Angiotensin-2 receptors (AT1-R and AT2-R), new prognostic factors for renal clear-cell carcinoma?

International audienceBackground: The growth factor Angiotensin-2 signals through Angiotensin receptor type 1 (AT1-R) in a broad range of cell types and tumours and through the type-2 receptor (AT2-R) in a more restricted group of cell types. Although numerous forms of cancer have been shown to overexpress AT1-R, expression of AT1-R and AT2-R by human renal clear-cell carcinoma (RCCC) is not well understood. In this study, the expression of both angiotensin receptors was quantified in a retrospective series of RCCC and correlated with prognostic factors.Methods: Angiotensin receptor type 1 and AT2-R expressions were quantified on tumour tissues by immunohistochemistry (IHC), western blot and quantitative reverse transcriptase PCR (qRT–PCR). IHC results were correlated to Fuhrman's grade and patient progression-free survival (PFS).Results: A total of 84 RCCC were analysed. By IHC, AT1-R and AT2-R were expressed to a greater level in high-grade tumours (AT1-R: P<0.001, AT2-R: P<0.001). Univariate analysis showed a correlation between PFS and AT1-R or AT2-R expression (P=0.001). By multivariate analysis, only AT2-R expression correlated with PFS (HR 1.021, P=0.006) and cancer stage (P<0.001). By western blot, AT1-R and AT1-R were also found to be overexpressed in higher Fuhrman's grade (P<0.01 and P=0.001 respectively). By qRT–PCR, AT1-R but not AT2-R mRNA were downregulated (P=0.001 and P=0.118, respectively).Conclusion: Our results show that AT1-R and AT2-R proteins are overexpressed in the most aggressive forms of RCCC and that AT2-R expression correlates with PFS. AT1-R or AT2-R blockage could, therefore, offer novel directions for anti-RCCC therapy

Genomic profiling using array comparative genomic hybridization define distinct subtypes of diffuse large b-cell lymphoma: a review of the literature

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin Lymphoma comprising of greater than 30% of adult non-Hodgkin Lymphomas. DLBCL represents a diverse set of lymphomas, defined as diffuse proliferation of large B lymphoid cells. Numerous cytogenetic studies including karyotypes and fluorescent in situ hybridization (FISH), as well as morphological, biological, clinical, microarray and sequencing technologies have attempted to categorize DLBCL into morphological variants, molecular and immunophenotypic subgroups, as well as distinct disease entities. Despite such efforts, most lymphoma remains undistinguishable and falls into DLBCL, not otherwise specified (DLBCL-NOS). The advent of microarray-based studies (chromosome, RNA, gene expression, etc) has provided a plethora of high-resolution data that could potentially facilitate the finer classification of DLBCL. This review covers the microarray data currently published for DLBCL. We will focus on these types of data; 1) array based CGH; 2) classical CGH; and 3) gene expression profiling studies. The aims of this review were three-fold: (1) to catalog chromosome loci that are present in at least 20% or more of distinct DLBCL subtypes; a detailed list of gains and losses for different subtypes was generated in a table form to illustrate specific chromosome loci affected in selected subtypes; (2) to determine common and distinct copy number alterations among the different subtypes and based on this information, characteristic and similar chromosome loci for the different subtypes were depicted in two separate chromosome ideograms; and, (3) to list re-classified subtypes and those that remained indistinguishable after review of the microarray data. To the best of our knowledge, this is the first effort to compile and review available literatures on microarray analysis data and their practical utility in classifying DLBCL subtypes. Although conventional cytogenetic methods such as Karyotypes and FISH have played a major role in classification schemes of lymphomas, better classification models are clearly needed to further understanding the biology, disease outcome and therapeutic management of DLBCL. In summary, microarray data reviewed here can provide better subtype specific classifications models for DLBCL

Gene dosage effects in 46, XY DSD: usefulness of CGH technologies for diagnosis

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Aide médicale à la procréation, malformations congénitales et santé postnatale

International audienceInfertility is considered as a major public health issue and the use of infertility treatments is increasing. Each year, 200,000 children worldwide and approximately 1 in 30 in France are born using assisted reproductive technologies (ART). The overall incidence of congenital malformations, including major features, is increasing in these children compared to the data observed in spontaneous pregnancies. The specific risk for congenital malformation is also increased and concerns mainly congenital heart defects, urogenital, nervous system, and musculoskeletal malformations. Risk of imprinting-related diseases appears also increased in children conceived by ART. ART itself may be implicated; nevertheless, other factors must be considered such as advanced age, factors leading to infertility, and way of life. The impact of ART on individual health is a major concern, particularly with the new French Bioethics law, which offers wider access to this procedure, and will inevitably result in an increased number of pregnancies conceived by ART. The pursuit of research on ART and their consequences on the health of children seems essential, and the data arising from the regional registers of congenital malformations could bring some help in this direction.L’infertilité est considérée comme un problème de santé publique majeur, et le recours aux traitements de l’infertilité est en augmentation. Chaque année, 200 000 enfants naissent dans le monde et 1 enfant sur 30 en France grâce aux techniques d’assistance médicale à la procréation (AMP). L’incidence globale des malformations congénitales (MC), y compris les formes majeures, semble augmentée chez ces enfants par rapport à celle observée chez les enfants conçus spontanément. Le risque malformatif spécifique est également augmenté avec notamment l’implication des systèmes cardiovasculaire, urogénital, nerveux et musculosquelettique. Le risque de maladies liées à l’empreinte parentale apparaît également plus élevé chez les enfants conçus par AMP. Les techniques d’AMP pourraient avoir un impact délétère. Néanmoins, d’autres facteurs sont à prendre en compte tels que l’âge parental avancé, les facteurs à l’origine de l’infertilité et le mode de vie. L’impact de l’AMP sur la santé des individus qui en sont issus est une préoccupation majeure, notamment avec l’arrivée de la nouvelle loi de bioéthique qui ouvre un accès élargi à cette procédure et qui se traduira inévitablement par une augmentation du nombre de grossesses conçues par AMP. La poursuite des recherches sur les différentes techniques d’AMP et leurs conséquences sur la santé des enfants paraît indispensable, les données issues des registres régionaux des MC pourraient apporter une aide en ce sens

Le carcinome rénal à cellules claires (CRCC) sans altération du gène de Von Hippel-Lindau (VHL) : une entité anatomo-clinique à part ?

National audienceObjectifs Le CRCC est caractérisé par une inactivation du gène suppresseur de tumeur VHL dans plus de 70 % des cas. La voie VHL/HIF est une voie principale d’oncogenèse aboutissant lorsque VHL est inactivé à une surexpression de gènes cibles pro-angiogéniques. L’objectif est de corréler le statut complet de VHL 1/aux critères anatomopathologiques, 2/à l’expression intra-tumorale de VEGF et 3/au suivi clinique des patients. Méthodes 98 CRCC opérés entre 2002 et 2005 ont été inclus rétrospectivement avec un suivi moyen de 10,5 ans. Dix critères histopronostiques et l’expression en immunohistochimie de VEGFA ont été étudiés. À partir des prélèvements congelés, la recherche de délétion de VHL par analyse de copies du gène (MLPA), de mutation de VHL par séquençage, d’une méthylation de son promoteur par MS-MLPA a été menée. Résultats Les CRCC présentaient une délétion, une mutation et/ou une méthylation du promoteur dans respectivement 72,4 %, 69,4 % et 14,2 % des cas, méthylation et mutation étant mutuellement exclusives. 33,6 % des CRCC avaient 0 ou 1 altération de VHL contre 66,3 % avec 2 anomalies. Ces CRCC étaient associés à un grade de Furhman 4 (p = 0,039), aux métastases synchrones (p = 0,043) et à une surexpression de VEGFA \textgreater 50 % (p = 0,003). De plus, les CRCC sans aucune anomalie de VHL (11,2 % de cas) étaient associés à une composante sarcomatoïde \textgreater 20 % (p \textless 0,001) et aux métastases ganglionnaires (p = 0,019), avec une survie spécifique de 33 mois comparés aux CRCC avec 1 ou 2 altérations de VHL (107 mois, p = 0,016). Conclusion Il s’agit de la première étude menée avec un suivi de 10 ans corrélant dans le CRCC le statut complet de VHL avec des critères anatomopathologiques et de suivi clinique. Nous montrons que les CRCC sans aucune altération de VHL sont des tumeurs hautement agressives, qu’il convient d’isole

Prenatal diagnosis of isolated Congenital Heart Defects: results of a prospective study genome-wide high resolution array-CGH versus karyotyping and 22q11 FISH

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Metastatic Clear-cell Renal Cell Carcinoma With a Long-term Response to Sunitinib A Distinct Phenotype Independently Associated With Low PD-L1 Expression

International audienceBACKGROUND: Long-term responders (LTRs) are defined by at least 18 months of response to sunitinib in metastatic clear-cell renal cell carcinoma (ccRCC). Well-described by clinical studies, the phenotype of these tumors has never been explored.PATIENTS AND METHODS: In a retrospective and multicenter study, 90 ccRCCs of patients with metastatic disease were analyzed. Immunohistochemistry (carbonic anhydrase IX, vascular endothelial growth factor, c-MET, programmed death-ligand 1 [PD-L1], and PD-1) and VHL status were performed. Progression-free survival and overall survival were calculated from sunitinib introduction and from progression. LTRs and their corresponding tumors were compared with others using univariate and multivariate analysis.RESULTS: Twenty-eight patients were LTRs. They had a median progression-free survival of 28 months versus 4 months for other patients (P < .001). Similarly, LTRs had a median overall survival of 49 months versus 14 months (P < .001), even from progression (median, 21 vs. 7 months; P = .029). They were associated with a favorable or intermediate risk (International Metastatic Renal Cell Carcinoma Database Consortium model) (P = .007) and less liver metastasis (P = .036). They experienced more frequent complete or partial responses at the first radiologic evaluation (P = .035). The corresponding ccRCCs were associated with less nucleolar International Society for Urological Pathology grade 4 (P = .037) and hilar fat infiltration (P = .006). They were also associated with low PD-L1 expression (P = .02). Only the International Metastatic Renal Cell Carcinoma Database Consortium model and PD-L1 expression remained significant after multivariate analysis (P = .014 and P = .029, respectively).CONCLUSION: Primary tumor characteristics of LTRs were studied for the first time and demonstrated a different phenotype. Interestingly, they were characterized by low expression of PD-L1, suggesting a potentially lower impact of targeted immunotherapy in these patients