LES APPORTS DE LA GENETIQUE MOLECULAIRE A LA CANCEROLOGIE VETERINAIRE, EXEMPLE DES TUMEURS MAMMAIRES DE LA CHIENNE

Les progrès de ces 25 dernières années ont permis d'identifier et de caractériser les acteurs moléculaires du processus de cancérisation. C'est grâce aux techniques de génétique moléculaire que la conception du cancer vu comme maladie du génome a émergé. Ainsi la carcinogenèse est un processus qui résulte de l'expansion clonale d'une cellule acquérant, par le jeu de l'accumulation de mutations génétiques, des avantages de croissance. Après avoir décrit les principaux acteurs moléculaires du processus de cancérisation et les connaissances acquises sur les altérations génétiques observées dans les tumeurs humaines, nous montrerons dans une deuxième partie que des études relativement récentes ont abouti, grâce à l'utilisation d'outils moléculaires, à la mise en évidence dans les cellules de tumeurs mammaires canines, d'anomalies somatiques (mutations, surexpression ou amplification) de gènes déjà fortement incriminés pour leurs rôles dans la pathogénie des tumeurs du sein chez la femme. Des observations concernant la réactivation de la télomérase et l'expression de la cycline D 1 suggèrent pourtant l'existence de différences inter-espèces dans les mécanismes moléculaires à la base de la cancérogenèse mammaire. Enfin, une dernière partie permet d'exposer des exemples pratiques d'application de l'analyse moléculaire aux différents domaines de la cancérologie clinique chez l'Homme. Elle permet également de montrer que l'approche génétique du cancer du Chien profite de l'expérience acquise en génétique du cancer chez l'Homme. Cependant, même si les études exposées ouvrent des perspectives intéressantes, elles sont trop peu nombreuses pour trouver une application pratique véritable en cancérologie vétérinaire avant plusieurs années.MAISONS-ALFORT-Ecole Vétérin (940462302) / SudocSudocFranceF

Analyse des publications par la bibliométrie

Présentation des usages de l'analyse des publications par la bibliométrie : La bibliométrie, pour quoi faire ? Quelles informations (données de l'OST, bases de données scientifiques, ressources disponibles dans les institutions), pour quels résultats (étude des acteurs : pays, auteurs, institutions/ études thématiques/ étude des revues) ?Elle sera basée sur les travaux récents réalisés par les cinq intervenants

Strengths and limits of transgenic zebra fish models to study the expression and the perturbation of steroidogenic genes by endocrine disrupting chemicals

International audienc

Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X

Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression, and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using machine learning classifiers trained to distinguish disease-associated from dispensable genes, we classify 247 genes, including 115 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants

Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features

IF 5.751International audienceThe Xq28 duplication involving the MECP2 gene (MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life

Further delineation of theduplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features

The Xq28 duplication involving thegene (duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitialduplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype ofduplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.status: accepte

Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes

Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts’ maps could uncover functionally and clinically related genes

Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance