RESUMEN

Background/Objectives: In 2020, ovarian cancer ranked fourth in global incidence among gynecological cancers and remains the deadliest cancer affecting women's health. Survival rates are significantly higher when the disease is detected at early stages; however, the lack of effective early detection methods underscores the importance of identifying risk factors in order to implement preventive strategies. The objective of this work is to provide an overview of the risk factors of ovarian cancer in South America, emphasizing those linked to social determinants, genetic components, and comorbidities. Methods: A literature search was performed using PubMed and Google Scholar. MeSH descriptors and keywords, such as "BRCA1 genes," "BRCA2 genes", "Latin America", and "ovarian neoplasms" were used, along with terms related to socioeconomic and health factors. Inclusion criteria focused on original studies published in the last five years involving South American women. Results: Studies were identified from Argentina, Brazil, Chile, Colombia, Ecuador, and Peru. These studies addressed genetic factors, health status at diagnosis, and sociodemographic factors, revealing important data gaps, particularly on contraception and hormone replacement therapy. The prevalence of BRCA1 and BRCA2 mutations in South America is estimated to be 15-20% among women with inherited risk factors. Social, demographic and economic factors vary by country, although commonalities include a higher prevalence among women over 50 years of age, those with limited education, and those who face barriers to accessing health care. Conclusions: Although the literature does not conclusively establish a direct link between obesity and/or diabetes and the development of ovarian cancer, the indirect association highlights the need for further clinical studies. A general research gap related to risk factors of ovarian cancer could be observed in the South American region.

RESUMEN

Introducción: Nuestro trabajo aborda una revisión bibliográfica realizada entre enero de 2019 y septiembre de 2023, se resalta la importancia de los genes BRCA1, BRCA2, AR y PTEN en la patogénesis, pronóstico y tratamiento del cáncer de próstata, especialmente en su forma metastásica resistente a la castración (mCRPC). Los genes BRCA1 y BRCA2 se identifican como marcadores clave para prever la agresividad del cáncer, sugiriendo la necesidad de terapias dirigidas y vigilancia estricta. La adaptabilidad de las células cancerosas y la variabilidad en la expresión del receptor de andrógenos (AR) limitan la efectividad de las terapias centradas únicamente en AR, señalando la importancia de identificar vías alternativas y biomarcadores para un tratamiento más efectivo. La función de PTEN se relaciona directamente con la progresión de la enfermedad, y su alteración sugiere posibles enfoques terapéuticos. Sin embargo, la heterogeneidad de las células cancerosas y la complejidad de las vías moleculares presentan desafíos significativos para el desarrollo de terapias universales. Conclusión: Los hallazgos promueven la investigación futura para confirmar la aplicabilidad de estos genes como biomarcadores y desarrollar estrategias de tratamiento personalizadas en el cáncer de próstata. (provisto por Infomedic International)

---

Introduction: Our work addresses a literature review conducted between January 2019 and September 2023, the importance of BRCA1, BRCA2, AR and PTEN genes in the pathogenesis, prognosis and treatment of prostate cancer, especially in its metastatic castration-resistant form (mCRPC), is highlighted. BRCA1 and BRCA2 genes are identified as key markers for predicting cancer aggressiveness, suggesting the need for targeted therapies and strict surveillance. The adaptability of cancer cells and variability in androgen receptor (AR) expression limit the effectiveness of therapies focused solely on AR, pointing to the importance of identifying alternative pathways and biomarkers for more effective treatment. PTEN function is directly related to disease progression, and its alteration suggests potential therapeutic approaches. However, the heterogeneity of cancer cells and complexity of molecular pathways present significant challenges to the development of universal therapies. Conclusion: The findings promote future research to confirm the applicability of these genes as biomarkers and to develop personalized treatment strategies in prostate cancer. (provided by Infomedic International)

RESUMEN

BACKGROUND: In this article, we delineate a loosely selected cohort comprising patients with a history of early-onset breast cancer and/or a familial occurrence of cancer. The aim of this study was to gain insights into the presence of breast cancer-related gene variants in a population from a micro-region in southern Brazil, specifically the Metropolitan Region of Curitiba. This area exhibits a highly genetically mixed population, mirroring the general characteristics of the Brazilian people. METHODS: Comprehensive next-generation sequencing (NGS) multigene panel testing was conducted on 12 patients from the region, utilizing three different library preparation methods. RESULTS: Two pathogenic variants and one candidate pathogenic variant were identified: BRCA2 c.8878C>T, p.Gln2960Ter; CHEK2 c.1100del, p.Thr367Metfs15, and BRCA2 c.3482dup, p.Asp1161Glufs3. CONCLUSION: BRCA2 c.3482dup, a novel candidate pathogenic variant, previously unpublished, is reported. The prevalence of pathogenic variants in this small cohort is similar to that described in the literature. All different library preparation methods were equally proficient in enabling the detection of these variants.

Asunto(s)

Proteína BRCA2 , Neoplasias de la Mama , Quinasa de Punto de Control 2 , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Proteína BRCA2/genética , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quinasa de Punto de Control 2/genética , Brasil , Persona de Mediana Edad , Adulto , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Predisposición Genética a la Enfermedad

RESUMEN

PURPOSE: To define the spectrum of germline pathogenic variants (PVs) and copy number variant (CNV) in cancer susceptibility genes to the burden of breast and ovarian cancer (BC, OvC) in high-risk Brazilians in Minas Gerais with health insurance, southeast Brazil, undergoing multigene panel testing (MGPT). METHODS: Genotyping eligible individuals with health insurance in the Brazilian healthcare system for Hereditary Breast and Ovarian Cancer Syndrome to undergo molecular testing for 44 or 141-gene panels, a decision that was insurance driven. RESULTS: Overall, 701 individuals clinically defined as high BC/OvC risk, underwent MGPT from 1/2021 to 10/2022, with ~ 50% genotyped with a 44-gene panel and the rest with a 141-gene panel. Overall, 16.4% and 22.6% of genotyped individuals harbored PVs using 44-gene and the 141 gene panel, respectively. The most frequently mutated genes were: BRCA2 (3.7%); BRCA1 (3.6%) and monoallelic MUTYH (3.1%). CONCLUSION: The rate of PVs detected in high-risk individuals in this study was twice the 10% threshold used in Brazilian health guidelines. MGPT doubled the detection rate of PVs in cancer susceptibility genes in high-risk individuals compared with BRCA1/BRCA2 genotyping alone. The spectrum of PVs in Southern Brazil is diverse, with few recurring variants such as TP53 (0.6%), suggesting regional founder effects. The use of MGPT in hereditary cancer in Minas Gerais significantly increased the detection rate of P/LPVs compared to existing guidelines and should be considered as the primary genotyping modality in assessing hereditary cancer risk in Brazil.

Asunto(s)

Predisposición Genética a la Enfermedad , Pruebas Genéticas , Mutación de Línea Germinal , Humanos , Femenino , Brasil/epidemiología , Persona de Mediana Edad , Adulto , Pruebas Genéticas/métodos , Síndrome de Cáncer de Mama y Ovario Hereditario/genética , Síndrome de Cáncer de Mama y Ovario Hereditario/epidemiología , Variaciones en el Número de Copia de ADN , Neoplasias Ováricas/genética , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/patología , Anciano , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Genotipo , Proteína BRCA1/genética , ADN Glicosilasas

RESUMEN

INTRODUCTION AND OBJECTIVE: Mexico reported 26,742 new cases of prostate cancer in 2020. Different risk factors have been identified in the pathogenesis of prostate cancer. Among them, genetic factors and alterations or mutations in specific genes have been described in different ethnic groups worldwide. The aim of our study is to report the prevalence of germline DNA-repair gene mutations in Mexican patients with prostate cancer. MATERIAL AND METHOD: We performed germline genetic testing in 50 patients with localized prostate cancer and 50 patients with metastatic prostate cancer. Demographic, clinical, and histopathological data were collected. RESULTS: Thirty-seven germline mutations were identified in 32 patients. The most commonly affected genes were ATM in 6%, followed by FANCA (5%), and ATR (4%). BRCA2 mutations were identified in 3%. The frequency of mutations was higher in the metastatic group. DISCUSSION AND CONCLUSION: The results of our study show different mutations from those reported in different populations or regions. The use of PARP inhibitors is indicated in patients with germline mutations, specifically BRCA2, showing improvement in overall survival and progression free survival. To our knowledge, this is the first study reporting the prevalence of mutations in DNA-repair genes in Mexican patients with prostate cancer.

Asunto(s)

Reparación del ADN , Mutación de Línea Germinal , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , México/epidemiología , Anciano , Persona de Mediana Edad , Reparación del ADN/genética , Prevalencia , Anciano de 80 o más Años

RESUMEN

Purpose: The aim was to assess the diagnostic yield of next generation sequencing (NGS) multi-gene panels for breast and ovarian cancer in a high-complexity cancer centre in Chile. Additionally, our goal was to broaden the genotypic spectrum of BRCA variants already identified in Chilean families. Methods: Retrospective analysis was conducted on the genetic test results of 722 individuals from Fundación Arturo López Pérez's genetic counselling unit between 2016 and 2021. A comprehensive literature review encompassing articles analysing the frequency of germinal pathogenic variants in BRCA1/2 within the Chilean population was undertaken. Results: 23.5% of the panels had positive results, with 60% due to pathogenic variants in the BRCA1/2 genes. Seven previously unreported variants in BRCA1 from Chilean studies were identified.One or more variants of uncertain significance were detected in 31% of the results, and 11.5% of the families in this cohort presented copy number variants (CNVs) in BRCA1/2.8 studies analysed the frequency of pathogenic variants in BRCA1/2 in the Chilean population between 2006 and 2023, with a frequency between 7.1% and 17.1%.51 BRCA1 variants in 149 families have been reported in Chile and 38 BRCA2 variants in 132 families. Nine founder pathogenic variants identified by one study were present in 51.9% of the total Chilean families reported. Conclusion: Our findings advocate for the integration of NGS multi-gene panel testing as a primary strategy within our population. This approach allows for the comprehensive assessment of single nucleotide variants and CNVs in BRCA1/2, alongside other high and moderately penetrant genes associated with breast and ovarian cancer.

RESUMEN

BACKGROUND: Germline mutations in BRCA1 and BRCA2 genes are among the main causes of hereditary ovarian cancer. Identifying these mutations may reduce cancer risk, facilitate early detection, and enable personalized treatment. However, genetic testing is limited in the Brazilian Public Health System, and data regarding germline mutations in many regions are scarce. Therefore, the study aimed to investigate the prevalence of germline mutations in BRCA1 and BRCA2 in women with ovarian cancer treated in the Public Health System in Pernambuco, Brazil. METHODS: A cross-sectional study was conducted in the Hereditary Cancer Program from two reference oncological centers in Pernambuco. Women (n = 45) with high-grade serous ovarian cancer underwent genetic counseling and DNA sequencing for BRCA1 and BRCA2 genes. RESULTS: The prevalence of deleterious mutations in the BRCA1 and BRCA2 genes was 33%. Of the 15 germline mutations found, 13 were in BRCA1 and 2 in BRCA2; two mutations of unknown clinical significance were also found in BRCA2. Mutations c.5266dupC and c.2215 A > T were the most frequent; each was mutation observed in three patients. Additionally, the mutations c.7645dupT and c.921dupT were reported for the first time. CONCLUSION: One in three women showed a pathogenic mutation, demonstrating a significant prevalence of germline mutations in this sample. Additionally, the small sample revealed an interesting number of mutations, indicating the need to explore more regions of the country.

Asunto(s)

Genes BRCA2 , Neoplasias Ováricas , Humanos , Femenino , Brasil/epidemiología , Mutación de Línea Germinal , Estudios Transversales , Salud Pública , Predisposición Genética a la Enfermedad , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Proteína BRCA2/genética , Proteína BRCA1/genética

RESUMEN

BACKGROUND: Admixture occurs between different ethnic human populations. The global colonization in recent centuries by Europeans led to the most significant admixture in human history. While admixture may enhance genetic diversity for better fitness, it may also impact on human health by transmitting genetic variants for disease susceptibility in the admixture population. The admixture by Portuguese global exploration initiated in the 15th century has reached over 20 million of Portuguese-heritage population worldwide. It provides a valuable model to study the impact of admixture on human health. BRCA1 and BRCA2 (BRCA) are two of the important tumor suppressor genes. The pathogenic variation (PV) in BRCA is well determined to cause high risk of hereditary breast and ovarian cancer. Tracing the distribution of Portuguese BRCA PV in Portuguese-heritage population will help to understand the impact of admixture on cancer susceptibility in modern humans. In this study, we analyzed the distribution of the Portuguese-originated BRCA variation in Brazilian population, which has high degree Portuguese-heritage. METHODS: By comprehensive data mining, standardization and annotation, we generated a Portuguese-derived BRCA variation dataset and a Brazilian-derived BRCA variation dataset. We compared the two BRCA variation datasets to identify the BRCA variants shared between the two populations. RESULTS: The Portuguese-derived BRCA variation dataset consists of 220 BRCA variants including 78 PVs from 11,482 Portuguese cancer patients, 93 (42.2%) in BRCA1 and 127 (57.7%) in BRCA2. Of the 556 Portuguese BRCA PV carriers carrying the 78 PVs, 331 (59.5%) carried the three Portuguese-BRCA founder PVs of BRCA1 c.2037delinsCC, BRCA1 c.3331_3334del and BRCA2 c.156_157insAlu. The Brazilian-derived BRCA variation dataset consists of 255 BRCA PVs from 7,711 cancer patients, 136 (53.3%) in BRCA1 and 119 (46.6%) in BRCA2. We developed an open database named dbBRCA-Portuguese ( https://genemutation.fhs.um.edu.mo/dbbrca-portuguese/ ) and an open database named dbBRCA-Brazilian ( https://genemutation.fhs.um.edu.mo/dbbrca-brazilian ) to host the BRCA variation data from Portuguese and Brazilian populations. We compared the BRCA PV datasets between Portuguese and Brazilian populations, and identified 29 Portuguese-specific BRCA PVs shared between Portuguese and Brazilian populations, 14 in BRCA1 including the Portuguese founder BRCA1 c.3331_3334del and BRCA1 c.2037delinsCC, and 15 in BRCA2 including the Portuguese founder BRCA2 c.156_157insAlu. Searching the 78 Portuguese BRCA PVs in over 5,000 ancient human genomes identified evolution origin for only 8 PVs in Europeans dated between 37,470 and 3,818 years before present, confirming the Portuguese-specificity of Portuguese BRCA PVs; comparing the 78 Portuguese BRCA PVs Portuguese, 255 Brazilian BRCA PVs, and 134 African BRCA PVs showed little overlapping, ruling out the possibility that the BRCA PVs shared between Portuguese and Brazilian may also be contributed by African. CONCLUSION: Our study provides evidence that the admixture in recent human history contributed to cancer susceptibility in modern humans.

Asunto(s)

Proteína BRCA1 , Proteína BRCA2 , Humanos , Proteína BRCA2/genética , Proteína BRCA1/genética , Portugal , Femenino , Predisposición Genética a la Enfermedad , Brasil , Variación Genética , Neoplasias de la Mama/genética , Neoplasias Ováricas/genética

RESUMEN

BACKGROUND: Approximately 3/4 of ovarian cancers are diagnosed in advanced stages, with the high-grade epithelial ovarian carcinoma (EOC) accounting for 90% of the cases. EOC present high genomic instability and somatic loss-of-function variants in genes associated with homologous recombination mutational repair pathway (HR), such as BRCA1 and BRCA2, and in TP53. The identification of germline variants in HR genes in EOC is relevant for treatment of platinum resistant tumors and relapsed tumors with therapies based in synthetic lethality such as PARP inhibitors. Patients with somatic variants in HR genes may also benefit from these therapies. In this work was analyzed the frequency of somatic variants in BRCA1, BRCA2, and TP53 in an EOC cohort of Brazilian patients, estimating the proportion of variants in tumoral tissue and their association with progression-free survival and overall survival. METHODS: The study was conducted with paired blood/tumor samples from 56 patients. Germline and tumoral sequences of BRCA1, BRCA2, and TP53 were obtained by massive parallel sequencing. The HaplotypeCaller method was used for calling germline variants, and somatic variants were called with Mutect2. RESULTS: A total of 26 germline variants were found, and seven patients presented germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2. The analysis of tumoral tissue identified 52 somatic variants in 41 patients, being 43 somatic variants affecting or likely affecting protein functionality. Survival analyses showed that tumor staging was associated with overall survival (OS), while the presence of somatic mutation in TP53 was not associated with OS or progression-free survival. CONCLUSION: Frequency of pathogenic or likely pathogenic germline variants in BRCA1 and BRCA2 (12.5%) was lower in comparison with other studies. TP53 was the most altered gene in tumors, with 62.5% presenting likely non-functional or non-functional somatic variants, while eight 14.2% presented likely non-functional or non-functional somatic variants in BRCA1 or BRCA2.

Asunto(s)

Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/genética , Brasil/epidemiología , Neoplasias Ováricas/genética , Reparación del ADN , Células Germinativas , Proteína p53 Supresora de Tumor/genética , Proteína BRCA1/genética , Proteína BRCA2/genética

RESUMEN

Malignant mixed müllerian tumor (MMMT) is a rare neoplasm, consisting of carcinomatous (epithelial) and sarcomatous (mesenchymal) components that most commonly arise in the endometrium and more infrequently in the ovaries, fallopian tube, cervix, and vagina. Primary peritoneal carcinosarcoma (PPCS) is an extremely rare extragenital presentation of MMMT. Although the occurrence of breast cancer and epithelial ovarian carcinoma in association with BRCA pathogenic variants is firmly established, the etiologic role of these genes in the development of other tumor types is less well known. Here, we present a rare case of PPCS in a 42-year-old Brazilian woman with a BRCA2 pathogenic variant, c.2808_2811del (NM_000059.3). The patient developed metastatic breast cancer at the age of 37 and underwent a risk-reducing bilateral salpingo-oophorectomy 2 years later. She was then diagnosed with PPCS 3 years after the risk-reducing surgery. She underwent treatment with surgery, chemotherapy, and targeted therapy but passed away almost 5 years after the second primary tumor diagnosis. To our knowledge, this is the first case of peritoneal carcinosarcoma described in a BRCA2 pathogenic variant carrier, and its report leads to a better understanding of the disease's molecular features and possible therapeutic approaches.

RESUMEN

The ability to evade protection mechanisms and uncontrolled cell growth can lead to the development of mutations, whether somatic or germline, and consequently to the dreaded diagnosis of cancer. Breast cancer is considered the most common type of cancer in women in several regions of Brazil, mainly in the South and Southeast, second only to non-melanoma skin cancer. Approximately 5% to 10% of neoplasms are related to germline alterations that lead to hereditary predisposition. There is evidence of an association with mutations in nine genes, the highest risk being breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2). Due to its epidemiological importance, in this narrative review we observed the main genetic mutations and syndromes associated with breast carcinoma, the recommendations for screening in high-risk patients, and the indication for genetic counseling. Bibliographic research on the PubMed and Cochrane databases and analysis of the Guidelines Breast Cancer Risk Reduction and Breast Cancer Screening and Diagnosis, from June 2022 to September 2023. In this review, we observed a greater influence of germline mutations on breast cancer related to the genes BRCA1, BRCA2, PALB2, PTEN, CDH1, STK11 and, in Brazil, considered a country of ethnic-racial diversity, to TP53. As cancer screening in the country is opportunistic, knowledge of germline mutations associated with breast cancer offers specific screening recommendations for high-risk patients, indications for genetic counseling, and guidelines for prophylactic surgery, in addition to impacting the formulation of public screening policies. (AU)

Asunto(s)

Humanos , Femenino , Neoplasias de la Mama , Mutación de Línea Germinal , Genes BRCA1 , Predisposición Genética a la Enfermedad , Genes BRCA2 , Genes

RESUMEN

BACKGROUND: The BRCA2 gene is a well-known tumor suppressor gene implicated in breast and ovarian cancers. BRCA1/2 mutations can be sensitive to poly ADP-ribose polymerase (PARP) inhibitors such as olaparib. However, some of these patients develop resistance to this treatment and an essential factor contributing to acquired insensitivity is the occurrence of reversion mutations in the BRCA1/2 genes. CASE PRESENTATION: We report the case of a 65-year-old Brazilian female patient who had previously been diagnosed with metastatic lung carcinoma carrying a BRCA2 mutation that had extended to the central nervous system. Following disease progression, olaparib was administered, resulting in a stabilizing effect on her condition for ~ 30 months. During a routine follow-up, a new triple-negative breast tumor was found. Genetic testing revealed the presence of two distinct BRCA2 gene mutations in the breast tumor. The original mutation (p.Val220Ilefs4) led to a frameshift, culminating in the production of a truncated and non-functional BRCA2 protein; the second mutation, K437fs22, rectified the reading frame of exon 11. Consequently, Rad51 could properly bind to BRCA2-an essential protein crucial for DNA repair. This restoration resulted in a functional BRCA2 protein, effectively elucidating the clinical resistance observed in the new breast tumor in this case. CONCLUSIONS: This case report highlights the clinical significance of comprehensive next-generation sequencing analyses for lung adenocarcinomas, both at diagnosis and upon progression. Such analyses enable informed decisions regarding targeted therapies and facilitate a deeper comprehension of resistance mechanisms.

Asunto(s)

Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Anciano , Proteína BRCA2/genética , Proteína BRCA1 , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación

RESUMEN

Background: There is an increasing amount of data from Latin America on the characterization of BRCA variants; however, there is limited information from Peru. We conducted a retrospective study to describe germline pathogenic/likely pathogenic(P/LP) variants and variants of uncertain/unknown significance (VUS) in the BRCA1 and BRCA2 genes in Peru, in patients with breast and ovarian cancer, candidates for treatment with poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors. Methods: The patients were evaluated during the period 2019-2021. Genomic DNA was isolated from peripheral blood samples and targeted sequencing was performed using the Ampliseq BRCA panel. Genetic variant interpretation was carried out in accordance with the recommendations of the American College of Medical Genetics and ClinVar. During this period, 525 patients (143 with breast cancer and 382 with ovarian cancer) were studied. Results: We found that 14.7% (21/143) of breast cancer patients and 20.7% (79/382) of ovarian cancer patients were carriers of P/LP variants in BRCA1/2. The most frequent pathogenic variants detected in BRCA1 were c.2105dupT (BIC: 2224insT, n=12, 18.75%), c.68_69delAG (BIC: 185delAG, n=6, 9.38%), c.140G>T and c.815_824dupAGCCATGTGG (n=5, 7.81%), while in BRCA2 were c.8023A>G (n=6, 16.67%), c.6024dupG (BIC: 6252insG, n=4, 11.11%), and c.9235delG (BIC: 9463delG, n=3, 8.33%). Regarding VUS, we found that 6.99% (10/143) of breast cancer patients and 7.33% (28/382) of ovarian cancer patients were carriers of a VUS in BRCA1/2. For BRCA1, the most frequent VUS was c.93C>G (n=2), and for BRCA2, c.5465A>T (n=4), c.3101T>C (n=3), c.205C>A and c.437T>C (n=2). Conclusion: We found a frequency of 14.7% germline mutations in breast cancer patients and 20.7% in ovarian cancer patients. The most recurrent mutations were BRCA1 c.2105dupT and BRCA2 c.8023A>G. We found that BRCA2 c.8023A>G, c.6024dupG, and c.9235delG were not previously reported in Peruvian patients. BRCA1 c.2344dupA is a novel mutation that has not been previously reported in any database. The frequency of VUS in our cohort was 7.2%.

RESUMEN

BACKGROUND: Triple-negative breast cancer (TNBC) is the neoplasia most associated with BRCA1 germline pathogenic variants (PV) and is more likely to develop metastases than the other breast cancer (BC) subtypes, mainly in the lungs and the central nervous system (CNS). Recently, BRCA2 carriers were shown to have a higher risk for developing CNS metastases. However, the patterns of recurrence and metastases of BRCA2 carriers with TNBC are unknown. METHODS: TNBC patient data attending the A.C. Camargo Cancer Center, from 1998 through 2020, were verified either by medical records or by BRCA1/2 genetic testing carried out. Multivariable logistic regression models were fit to the data to assess the independent factors for bone and CNS metastases. Adjustment was done using all independent variables with p < 0.2 in the univariable Cox model to describe the relationship between the independent variables until time of death. RESULTS: A total of 388 TNBC patients were evaluated. We identified PV in BRCA1/2 genes in 21% (82/388), being 17.7% (69/388) in BRCA1 and only 3.3% (13/388) in BRCA2. A total of 120 patients (31%) developed distant metastases. Bone or CNS metastases were observed in 40% and 60% of BRCA2 PV carriers (p = 0.155), respectively. The BRCA2 carriers tended to have a higher likelihood of developing bone metastases (OR, 4.06; 95% CI, 0.82-20.01; p = 0.085), when compared to BRCA1 carriers (OR, 0.6; 95% CI, 0.12-2.87; p = 0.528). BRCA2 carriers had an OR of 1.75 (95% CI, 0.33-9.14; p = 0.503) for CNS metastasis development, while BRCA1 carriers had an OR of 0.72 (95% CI, 0.23-2.23; p = 0.574). CONCLUSIONS: Patients with TNBC and PV in the BRCA2 gene had higher frequencies of secondary bone involvement and CNS in the course of the disease. However, the BRCA2 PV did not represent an independent outcome predictor of metastases and overall survival. Efforts to increase the number of BRCA2 carriers among TNBC patients are crucial for determining their risk of developing bone and CNS metastases compared to BRCA2 noncarriers.

Asunto(s)

Neoplasias del Sistema Nervioso Central , Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias del Sistema Nervioso Central/secundario , Genes BRCA2 , Predisposición Genética a la Enfermedad , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología

RESUMEN

The trapping of Poly-ADP-ribose polymerase (PARP) on DNA caused by PARP inhibitors (PARPi) triggers acute DNA replication stress and synthetic lethality (SL) in BRCA2-deficient cells. Hence, DNA damage is accepted as a prerequisite for SL in BRCA2-deficient cells. In contrast, here we show that inhibiting ROCK in BRCA2-deficient cells triggers SL independently from acute replication stress. Such SL is preceded by polyploidy and binucleation resulting from cytokinesis failure. Such initial mitosis abnormalities are followed by other M phase defects, including anaphase bridges and abnormal mitotic figures associated with multipolar spindles, supernumerary centrosomes and multinucleation. SL was also triggered by inhibiting Citron Rho-interacting kinase, another enzyme that, similarly to ROCK, regulates cytokinesis. Together, these observations demonstrate that cytokinesis failure triggers mitotic abnormalities and SL in BRCA2-deficient cells. Furthermore, the prevention of mitotic entry by depletion of Early mitotic inhibitor 1 (EMI1) augmented the survival of BRCA2-deficient cells treated with ROCK inhibitors, thus reinforcing the association between M phase and cell death in BRCA2-deficient cells. This novel SL differs from the one triggered by PARPi and uncovers mitosis as an Achilles heel of BRCA2-deficient cells.

Asunto(s)

Daño del ADN , Mutaciones Letales Sintéticas , Anafase , Mitosis , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Quinasas Asociadas a rho/antagonistas & inhibidores , Proteína BRCA2/genética , Humanos

RESUMEN

We determined the frequency and mutational spectrum of BRCA1 and BRCA2 in a series of patients at high risk for developing breast cancer from Brazil. A total of 1267 patients were referred for BRCA genetic testing, and no obligation of fulfilling criteria of mutation probability methods for molecular screening was applied. Germline deleterious mutations in BRCA1/2 (i.e., pathogenic/likely pathogenic variants) were identified in 156 out of 1267 patients (12%). We confirm recurrent mutations in BRCA1/2, but we also report three novel mutations in BRCA2, not previously reported in any public databases or other studies. Variants of unknown significance (VUS) represent only 2% in this dataset and most of them were detected in BRCA2. The overall mutation prevalence in BRCA1/2 was higher in patients diagnosed with cancer at age > 35 years old, and with family history of cancer. The present data expand our knowledge of BRCA1/2 germline mutational spectrum, and it is a valuable clinical resource for genetic counseling and cancer management programs in the country.

Asunto(s)

Proteína BRCA1 , Proteína BRCA2 , Neoplasias de la Mama , Adulto , Femenino , Humanos , Brasil/epidemiología , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Mutación , Neoplasias Ováricas/genética

RESUMEN

BRCA2 is a well-established cancer driver in several human malignancies. While the remarkable success of PARP inhibitors proved the clinical potential of targeting BRCA deficiencies, the emergence of resistance mechanisms underscores the importance of seeking novel Synthetic Lethal (SL) targets for future drug development efforts. In this work, we performed a BRCA2-centric SL screen with a collection of plant-derived compounds from South America. We identified the steroidal alkaloid Solanocapsine as a selective SL inducer, and we were able to substantially increase its potency by deriving multiple analogs. The use of two complementary chemoproteomic approaches led to the identification of the nucleotide salvage pathway enzyme deoxycytidine kinase (dCK) as Solanocapsine's target responsible for its BRCA2-linked SL induction. Additional confirmatory evidence was obtained by using the highly specific dCK inhibitor (DI-87), which induces SL in multiple BRCA2-deficient and KO contexts. Interestingly, dCK-induced SL is mechanistically different from the one induced by PARP inhibitors. dCK inhibition generates substantially lower levels of DNA damage, and cytotoxic phenotypes are associated exclusively with mitosis, thus suggesting that the fine-tuning of nucleotide supply in mitosis is critical for the survival of BRCA2-deficient cells. Moreover, by using a xenograft model of contralateral tumors, we show that dCK impairment suffices to trigger SL in-vivo. Taken together, our findings unveil dCK as a promising new target for BRCA2-deficient cancers, thus setting the ground for future therapeutic alternatives to PARP inhibitors.

Asunto(s)

Antineoplásicos , Desoxicitidina Quinasa , Humanos , Desoxicitidina Quinasa/genética , Desoxicitidina Quinasa/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Nucleótidos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteína BRCA2/genética

RESUMEN

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.

RESUMEN

Breast cancer is the most common type of cancer globally. Hereditary breast cancer accounts for 10% of new cases and 4%-5% of cases are associated to pathogenic variants in BRCA1 or BRCA2 genes. In recent years, poly-adenosine-diphosphate-ribose polymerase inhibitors (PARPi) olaparib and talazoparib have been approved for patients with BRCA-associated, HER2 -negative breast cancer. These drugs have shown positive results in the early and advanced setting with a favourable toxicity profile based on the OlympiAD, OlympiA and EMBRACA phase 3 trials. However, patients included in these randomised trials are highly selected, making toxicity and efficacy in patients encountered in routine clinical care a concern. Since the approval of olaparib and talazoparib for advanced human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer, several phase IIIb-IV trials, expanded access cohorts, and retrospective cohorts have provided information on the efficacy and tolerability of these treatments in patient subgroups underrepresented in the registration trials, such as older adults, patients with poor performance status, and heavily pretreated patients. The aim of this review is to present a critical review of the information regarding the use of PARPi in real-world breast cancer patients.

RESUMEN

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.

Asunto(s)

Humanos , Femenino , Neoplasias de la Mama , Pruebas Genéticas , Genes BRCA1 , Genes BRCA2 , Detección Precoz del Cáncer , Mutación , Mujeres , Imagen por Resonancia Magnética