The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin.

Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo Furthermore, spliceosome inhibitors reduced BRCA1-Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance. Cancer Res; 76(9); 2778-90. ©2016 AACR.

Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.

PURPOSE: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. EXPERIMENTAL DESIGN: We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model. RESULTS: The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%-31%] for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer-specific mortality. CONCLUSIONS: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.

Síndrome confusional agudo en pacientes posquirúrgicos de cirugía de revascularización miocárdica / Acute confusional state in postoperative surgical patients myocardial revascularization

Se realizó un estudio de investigación con un diseño cuantitativo, analítico, retrospectivo, transversal, conmetodología de Casos y Controles, seleccionando una muestra de 90 pacientes, a través de un muestreo aleatorio simple de un total de 246 pacientes posquirúrgicos de revascularización miocárdica, los cuales fueron distribuidos en grupo de casos y grupo de controles. En el grupo casos se incluyeron 30 pacientes, mientras que en el grupo control se incluyeron 60 pacientes. Esto fue realizado en el Instituto de Cardiología de Juana Francisca Cabral, de la ciudad de Corrientes, capital. Las operaciones estadísticas utilizadas fueron porcentajes, promedios; y para establecer las asociaciones, OddsRatio, el nivel de significación fue de p< 0,05, se utilizó el programa “SPPS, versión 17.0”. Cuando se analizó la CEC (Circulación Extracorpórea), en relación al Síndrome Confusional Agudo, se encontró que los pacientes que requirieron CEC tienen 1,75 veces más de probabilidades de desarrollar S.C.A. que los pacientes que no requirieron CEC, con Intervalo de Confianza = 0,71 – 4,17 y P= 0,162 (NS= no significativo). Al analizar el antecedente de tabaquismo, se observó que los pacientes con antecedente de tabaquismo, tienen 1,83 veces más de probabilidades de desarrollar S.C.A. en el posoperatorio de cirugía de revascularización miocárdica con circulación extracorpórea, que de los pacientes sin antecedente de tabaquismo, con un Intervalo de Confianza = 0,58 – 3,36 y P= 0,3 (NS= no significativo). Por último, al analizar la variable sexo, se encontró que el grupo de mujeres tienen 2,11 veces más de probabilidades de desarrollar S.C.A., en el posoperatorio de cirugía de revascularización miocárdica con circulación extracorpórea, que los pacientes del sexo masculino, con Intervalo de Confianza = 0,78 – 7,09 y P= 0,10 (NS= no significativo...

A research study was conducted with quantitative, analytical, retrospective, cross-sectional design with CaseControlmethodology, selecting a sample of 90 patients, through simple random sampling a total of 246 patientspostoperative myocardial revascularization, the which were distributed in the case group and control group. In the case group included 30 patients, whereas in the control group 60 patients were included. This was done at the Institute of Cardiology of Juana Francisca Cabral, city of Corrientes, capital. The statistics operations were used percentages, averages; and to establish partnerships, Odds Ratio, the level ofsignificance was p <0.05, the program was used "SPPS, version 17.0."When the CEC was analyzed in relation to acute confusional syndrome, found that patients who required CPB are1.75 times more likely to develop SCA Patients who required NO CEC, with confidence interval = 0.71 to 4.17 and P= 0.162 (NS = not significant).When analyzing the History of Smoking, it was observed that patients with a history of Tobacco, have 1.83 timesmore likely to develop SCA in the postoperative CABG with cardiopulmonary bypass patients without a history of smoking, a confidence interval = 0.58 to 3.36 and P = 0.3 (NS = not significant). Finally when analyzing the gender variable, it was found that in the group of women, are 2.11 times more likely to develop SCA in the postoperative CABG with cardiopulmonary bypass, that male patients with confidence interval = 0.78 to 7.09 and P = 0.10 (NS = not significant)...