45 research outputs found
Integrin Alpha 8 Recessive Mutations Are Responsible for Bilateral Renal Agenesis in Humans
Renal hypodysplasia (RHD) is a heterogeneous condition encompassing a spectrum of kidney development defects including renal agenesis, hypoplasia, and (cystic) dysplasia. Heterozygous mutations of several genes have been identified as genetic causes of RHD with various severity. However, these genes and mutations are not associated with bilateral renal agenesis, except for RET mutations, which could be involved in a few cases. The pathophysiological mechanisms leading to total absence of kidney development thus remain largely elusive. By using a whole-exome sequencing approach in families with several fetuses with bilateral renal agenesis, we identified recessive mutations in the integrin α8-encoding gene ITGA8 in two families. Itga8 homozygous knockout in mice is known to result in absence of kidney development. We provide evidence of a damaging effect of the human ITGA8 mutations. These results demonstrate that mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease
The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies
Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease
High Cyclin E Staining Index in Blastemal, Stromal or Epithelial Cells Is Correlated with Tumor Aggressiveness in Patients with Nephroblastoma
PURPOSE: Identifying among nephroblastoma those with a high propensity for distant metastases using cell cycle markers: cyclin E as a regulator of progression through the cell cycle and Ki-67 as a tumor proliferation marker, since both are often deregulated in many human malignancies. METHODOLOGY/PRINCIPAL FINDINGS: A staining index (SI) was obtained by immunohistochemistry using anti-cyclin E and anti-Ki-67 antibodies in paraffin sections of 54 postchemotherapy nephroblastoma including 42 nephroblastoma without metastasis and 12 with metastases. Median cyclin E and Ki-67 SI were 46% and 33% in blastemal cells, 30% and 10% in stromal cells, 37% and 29.5% in epithelial cells. The highest values were found for anaplastic nephroblastoma. A correlation between cyclin E and Ki-67 SI was found for the blastemal component and for the epithelial component. Univariate analysis showed prognostic significance for metastases with cyclin E SI in stromal cells, epithelial cells and blastemal cells (p = 0.03, p = 0.01 and p = 0.002, respectively) as well as with Ki-67 SI in blastema (p<10(-4)). The most striking data were that both cyclin E SI and blastemal Ki-67 SI discriminated between patients with metastases and patients without metastasis among intermediate-risk nephroblastoma. CONCLUSIONS: Our findings show that a high cyclin E SI in all components of nephroblastoma is correlated with tumor aggressiveness and metastases, and that assessment of its expression may have prognostic value in the categorization of nephroblastoma
Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models
Rôle crucial de FGF20 et FGF9 pour le maintien des progéniteurs rénaux lors du développement rénal
Caractérisation du rôle du chromosome 12 dans l'étiologie du néphroblastome
Bien que le néphroblastome soit l'une des tumeurs solides de l'enfant les plus fréquentes, les mécanismes moléculaires impliqués sont encore très mal caractérisés. Des analyses d'expression différentielle entre tumeurs et reins sains m'ont permis de montrer que l'altération du contrôle de la transition G1/S du cycle cellulaire, via la surexpression spécifique de deux gènes formant un complexe majeur de régulation de ce point de contrôle, CCND2 et CDK4, est impliquée de façon significative dans le développement de cette tumeur. Ces deux gènes sont localise s sur le chromosome 12 (12p13 et 12q13), chromosome peu étudié jusqu'à présent bien que dupliqué dans 20 % des néphroblastomes. La recherche des mécanismes de surexpression de CCND2 et CDK4 m'a permis d'identifier une augmentation du nombre de copies de l'un ou des deux gènes dans 61 % des tumeurs, soit par duplication de l'un des chromosomes 12, soit par amplification conjointe et clonale de régions du 12p et du 12q. Il s'agit de la première description d'un tel mécanisme dans le néphroblastome. Ces anomalies génomiques ne sont pas associées à la surexpression de CCND2 et CDK4, indiquant qu'ils ne sont pas les "cibles" des amplicons. En revanche, j'ai montré une corrélation significative entre l'amplification des régions 12p13 et 12q13 et le décès des patients (p=0,02). Les anomalies du chromosome 12 semblent donc constituer une étape critique dans la progression tumorale et se révèlent beaucoup plus fréquentes que précédemment rapportées. L'identification des gènes conférant un risque de décès et l'établissement de profils moléculaires à valeur pronostique permettra, à terme, un traitement personnalisé des patients.Nephroblastoma, or Wilms' tumor (WT), is one of the most frequent pediatric solid tumors, but little is known about the genetic events involved. By differential gene expression analyses between tumors and normal kidneys, I demonstrated that alteration at the G1/S cell cycle control point, via a specific overexpression of the CCND2 and CDK4 genes, is of biological significance in WTs. These genes map on chromosome 12, at 12p13 and 12q13 respectively. Although trisomy 12 is one of the most frequent alterations in WTs (20% of cases), the underlying mechanisms remained unstudied in this tumor. To investigate the molecular mechanisms responsible for CCND2 and CDK4 overexpression, I quantified CCND2 and CDK4 copy numbers. Overrepresentation of these sequences was shown in 61% of the tumors, either by chromosome 12 duplication, or by clonal amplification of both 12p and 12q regions. This is the first evidence of such a mechanism in WT. CCND2 and CDK4 overexpression and genomic abnormalities were not associated, indicating that these genes are not the targets of the amplification process. Interestingly, statistical analyses highlighted a significant correlation between amplification of both the 12p13 and 12q13 regions and fatal outcome (p=0.02). These results strongly suggest that chromosome 12 is a relevant actor in nephroblastoma. Identification of the genes associated with an increased risk of death and establishment of molecular profiles with a prognostic value will allow, at end, a customized treatment.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF
Vers la caractérisation de deux mécanismes pour le néphroblastome
Le néphroblastome, ou tumeur de Wilms, est une tumeur d'origine embryonnaire dans laquelle coexistent, en proportions variables, les différents types cellulaires du rein en différenciation : blastème, tubes et glomérules, ainsi que du stroma. Mon travail de thèse a consisté à préciser la caractérisation des néphroblastomes et d'améliorer la compréhension des mécanismes associés. J'ai tout d'abord réalisé l'analyse d'une série de 60 tumeurs, en combinant la recherche de mutations et l'analyse de l'expression des gènes WT1 et CTNNB1 avec l'analyse pangénomique des profils transcriptionnels et génomiques. J'ai ainsi confirmé l'existence de deux classes bien distinctes de néphroblastome présentant des profils transcriptionnels et génomiques spécifiques. Puis j'ai élaboré un modèle cellulaire de néphroblastome. Enfin, nous avons identifié des mutations de WTX dans 16 % de ces tumeurs et nous avons confirmé qu'elles sont indépendantes des mutations de WT1/CTNNB1 et associées au mauvais pronostic.Based on a tumor classification that took into account both genomic and expression status of WTl,beta-catenin and WTX, combined with genome-wide expression and genomic profiling analyses, we present the first molecular evidence that dysregulation of the Wnt pathway occurs in all tumors, with and without CTNNB1 mutations. Our strategy of sample class comparison including comparisons with control samples allowed us to identified two sets of target genes, one specific of tumors with WTl/beta-catenin alterations and one common to all tumors. We present evidence that activation of the Wnt pathway in absence ofCTNNBl mutations is not restricted to rumors with WTX mutations. By genome transcriptome correlation analysis, we identified genes encoding Wnt pathway regulators (BCL9, CTNNBIP1 and CBY1) whose dysregulation in tumors with chromosomal gain or losses could participate in Wnt pathway activation. Finally, we present data suggesting the prognostic value of WTX mutations.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF
Recherche de nouveaux marqueurs de progression tumorale dans le néphroblastome
LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF
Nephrocystins play a crucial role in renal epithelial morphogenesis via the regulation of Wnt/PCP components Dishevelled and Rho GTPases
International audienc