RESUMEN
High-risk neuroblastoma is an aggressive malignancy, with high rates of treatment failure. We evaluated genetic variants associated with in vitro sensitivity to two derivatives of cyclophosphamide for association with clinical response in a separate replication cohort of neuroblastoma patients (n = 2,709). To determine sensitivity, lymphoblastoid cell lines (LCLs) were exposed to increasing concentrations of 4-hydroperoxycyclophosphamide (4HC; n = 422) and phosphoramide mustard (PM; n = 428). Genome-wide association studies were performed to identify single-nucleotide polymorphisms (SNPs) associated with sensitivity to 4HC and PM. SNPs consistently associated with LCL sensitivity were analyzed for associations with event-free survival (EFS) in patients. Two linked SNPs, rs9908694 and rs1453560, were found to be associated with (i) sensitivity to PM in LCLs across populations and (ii) EFS in all patients (P = 0.01) and within the high-risk subset (P = 0.05). Our study highlights the value of cell-based models to identify candidate variants that may predict response to treatment in patients with cancer.
Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Estudio de Asociación del Genoma Completo , Neuroblastoma/genética , Neuroblastoma/patología , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Niño , Estudios de Cohortes , Ciclohexilaminas/metabolismo , Ciclofosfamida/análogos & derivados , Ciclofosfamida/metabolismo , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Neuroblastoma/tratamiento farmacológico , Fenotipo , Polimorfismo de Nucleótido Simple , Control de Calidad , ARN Interferente Pequeño , Reacción en Cadena en Tiempo Real de la Polimerasa , Medición de Riesgo , Insuficiencia del TratamientoRESUMEN
OBJECTIVE: This study aimed to identify the oncogenes at 20q involved in colorectal adenoma to carcinoma progression by measuring the effect of 20q gain on mRNA expression of genes in this amplicon. METHODS: Segmentation of DNA copy number changes on 20q was performed by array CGH (comparative genomic hybridisation) in 34 non-progressed colorectal adenomas, 41 progressed adenomas (ie, adenomas that present a focus of cancer) and 33 adenocarcinomas. Moreover, a robust analysis of altered expression of genes in these segments was performed by microarray analysis in 37 adenomas and 31 adenocarcinomas. Protein expression was evaluated by immunohistochemistry on tissue microarrays. RESULTS: The genes C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5, mapping at 20q, were significantly overexpressed in carcinomas compared with adenomas as a consequence of copy number gain of 20q. CONCLUSION: This approach revealed C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5 genes to be important in chromosomal instability-related adenoma to carcinoma progression. These genes therefore may serve as highly specific biomarkers for colorectal cancer with potential clinical applications.
Asunto(s)
Adenoma/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 20/genética , Neoplasias Colorrectales/genética , Oncogenes , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenoma/metabolismo , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/metabolismo , Hibridación Genómica Comparativa/métodos , ADN de Neoplasias/genética , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Estudios Prospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodosRESUMEN
Psychophysiological and self-report measures of reactivity were obtained from 135 police deputies exposed to a stressful film. Subjects categorized according to trait anxiety level and character defense pattern were encouraged to anticipate benign or threatening experiences or were given no preparatory information. In general, information abetted stress reduction; individual personality variables also influenced reactivity. The vigilant coper group uniformly demonstrated intolerance for uncertainty, whereas the responses of the neutral and avoider groups were separable according to anxiety level, in which lower anxiety facilitated adaptation to the stressor. The dramatic correspondence of supervisory ratings of field performance and the data for the no-warning condition suggests that the demands for success in law enforcement service were approximated by the simulated stress procedure.