Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma

IntroductionThe percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPGL patients. Moreover, the application of NGS to the diagnosis of PPGL detects unexpected co-occurrences of pathogenic allelic variants in different susceptibility genes.MethodsHerein we uncover several cases with dual mutations in NF1 and other PPGL genes by targeted sequencing. We studied the molecular characteristics of the tumours with co-occurrent mutations, using omic tools to gain insight into the role of these events in tumour development.ResultsAmongst 23 patients carrying germline NF1 mutations, targeted sequencing revealed additional pathogenic germline variants in DLST (n=1) and MDH2 (n=2), and two somatic mutations in H3-3A and PRKAR1A. Three additional patients, with somatic mutations in NF1 were found carrying germline pathogenic mutations in SDHB or DLST, and a somatic truncating mutation in ATRX. Two of the cases with dual germline mutations showed multiple pheochromocytomas or extra-adrenal paragangliomas - an extremely rare clinical finding in NF1 patients. Transcriptional and methylation profiling and metabolite assessment showed an “intermediate signature” to suggest that both variants had a pathological role in tumour development.DiscussionIn conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients

Impacto del modelo constructivista para gestionar la innovación universitaria en el deporte

Innovation by projects is considered one of the main sources of impact of science and technology, however, the valuation of these is a problem, not yet fully resolved, despite the efforts made by different researchers and organizations, this reality does not escape the sports organizations. The aim of this article is to assess the impact of innovation by projects, managed by the Faculty of Physical Culture of Granma, from a constructivist model. The research required empirical methods such as the review of official documents, observation and interview, as well as the multivariate graphic method and arithmetic procedures; the latter allowed the impact of the innovations to be evaluated as favourable, relevant, sustainable and with performance in the saturation phase, five years after the financial execution of the projects used as a sample was concluded.A inovação por projetos é considerada uma das principais fontes de impacto da ciência e da tecnologia, porém, a valorização destes é um problema, ainda não totalmente resolvido, apesar dos esforços feitos por diferentes pesquisadores e organizações, esta realidade não escapa às organizações esportivas. O objectivo deste artigo é avaliar o impacto da inovação por projetos, geridos pela Faculdade de Cultura Física de Granma, a partir de um modelo construtivista. A investigação exigiu métodos empíricos como a revisão de documentos oficiais, observação e entrevista, bem como o método gráfico multivariado e procedimentos aritméticos; estes últimos permitiram avaliar o impacto das inovações como favoráveis, relevantes, sustentáveis e com desempenho na fase de saturação, cinco anos após a conclusão da execução financeira dos projetos utilizados como amostra. La innovación por proyectos es considerada una de las principales fuentes de impactos de la ciencia y la tecnología, sin embargo, la valoración de estos constituye un problema, aún no resuelto en su totalidad, a pesar de los esfuerzos realizados por diferentes investigadores y organizaciones; a esta realidad no escapan las organizaciones deportivas. El objetivo del presente artículo es valorar el impacto de la innovación por proyectos, gestionados por la Facultad de Cultura Física de Granma, desde un modelo constructivista. La investigación exigió métodos empíricos como revisión de documentos oficiales, la observación y la entrevista, así como el método gráfico multivariado y procedimientos aritméticos; estos últimos permitieron valorar el impacto de las innovaciones como favorable, relevante, sostenible y con rendimiento en fase de saturación, cinco años después de concluir la ejecución financiera de los proyectos usados como muestra

Modelo para la gestión de la innovación universitaria por proyectos en el contexto deportivo

In management there has always been present the psychological position, although, this is not always identified by managers, employees, and people with great knowledge of the matter. This article shows the results of a deep bibliographical research which allowed the definition of the process of management by projects in the cuban sports context, with a psychological position, predominantly constructivist and the representation of such conceptualization. The way of dealing with it and the main elements for putting it into practice, by means of a model, superior in pertinence and impact to the present day conception which is predominantly behaviourist. To obtain these results the modelation method was used.En la gestión siempre ha estado presente el posicionamiento psicológico, aunque no siempre es identificado por gerentes, subordinados y estudiosos del tema. En el artículo se expone un modelo para la gestión de la innovación universitaria por proyectos, en el contexto deportivo cubano, con un posicionamiento psicológico predominantemente constructivista, y la representación de dicha conceptualización, el enfoque de su gestión y los principales elementos para su implantación, a través de un modelo superior en pertinencia e impacto a la concepción actual predominantemente conductista. Para obtener estos resultados se utilizó el método de modelación

Modelo para la gestión de la innovación universitaria por proyectos en el contexto deportivo

En la gestión siempre ha estado presente el posicionamiento psicológico, aunque no siempre es identificado por gerentes, subordinados y estudiosos del tema. En el artículo se expone un modelo para la gestión de la innovación universitaria por proyectos, en el contexto deportivo cubano, con un posicionamiento psicológico predominantemente constructivista, y la representación de dicha conceptualización, el enfoque de su gestión y los principales elementos para su implantación, a través de un modelo superior en pertinencia e impacto a la concepción actual predominantemente conductista. Para obtener estos resultados se utilizó el método de modelación

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) provide some of the clearest genetic evidence for the critical role of metabolism in the tumorigenesis process. Approximately 40% of PPGLs are caused by driver germline mutations in 16 known susceptibility genes, and approximately half of these genes encode members of the tricarboxylic acid (TCA) cycle. Taking as a starting point the involvement of the TCA cycle in PPGL development, we aimed to identify unreported mutations that occurred in genes involved in this key metabolic pathway and that could explain the phenotypes of additional individuals who lack mutations in known susceptibility genes. To accomplish this, we applied a targeted sequencing of 37 TCA-cycle-related genes to DNA from 104 PPGL-affected individuals with no mutations in the major known predisposing genes. We also performed omics-based analyses, TCA-related metabolite determination, and 13C5-glutamate labeling assays. We identified five germline variants affecting DLST in eight unrelated individuals (∼7%); all except one were diagnosed with multiple PPGLs. A recurrent variant, c.1121G>A (p.Gly374Glu), found in four of the eight individuals triggered accumulation of 2-hydroxyglutarate, both in tumors and in a heterologous cell-based assay designed to functionally evaluate DLST variants. p.Gly374Glu-DLST tumors exhibited loss of heterozygosity, and their methylation and expression profiles are similar to those of EPAS1-mutated PPGLs; this similarity suggests a link between DLST disruption and pseudohypoxia. Moreover, we found positive DLST immunostaining exclusively in tumors carrying TCA-cycle or EPAS1 mutations. In summary, this study reveals DLST as a PPGL-susceptibility gene and further strengthens the relevance of the TCA cycle in PPGL development