Hereditary predisposition to malignant myeloid hemopathies: Caution in use of saliva and guideline based on our experience

BackgroundPredisposition to myeloid malignancies is a field at the border of hematology and genetics. Knowledge in this domain has so rapidly increased that WHO defined in 2016 the new “Myeloid Neoplasms with Germline Predisposition” category of tumors. High throughput sequencing is frequently performed in tumors either for diagnosis or prognosis, but this approach may identify potential germline variants that have to be confirmed on non-infiltrated tissues.MethodIn this study, we systematically compared NGS data from genetic analysis performed on all sample types (bone marrow, blood, saliva, skin fibroblasts and hair follicles) in 29 patients, and 44 of their relatives (blood and saliva).ResultsWe showed that saliva was usable for relatives, but only for 24% (7/29) of our patients. Most of patients’ saliva were either “non-contributive” (14/29 i.e., 48% because clearly or probably infiltrated) or “inconclusive” (8/29 corresponding to 28%).ConclusionThe recommendations for the use of saliva we present here focus on the importance of collecting saliva during remission when possible. Moreover, we propose hair follicles as an alternative to skin biopsy, that remains the gold standard especially in case of allogenic hematopoietic stem cells transplantation. Technological progresses have revolutionized the diagnosis of predisposition to solid or hematological malignancies, and it is very likely that new techniques will help to manage the familial predisposition in the future

Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS):new insights from the fetal perspective

INTRODUCTION: Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described.METHOD: After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases.RESULTS: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots.CONCLUSION: Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.</p

Etude in vitro des effets génotoxiques des radiofréquences de type GSM-900

Le développement et l'augmentation constante des systèmes de télécommunication s'accompagnent de nombreuses questions, en particulier sur le risque sanitaire et oncogène des radiofréquences. La cancérogenèse est un processus multi-étape lié à l'accumulation d'anomalies génétiques dans des régions critiques du génome. Ces lésions génomiques sont généralement détectées et réparées par les cellules. Des erreurs ou défauts de réparation peuvent conduire à des instabilités génomiques pouvant initier un processus cancérogène. Notre travail a porté sur l'étude des effets génotoxiques des radiofréquences utilisées par la téléphonie mobile (GSM-900) sur des amniocytes humains. Les cellules ont été exposées in vitro pendant 24 heures à des ondes GSM-900 dans une cellule fil-plaque. La génotoxicité a été évaluée selon différentes approches (1) étude des remaniements chromosomiques et des aneuploïdies à l'aide du caryotype en bandes R (DAS moyen de 0,25 W/kg) et de la FISH (DAS moyens de 0,25 ; 1 ; 2 et 4 W/kg), (2) étude de l'expression et de l'activation de protéines impliquées dans les voies de signalisation des lésions de l'ADN telles que l'activation de p53 et H2AX par western blot (DAS moyens de 0,25 ; 1 ; 2 et 4 W/kg) et (3) étude de certaines réponses cellulaires aux lésions de l'ADN comme l'apoptose par détection du clivage de la caspase 3 par western blot (DAS moyens de 0,25 ; 1 ; 2 et 4 W/kg). Les résultats obtenus ne montrent pas d'effet génotoxique significatif des radiofréquences de type GSM-900 sur des amniocytes humains exposés pendant 24 heures quels que soient la méthode utilisée et le niveau de puissance testé. Ces résultats semblent en adéquation avec la majorité des études publiées dans la littérature.LIMOGES-BU Médecine pharmacie (870852108) / SudocSudocFranceF

Comparaison de deux méthodes d'analyse pour l'étude des remaniements subtélomériques (FISH et MLPA)

LIMOGES-BU Médecine pharmacie (870852108) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Diagnostic d'anomalies chromosomiques chez les jumeaux, mosaïques et chimères (à propos d'un cas et revue de la littérature)

Deux jumelles de phénotypes discordants, H. normale et J. anormale, présentent toutes les deux une duplication directe 11p en mosaïque concernant un 1/5 de leurs lymphocytes sanguins. La discordance phénotypique a motivé des explorations complémentaires en cytogénétique moléculaire où des cellules du frottis jugal et du sédiment urinaire ont été analysées. Deux tiers des cellules de J. présentent une trisomie 11p alors qu'aucune cellule anormale n'a été retrouvée chez H. Le phénotype paraît donc particulièrement corrélé à la répartition des cellules au niveau des tissus somatiques autres que le sang. La mosaïque retrouvée au niveau du sang des deux jumelles est probablement due à des échanges sanguins in utero entre les deux circulations foetales par l'intermédiaire d'anastomoses placentaires. La transfusion foeto-foetale in utero entre jumeaux peut être à l'origine de mosaïques et de chimères. Ces deux phénomènes peuvent être source d'erreurs au cours du diagnostic cytogénétique.TOULOUSE3-BU Santé-Centrale (315552105) / SudocTOULOUSE3-BU Santé-Allées (315552109) / SudocSudocFranceF

Apoptosis is induced by radiofrequency fields through the caspase-independent mitochondrial pathway in cortical neurons.

ERMAInternational audienceIn the present study, we investigated whether continuous-wave (CW) radiofrequency (RF) fields induce neuron apoptosis in vitro. Rat primary neuronal cultures were exposed to a CW 900 MHz RF field with a specific absorption rate (SAR) of 2 W/kg for 24 h. During exposure, an increase of 2 degrees C was measured in the medium; control experiments with neurons exposed to 39 degrees C were then performed. Apoptosis was assessed by condensation of nuclei with 4',6-diamino-2-phenylindole (DAPI) staining observed with an epifluorescence microscope and fragmentation of DNA with TdT-mediated dUTP nick-end labeling (TUNEL) analyzed by flow cytometry. A statistically significant difference in the rate of apoptosis was found in the RF-field-exposed neurons compared to the sham-, 37 degrees C- and 39 degrees C-exposed neurons either 0 or 24 h after exposure using both methods. To assess whether the observed apoptosis was caspase-dependent or -independent, assays measuring caspase 3 activity and apoptosis-inducing factor (AIF) labeling were performed. No increase in the caspase 3 activity was found, whereas the percentage of AIF-positive nuclei in RF-field-exposed neurons was increased by three- to sevenfold compared to other conditions. Our results show that, under the experimental conditions used, exposure of primary rat neurons to CW RF fields may induce a caspase-independent pathway to apoptosis that involves AIF

Chromosomal studies of human amniotic cells exposed to GSM-900: Karyotyping and fish

International audienceThe possible effects of radiofrequency (RF) exposure on the genetic material of cells are very important to determine since DNA damage of somatic cells may be linked to cancer development. The first objective of our studies was to study the complete R-banded karyotype of cultured human amniotic cells exposed to RF similar to those emitted by mobile phones of second generation (GSM). Our second objective was to investigate whether the GSM-exposure may induce aneuploidy by FISH (Fluorescent in Situ Hybridization) using the same probes as those used by Mashevich et al. (2003) and Mazor et al. (2008)

No variation of p53 expression and activation is induced in human amniotic cells exposed to GSM-900 RF

International audienc

Study of p53 expression and post-transcriptional modifications after GSM-900 radiofrequency exposure of human amniotic cells

International audienceThe potential effects of radiofrequency (RF) exposure on the genetic material of cells are very important to determine since genome instability of somatic cells may be linked to cancer development. In response to genetic damage, the p53 protein is activated and can induce cell cycle arrest allowing more time for DNA repair or elimination of damaged cells through apoptosis. The objective of this study was to investigate whether the exposure to RF electromagnetic fields, similar to those emitted by mobile phones of the second generation standard, Global System for Mobile Communications (GSM), may induce expression of the p53 protein and its activation by post-translational modifications in cultured human cells. The potential induction of p53 expression and activation by GSM-900 was investigated after in vitro exposure of human amniotic cells for 24 h to average specific absorption rates (SARs) of 0.25, 1, 2, and 4 W/kg in the temperature range of 36.3-39.7 °C. The exposures were carried out using a wire-patch cell (WPC) under strictly controlled conditions of temperature. Expression and activation of p53 by phosphorylation at serine 15 and 37 were studied using Western blot assay immediately after three independent exposures of cell cultures provided from three different donors. Bleomycin-exposed cells were used as a positive control. According to our results, no significant changes in the expression and activation of the p53 protein by phosphorylation at serine 15 and 37 were found following exposure to GSM-900 for 24 h at average SARs up to 4 W/kg in human embryonic cells. Bioelectromagnetics. © 2012 Wiley Periodicals, Inc