gène BRCA1 , Gène BRCA2 , Dépistage précoce du cancer , Mutation , Femmes , Imagerie par résonance magnétiqueRésumé
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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Tumeurs du sein , Dépistage génétique , Gène BRCA1 , Gène BRCA2 , Déontologie médicaleRésumé
Resumen El cáncer de próstata metastásico resistente a la castración (CPRC) es una neoplasia heterogénea letal entre los hombres. 30% de los tumores acumulan errores deletéreos en genes implicados en la respuesta al daño del ADN (DNA damage response en inglés, DDR). Algunos de estos genes asociados a cáncer son BRCA 1 y BRCA 2. Mutaciones en estos genes favorecen la pérdida o la modificación de la función provocando un cambio permanente y transmisible, lo que conduce al desarrollo de cáncer de próstata agresivo. El objetivo del estudio fue identificar mediante secuenciación dirigida (Next-generation sequencing; NGS) variantes génicas de BRCA 1 y BRCA 2 en el genoma de pacientes con CPRC del Hospital Central Militar. Es importante destacar que los resultados demostraron una serie de alteraciones clínicas, así como una pérdida de la función de las proteínas relacionadas con mecanismos de reparación del ADN. Curiosamente, algunas de las variantes en el gen BRCA, de las que se informa aquí, son de significado incierto, lo que nos ha sido comunicado por primera vez.
Abstract Metastatic castration-resistant prostate cancer (CRPC) is a heterogeneous lethal neoplasm among men. 30% of tumors harbor deleterious errors in genes involved in the DNA damage response (DDR). Some of these cancer-associated genes are BRCA 1 and BRCA 2. Mutations to these genes favor loss or modification of function causing a permanent and transmissible change, leading to the development of aggressive prostate cancer. The aim of the study was to identify by Next-generation sequencing (NGS) BRCA 1 and BRCA 2 gene variants in peripheral blood of patients with CRPC at the Hospital Central Militar. Importantly, the results demonstrated a number of clinical alterations, as well as a loss of function of proteins related to DNA repair mechanisms. Interestingly, some of the variants in the BRCA gene, reported here, are of uncertain significance, which has been reported to us for the first time.
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Ovarian cancer (OC) is one of the most lethal gynecological cancers with a 5?year survival rate that ranges from 30% to 40%. Breast cancer genes (BRCA1 and BRCA2) play a key role in maintaining genomic stability. Mutations in BRCA1/2 genes lead to the accumulation of double?strand breaks, resulting in tumorigenesis. The risk of developing OC in women with BRCA1 and BRCA2 mutations is 39% and 11%, respectively, by 70 years of age. BRCA1/2 mutation testing is thus important to identify women at greatest risk of developing OC in addition to its impact on diagnosis, prognosis, and targeted therapy. Genetic testing is required to identify the BRCA mutations and thus select patients who can benefit from polyadenosine diphosphate (ADP)杛ibose polymerase (PARP) inhibitor therapy. Tumor BRCA mutation testing can detect both germline and somatic mutations allowing implementation of preventive strategies on a broader population. Various international guidelines recommend BRCA1/2 mutation genetic testing in all OC patients irrespective of age and family history. This review focuses on the role of BRCA mutation testing in OC
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To analyze the occurrence of genetic mutations in a sample of patients with high risk of breast cancer in Florianopolis/ SC from December 1st, 2021, to January 31, 2022. Methods: An observational, descriptive and retrospective study carried out through data collection of a preexisting database. A total of 194 tests were analyzed. Of these, 192 met the inclusion criteria and composed the final sample of 205 genes. Data were classified and reported the frequency and percentage of the variables: gene and presence or absence of mutation. Results: Mean age of the analyzed patients was 52.3 years, and most underwent the test due to personal history of breast cancer (80%). Clinical significance classification showed that, of the 192 gene panels, 62% were variants of uncertain significance; 14% were pathogenic; and 24%, negative. Of the 205 mutations, the most prevalent genes were: ATM 8.7%, MUTYH 5.8%, POLE 5.8%, BRCA2 4.8%, MSH6 4.8% and RECQL4 4.8%. Of the pathogenic tests regarding genetic predisposition to cancer (n=38/14.1%), the most common mutations were MUTYH (23%) and BRCA1 (15%), with mean age of 52 years (±14.3). In variants of uncertain significance panels (n=168/62%) the frequency rates were ATM (7.7%), POLE (7.1%) and MSH6 (5.9%) genes. The high penetrance genes were present in 18% of the genetic predisposition to cancer panels. Of those with positive family history (n=40), 19% of the genes were pathogenic, 53% were variants of uncertain significance; and 26% were negative. Furthermore, in patients with pathogenic mutations and positive family history (n=11), the most common mutations were in BRCA1 (27%) and BRCA2 (27%). Of the patients who tested due to personal history (n=152), 64% of the genes presented variants of uncertain significance, 13% were pathogenic and 22% were negative.
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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.
Sujets)
ADN , Séquençage nucléotidique à haut débit , Analyse de séquence , Gène BRCA1 , Gène BRCA2Résumé
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.
Sujets)
Tumeurs , Patients , Stratégies de Santé , GénétiqueRésumé
Con el objetivo de realizar la caracterización epidemiológica del cáncer de mama de las pacientes que asisten a la consulta externa de ginecología oncológica en el Instituto Guatemalteco de Seguridad Social (IGSS) de enero a marzo de 2,018, se realizó un estudio descriptivo transversal en 155 pacientes que acudieron a la clínica de mama del Hospital de Gineco Obstetricia del IGSS, con una media de edad de 62 años, el adenocarcinoma ductal infiltrante es el tipo histológico más frecuente en nuestra población tanto en edad reproductiva como en menopausia. Como factor protector el 69% dio lactancia materna. La etapa clínica más comúnmente diagnosticada es IIA. El Luminal A, el más frecuentemente diagnosticado por inmunohistoquímica, seguido del Luminal B y HER2neu. Se diagnostican pacientes mayormente en etapas clínicas tempranas (I y II).
In order to carry out the epidemiological characterization of breast cancer in patients attending the outpatient gynecology oncology consultation at the Guatemalan Social Security Institute (IGSS) from January to March 2018, a descriptive cross-sectional study was carried out in 155 patients who attended the breast clinic of the IGSS Obstetrics Gynecology Hospital, with a mean age of 62 years, infiltrating ductal adenocarcinoma is the most frequent histological type in our population both in reproductive age and in menopause. As a protective factor, 69% breastfed. The most diagnosed clinical stage is IIA. Luminal A, the most frequently diagnosed by immunohistochemistry, followed by Luminal B and HER2neu. Patients are diagnosed mostly in early clinical stages (I and II).
Sujets)
Humains , Femelle , Adulte , Adulte d'âge moyen , Tumeurs du sein/diagnostic , Tumeurs du sein/épidémiologie , Adénocarcinome/diagnostic , Protéine BRCA1/analyse , Protéine BRCA2/analyse , Allaitement naturel , Tumeurs du sein/prévention et contrôle , Études épidémiologiques , Facteurs de risque , Post-ménopause/physiologieRésumé
The incidence of prostate cancer is increasing year by year in China. People with BRCA mutation are at high risk of prostate cancer. However, there is no clear and effective treatment for mHSPC with high metastatic load carrying BRCA mutation. In this study, we report a mHSPC patient with high metastatic burden and germline BRCA1 gene mutation who rapidly progressed to mCRPC after traditional CAB therapy and then received ADT combined with abiraterone and achieved significant PSA response, suggesting that ADT combined with abiraterone may be an effective therapy for mHSPC patients with BRCA1 germline mutation.
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Breast cancer susceptibility gene (BRCA) is a tumor suppressor gene. The carriers of BRCA mutation have a significantly higher risk of breast, ovarian, pancreatic, prostate and rectal cancers than the general population. BRCA gene detection can effectively evaluate the risk of relevant malignant tumors. In this article, the recent research progress on the relationship between BRCA gene mutations and related cancers is summarized, and the roles of BRCA gene testing in the prevention and management of relevant malignant tumors are discussed.
Résumé
Objective:To investigate the expressions and clinical significances of breast cancer susceptibility gene 1 (BRCA1) and tubulin β3 (TUBB3) in patients with gastric cancer, so as to provide a basis for accurate diagnosis and treatment of gastric cancer.Methods:The data of 46 hospitalized patients with gastric cancer who underwent gastroscopebiopsy or operation in Maanshan People's Hospital in Anhui Province from December 2018 to May 2020 were collected. The expressions of BRCA1 and TUBB3 in tumor tissues and peritumoral tissues were determined by immunohistochemistry. Real-time fluorescent quantitative polymerase chain reaction (qRT-PCR) was used to detect BRCA1 and TUBB3 mRNA expressions in tumor tissues and peritumoral tissues. The correlations between expressions of BRCA1 and TUBB3 in gastric cancer tissues and clinicopathologic features were analyzed.Results:The positive rates of BRCA1 and TUBB3 proteins in gastric cancer tissues were higher than those in peritumoral tissues [43.5% (20/46) vs. 16.7% (5/30), 65.2% (30/46) vs. 6.7% (2/30), both P < 0.05]. qRT-PCR showed that the relative expression of BRCA1 mRNA in gastric cancer tissues was higher than that in peritumoral tissues (15.5±6.8 vs. 5.0±1.6, t = 9.41, P < 0.01); the relative expression of TUBB3 mRNA in gastric cancer tissues was higher than that in peritumoral tissues (22.1±6.3 vs. 5.7±1.9, t = 3.51, P < 0.01). The positive rate of TUBB3 protein in female patients was lower than that in male patients [15.4% (2/13) vs. 84.8% (28/33)], the positive rate of BRCA1 protein in patients with positive human epidermal growth factor receptor 2 (HER2) was higher than that in patients with negative HER2 [87.5% (7/8) vs. 47.4% (18/38)], the positive rate of BRCA1 protein in patients with family history was higher than that in patients without family history [85.7% (6/7) vs. 35.9% (14/39)], and the differences were statistically significant (all P < 0.05). The positive expressions of BRCA1 and TUBB3 proteins in gastric cancer tissues were both correlated with tumor stage and differentiation (all P < 0.05), and the expressions of BRCA1 and TUBB3 proteins were correlated ( χ2 = 33.52, P < 0.01). Conclusions:BRCA1 and TUBB3 may be related to the occurrence and development of gastric cancer, and there may be a certain relationship between BRCA1 and TUBB3, BRCA1 and HER2. BRCA1 and TUBB3 may have significances in the diagnosis and treatment of gastric cancer.