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

International audienc

Surexpression de la protéine PAR-3 : facteur de mauvais pronostic dans le carcinome rénal à cellules claires (ccRCC)

National audienceno abstrac

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

International audienc

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