176 research outputs found
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Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
No full textGenome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium, and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (eQTL), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways, were over-represented among the highest confidence target genes.Version of Recor
Ecologías de Aprendizaje e Identidad Profesional del profesorado de Educación Secundaria
No full text[Resumen]: La presente investigación tiene como objetivo identificar cómo se configuran las Ecologías de Aprendizaje y las Identidades Profesionales de los Docentes de Educación Secundaria en la Sociedad del Conocimiento, y tras analizar la relación entre ambos constructos, valorar su contribución al desarrollo profesional del docente de Educación Secundaria.A tal fin, se ha llevado a cabo una investigación con un diseño mixto secuencial-exploratorio. Se desarrolló una primera fase de corte cualitativo, basado en la tradición de investigación de Estudio de Caso mediante la realización de dos entrevistas a cada uno de los cinco docentes participantes. Posteriormente, se abordó una segunda fase de corte cuantitativo y de carácter descriptivo correlacional, a través de la aplicación de un cuestionario a 311 docentes de Educación Secundaria en la ciudad de A Coruña.Los resultados caracterizan, de forma global, a un profesorado motivado intrínsecamente, con una identidad profesional definida y una ecología de aprendizaje en desarrollo. Además, desvelan un avance hacia la inclusión de los recursos digitales en los procesos de aprendizaje y actualización del profesorado, apuntando hacia la necesidad de ampliar la formación de carácter formal y no formal ofrecida por instituciones como los Centros de Formación y Recursos y las Universidades.[Resumo]: A presente investigación ten como obxectivo identificar como se configuran as Ecoloxías de Aprendizaxe e as Identidades Profesionais dos Docentes de Educación Secundaria na Sociedade do Coñecemento, e tras analizar a relación entre ambos constructos, valorar a súa contribución ao desenvolvemento profesional do docente de Educación Secundaria.A tal fin, levouse a cabo unha investigación baseada cun deseño mixto secuencial-exploratorio. Desenvolveuse unha primeira fase de corte cualitativo, baseado na tradición de investigación de Estudo de Caso mediante a realización de dúas entrevistas a cada un dos cinco docentes participantes. Posteriormente, abordouse unha segunda fase de corte cuantitativo e de carácter descriptivo correlacional, a través da aplicación dun cuestionario a 311 docentes de Educación Secundaria na cidade de A Coruña.Os resultados caracterizan, de forma global, a un profesorado motivado intrinsecamente, cunha identidade profesional definida e unha ecoloxía de aprendizaxe en desenvolvemento. Ademais, desvelan un avance cara á inclusión dos recursos dixitais nos procesos de aprendizaxe e actualización do profesorado, apuntando cara á necesidade de ampliar a formación de carácter formal e non formal ofrecida por institucións como os Centros de Formación e Recursos e as Universidades.[Abstract]: The aim of this research was to identify how learning ecologies and secondary education teachers´ professional identities are configured in the knowledge society. After analysing the relationship between these two constructs, the goal was to assess their contribution to secondary-school teachers’ professional development.To that end, a study was performed following a sequential exploratory mixed design. The first phase was qualitative, based on the case study research tradition, involving two interviews with each of the five participating teachers. The second phase, which was quantitative and descriptive-correlational, was done by applying a questionnaire to 311 secondary school teachers in the city of A Coruña.The results overall characterise a teaching staff that is intrinsically motivated, with a defined professional identity and a developing learning ecology. They also demonstrate progress towards including digital resources in teachers’ learning and continuing professional development processes, highlighting the need to expand both formal and non-formal training offered by training and resource centres and universities
Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
No full textA combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74–0.81, p = 3.1 × 10−31).</p
Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
No full textFine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions. Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.</p
Possession of the ATM Codon 1853 SNP is Associated With an Increased Risk for Radiation-Induced Toxicity
No full textLimited family structure and triple-negative breast cancer (TNBC) subtype as predictors of BRCA mutations in a genetic counseling cohort of early-onset sporadic breast cancers
No full textEGFR testing and clinical management of advanced NSCLC: a Galician Lung Cancer Group study (GGCP 048-10)
No full textSergio Vázquez,1 Joaquín Casal,2 Francisco Javier Afonso Afonso,3 José Luis Fírvida,4 Lucía Santomé,5 Francisco Barón,6 Martín Lázaro,7 Carolina Pena,7 Margarita Amenedo,8 Ihab Abdulkader,9 Carmen González-Arenas,10 Laura Fachal,11 Ana Vega11 On behalf of the Galician Lung Cancer Group (GGCP)1Medical Oncology Department, Lucus Augusti University Hospital, Lugo, 2Medical Oncology Department, University Hospital Complex of Vigo, Pontevedra, 3Medical Oncology Department, University Hospital Complex of Ferrol, Ferrol, 4Medical Oncology Department, University Hospital Complex of Ourense, Ourense, 5Medical Oncology Department Povisa Hospital, Vigo, 6Medical Oncology Department, University Hospital Complex of Santiago de Compostela, Santiago de Compostela, 7Medical Oncology Department, Hospital Complex of Pontevedra, Pontevedra, 8Medical Oncology Department, Oncology Center of Galicia, A Coruña, 9Anatomical Pathology Department, University Hospital Complex of Santiago de Compostela, Santiago de Compostela, 10AstraZeneca, Madrid, 11Galician Public Foundation of Genomic Medicine-SERGAS, Santiago de Compostela Clinic Hospital, Santiago de Compostela, Spain Purpose: This study aimed to assess the incidence of mutations in the epidermal growth factor receptor (EGFR) gene in non-small-cell lung cancer (NSCLC) patients in the Galician region of Spain and the clinical management and outcome of patients carrying EGFR mutations. Patients and methods: All newly diagnosed advanced or metastatic NSCLC patients were screened for EGFR mutations in matched tumor samples (tissue or cytology specimens) and serum samples. Results: Of 198 patients screened for EGFR mutations in tumor samples, 184 had evaluable data and, of these, 25 (13.6%) had EGFR mutations (84% sensitizing mutations). EGFR mutation was found in serum in 14 (8.1%) patients (of 174 evaluable). Compared to matched tumor tissue, serum EGFR mutation testing specificity and sensitivity were 99% and 52%, respectively. All but two patients received gefitinib. Median progression-free survival and overall survival were 10 (95% confidence interval: 4.8–15.3) months and 17.8 (95% confidence interval: 13.9–21.6) months, respectively, in patients carrying sensitizing mutations. Conclusion: The incidence of EGFR mutations in Galicia is consistent with previous data in Spain. Our results also support the feasibility of EGFR testing to guide treatment decision making using tumor tissue or cytology samples, or serum samples if tumor specimens are unavailable. These findings also confirm that first-line gefitinib is an active treatment option in Caucasians with EGFR mutation-positive NSCLC. Keywords: epidermal growth factor receptor, EGFR tyrosine inhibitors, TKIs, EGFR gene mutation, EGFR mutation testing, non-small-cell lung cance
Characterization of BRCA1 and BRCA2 splicing variants: A collaborative report by ENIGMA consortium members
No full textA multi-centre international quality control study comparing mRNA splicing assay protocols and reporting practices from the ENIGMA consortium
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