Étude du profil histologique et moléculaire des carcinomes rénaux à cellules claires et leurs métastases

National audienceLe carcinome rénal à cellules claires (CCCR) est la forme histologique la plus fréquente des cancers du rein. Au cours de l’évolution, si le patient progresse sous traitement, les métastases sont rarement biopsiées. Leur profil phénotypique et moléculaire par rapport à la tumeur d’origine est mal connu. Trois patients ayant un CCCR opéré par néphrectomie totale ou partielle, avec métastase synchrone ou métachrone (hépatique, ganglionnaire, et pulmonaire) ont été inclus rétrospectivement. Les prélèvements tumoraux ont été analysés sur le plan histologique, immuno-histochimique (VEGF-A, CD31-AML, Ki67, p53 et PAR-3), cytogénétique (ACPA, FISH), et moléculaire (NGS : statut du gène VHL : délétion, mutation et/ou hyperméthylation du promoteur). L’aspect histologique et immuno-histochimique des métastases était superposable à la composante de plus haut grade de la tumeur primitive, toutes les tumeurs étant de grade 4 de Fuhrman. Les analyses par FISH et NGS ont mis en évidence une délétion hétérozygote du gène VHL et la présence de la même mutation dans chacun des couples tumeur primitive/métastase, sans hyperméthylation du promoteur. L’ACPA a comparé l’ADN des métastases à celui des tumeurs primitives et a montré des profils chromosomiques distincts. Par rapport à leur tumeur primitive, un gain en 3q22 (environ 1 Mb) a été retrouvé dans les métastases de tous les patients. Cette région contient des gènes (PPP2R3A, STAG1, MSL2, NCK1, TMEM22) qui pourraient être impliqués dans la prolifération des cellules tumorales et/ou dissémination métastatique. En particulier, la surexpression de la protéine TMEM22 a été décrite comme favorisant la croissance des cellules des carcinomes rénaux à cellules claires. Ce travail confirme que le profil chromosomique des métastases des CRCC est distinct de celui des tumeurs primitives. Des études complémentaires sont en cours pour préciser l’implication de gènes de la région 3q22 dans le potentiel métastatique des CRC

Understanding the Pathophysiology of Intracranial Aneurysm: The ICAN Project

International audienceBACKGROUND: Understanding the pathophysiologic mechanism of intracranial aneurysm (IA) formation is a prerequisite to assess the potential risk of rupture. Nowadays, there are neither reliable biomarkers nor diagnostic tools to predict the formation or the evolution of IA. Increasing evidence suggests a genetic component of IA but genetics studies have failed to identify genetic variation causally related to IA.OBJECTIVE: To develop diagnostic and predictive tools for the risk of IA formation and rupture.METHODS: The French ICAN project is a noninterventional nationwide and multicentric research program. Each typical IA of bifurcation will be included. For familial forms, further IA screening will be applied among first-degree relatives. By accurate phenotype description with high-throughput genetic screening, we aim to identify new genes involved in IA. These potential genetic markers will be tested in large groups of patients. Any relevant pathway identified will be further explored in a large cohort of sporadic carriers of IA, which will be well documented with clinical, biological, and imaging data.EXPECTED OUTCOMES: Discovering genetic risk factors, better understanding the pathophysiology, and identifying molecular mechanisms responsible for IA formation will be essential bases for the development of biomarkers and identification of therapeutic targets.DISCUSSION: Our protocol has many assets. A nationwide recruitment allows for the inclusion of large pedigrees with familial forms of IA. It will combine accurate phenotyping and comprehensive imaging with high-throughput genetic screening. Last, it will enable exploiting metadata to explore new pathophysiological pathways of interest by crossing clinical, genetic, biological, and imaging information

Rare coding variants in CTSO , a potential new actor of arterial remodeling, are associated to familial intracranial aneurysm

Background Intracranial aneurysm (IA) is a common cerebrovascular abnormality characterized by localized dilation and wall thinning in intracranial arteries, that frequently leads to fatal vascular rupture. The mechanisms underlying IA formation, growth and rupture are mostly unknown, and while increasing evidence suggest a genetic component of IA, identification of specific genes or causal molecular pathways remains largely inconclusive and only a small fraction of the risk attributable to genetics for IA in the general population. Methods: Here, we combined whole exome sequencing and identity-by -descent analyses with functional investigations to identify rare IA predisposing variants in familial forms of IA and understand their contribution to the pathophysiology of IA. Results We identified two rare missense variants in the CTSO gene shared by all the affected relatives in two large pedigrees with multiple IA-affected relative. CTSO encodes for the cysteine-type papain-like cathepsin CTSO. Functional analyses revealed that CTSO acts as an extracellular protease controlling vascular smooth muscle cell migration and adhesion to the extracellular matrix. CTSO depletion, as well as expression of the two CTSO variants, which were poorly secreted, led to increase the amount of fibronectin. This effect is associated with a marked increase in VSMC stiffness which was rescued by exogenous CTSO. Conclusions This report identifies rare CTSO variants in familial IA patients and suggests that the increased susceptibility to IA induced by these variants is likely related to their primary effects on the vascular tissue, and more particularly on the media layer of the wall of cerebral arteries

Successful Thrombectomy Improves Functional Outcome in Tandem Occlusions with a Large Ischemic Core

International audienceBackground: Emergent stenting in tandem occlusions and mechanical thrombectomy (MT) of acute ischemic stroke related to large vessel occlusion (LVO-AIS) with a large core are tested independently. We aim to assess the impact of reperfusion with MT in patients with LVO-AIS with a large core and a tandem occlusion and to compare the safety of reperfusion between large core with tandem and nontandem occlusions in current practice. Methods: We analyzed data of all consecutive patients included in the prospective Endovascular Treatment in Ischemic Stroke Registry in France between January 2015 and March 2023 who presented with a pretreatment ASPECTS (Alberta Stroke Program Early CT Score) of 0–5 and angiographically proven tandem occlusion. The primary end point was a favorable outcome defined by a modified Rankin Scale (mRS) score of 0–3 at 90 days. Results: Among 262 included patients with a tandem occlusion and ASPECTS 0–5, 203 patients (77.5%) had a successful reperfusion (modified Thrombolysis in Cerebral Infarction grade 2b-3). Reperfused patients had a favorable shift in the overall mRS score distribution (adjusted odds ratio [aOR], 1.57 [1.22–2.03]; P < 0.001), higher rates of mRS score 0–3 (aOR, 7.03 [2.60–19.01]; P < 0.001) and mRS score 0–2 at 90 days (aOR, 3.85 [1.39–10.68]; P = 0.009) compared with nonreperfused. There was a trend between the occurrence of successful reperfusion and a decreased rate of symptomatic intracranial hemorrhage (aOR, 0.5 [0.22–1.13]; P = 0.096). Similar safety outcomes were observed after large core reperfusion in tandem and nontandem occlusions. Conclusions: Successful reperfusion was associated with a higher rate of favorable outcome in large core LVO-AIS with a tandem occlusion, with a safety profile similar to nontandem occlusion