Physiopathologie de la neurofibromatose de type 1

PARIS-BIUP (751062107) / SudocSudocFranceF

Génétique moléculaire des tumeurs bénignes et malignes des gaines nerveuses périphériques chez les patients atteints de neurofibromatose de type 1

Avec une incidence estimée à une naissance sur 3500 la neurofibromatose de type 1 est l une des maladies génétiques à transmission autosomique dominante les plus fréquentes. Les signes cliniques sont très variables même au sein d une famille ; cependant la présence de neurofibromes, tumeurs bénignes des gaines nerveuses périphériques, reste pathognomonique de cette maladie. Il est classique de distinguer les neurofibromes cutanés des neurofibromes plexiformes qui seuls peuvent se transformer en tumeurs malignes des gaines nerveuses (MPNST) ou neurofibrosarcomes, de très mauvais pronostic. Les mutations du gène NF1 à l origine de la maladie sont très hétérogènes et, à ce jour, aucune relation génotype-phénotype n a pu être démontrée. De même, les mécanismes moléculaires régulant le développement et l évolution des neurofibromes chez les patients restent à élucider. Dans cette optique, nous avons réalisé une analyse ciblée puis à grande échelle du transcriptome de neurofibromes plexiformes et de neurofibrosarcomes ainsi que l étude de l expression d une quinzaine de gènes localisés à proximité du gène NF1 et délétés avec ce dernier dans les syndromes microdélétionnels. Les résultats obtenus nous ont permis de définir une signature moléculaire constituée de 5 gènes prédictive du risque d évolution vers la malignité des neurofibromes plexiformes et d identifier un certain nombre de voies et de gènes plus particulièrement impliqués dans la genèse des neurofibromes plexiformes et leur transformation en MPNSTs apportant ainsi de nouvelles données permettant d envisager la mise en place de thérapeutiques ciblées.NF1 is one of the most common autosomal dominant disorder occurring in man, affecting 1 in every 3,500 newborn infants.The hallmarks of NF1 vary widely even within a family but the presence of neurofibromas, benign peripheral nerve sheaths tumors, remains pathognomonic of the disease. It is traditional to distinguish cutaneous neurofibromas and plexiform neurofibromas which alone can progress to malignant peripheral nerve sheaths tumor (MPNST) also known as neurofibrosarcoma with a very poor prognosis.The NF1 gene mutations causing the disease are very heterogeneous and, to date, no genotype-phenotype relationship has been demonstrated.The molecular mechanisms that regulate the development and evolution of neurofibromas in patients remain unclear.In this context, we conducted targeted and large-scale analysis over Plexiform neurofibromas and neurofibrosarcoma s transcriptome. We also studied expression of a fortnight of genes located near the NF1 deleted gene and with it the microdeletional syndromes. The results have enabled us to define a molecular signature of 5 genes predictive of the risk of Plexiform neurofibromas progression to malignancy and identify a number of pathways and genes specifically involved in the genesis of Plexiform neurofibromas and MPNSTs transformation thus providing new data to consider the introduction of targeted therapiesPARIS-BIUP (751062107) / SudocSudocFranceF

Supervised Physical Activity Quickly Improves Social Dimension of Quality of Life in Breast Cancer Patients

PurposeThe objectives of the present study was to evaluate the implementation of the program in real life and the evolution of the quality of life (QoL) in breast cancer patients after 3 months of supervised PA in real life and to determine the factors associated with changes in various QoL dimensions.MethodsThis prospective cohort study was carried out in female patients with breast cancer diagnosed within a maximum of 3 yr. QoL and physical exertion intensity during the supervised physical activity (PA) sessions were assessed by the Quality of Life Questionnaire for Cancer and Borg scale, respectively. Statistical analyses comparing QoL scores between the start and the end of supervised PA program were assessed using paired Student's t-tests. Multivariate analysis was performed by linear regression with only variables with a P value ResultsA total of 93 patients were included in the analyses. There was a significant improvement of social functioning at T3 ( increment = 11.5; P < 0.001). The improvement of social functioning was significantly and independently associated with the Borg improvement (beta = 2.66 +/- 1.31, P = 0.046), chemotherapy (beta = 11.03 +/- 5.45, P = 0.046), hormone therapy (beta = -13.91 +/- 5.51, P = 0.013), social isolation (beta = -14.81 +/- 6.55, P = 0.026), and comorbidities (beta = -15.32 +/- 5.59, P = 0.007).ConclusionsWe observed a real enthusiasm and need among patients for practicing PA supervised by a sport trainer near their home. The increase in the intensity of exercise over time contributes to the improvement of the QoL, especially on the social functioning. These results, consistent with previous literature, reinforce the importance of exercise intensity on many dimensions of QoL. In addition, patients expressed great satisfaction with the supervised program, resulting in a strong desire to maintain long-term PA