Aggregation dynamics and identification of aggregation-prone mutants of the von Hippel-Lindau tumor suppressor protein

International audienceQuality control mechanisms promote aggregation and degradation of misfolded proteins. In budding yeast, the human von Hippel-Lindau protein (pVHL, officially known as VHL) is misfolded and forms aggregates. Here, we investigated the aggregation of three pVHL isoforms (pVHL213, pVHL160, pVHL172) in fission yeast. The full-length pVHL213 isoform aggregates in highly dynamic small puncta and in large spherical inclusions, either close to the nucleus or to the cell ends. The large inclusions contain the yeast Hsp104 chaperone. Aggregate clearance is regulated by proteasomal degradation. The pVHL160 isoform forms dense foci and large irregularly shaped aggregates. In silico, prediction of pVHL aggregation propensity identified a key aggregation-promoting region within exon 2. Consistently, the pVHL172 isoform, which lacks exon 2, formed rare reduced inclusions. We studied the aggregation propensity of pVHL variants harbouring missense mutations found in kidney carcinomas. We show that the P86L mutation stimulated small aggregate formation, the P146A mutation increased large inclusion formation, whereas the I151S mutant destabilized pVHL. The prefoldin subunit Pac10 (the human homolog VBP-1 binds to pVHL) is required for pVHL stability. Reduction of soluble functional pVHL might be crucial in VHL-related diseases

Système rénine-angiotensine et cancers urologiques / Renin-angiotensin system and urological cancers.

International audienceIntroduction: A controversy animates the literature on the potential role of the rennin-angiotensin system (RAS) in tumorogenesis. The objective of this review was to determine the involvement of this pathway in cancer, and more specifically in urological cancers. Material and Method: We made a systematic review of articles referenced in Pubmed, using the following keywords alone or combined: cancer, renin, angiotensin, VEGF, AT1R, antagonists of angiotensin-2 receptors, inhibitors of angiotensinogen converting. Results: Many types of cancers overexpress AT1-R in their tumoral tissues (breast, stomach, bladder, astrocytoma, glioblastoma, ovary, uterus, pancreas, kidney, prostate, adrenal gland). Ang-II can induce VEGF-A expression and promote neoangiogenesis, but also can trigger different molecular pathways involved in cell proliferation or inhibit apoptosis. Several xenograft murin models demonstrated anti-tumoral efficacy of RAS blockers, alone or using combined therapies, targeting angiogenesis and slowing down tumor growth. Retrospective studies in patients have also revealed a better progression-free survival and a better response to therapies in those treated with RAS blockers. Conclusion: Many data seem to demonstrate the involvement of the RAS in carcinogenesis, as well as anti-tumoral effect of RAS blockers in addition to anti-cancer treatments. Clinical data are now expected to confirm these experimental findings

Cytogénétique des carcinomes rénaux [Cytogenetics profiles of renal carcinoma]

National audienc

Pretransplant renal function according to CKD-EPI cystatin C equation is a prognostic factor of death after liver transplantation

International audienceBackground & aims - In patients with cirrhosis, cystatin C (CystC) based equations may be more accurate indicators of glomerular filtration rate (GFR) than creatinine (Pcr) based equations. Renal function before liver transplantation (LT) is thought to impact survival after LT. We aimed at assessing pretransplant creatinine and CystC based equations with respect to their predictive value on long-term survival after LT. Methods - From 2001 to 2011, CystC was determined at pre-LT evaluation in 682 patients together with GFR assessed using MDRD-4, MDRD-6, CKD-EPI-cystatin C, CKD-EPI-creatinine and CKD-EPI-creatinine-cystatin C equations. Patients were classified according to the Kidney Disease Outcomes Quality Initiative classification (KDOQI). Results - Median age at LT was 55 [49-60] years with a median MELD score of 13.5 [8.3-19.2] and a median post-transplant follow-up of 60 [26-89] months. Using CKD-EPI Cystatin C and the KDOQI classification, 21.1% of patients were stage 1, 43.1% stage 2, 29.1% stage 3 and 6.5% stage 4. Kaplan-Meier survival estimates were significantly different between KDOQI stages when determined using the CKD-EPI-CystatinC equation. This was not the case when using the other equations. At multivariate analysis, GFR and KDOQI estimated using the CKD-EPI-CystatinC equation were significantly associated with death (HR: 0.992; CI95%: 0.986-0.999 and 1.24; CI95%: 1.02-1.50 respectively). When assessed using the MDRD-4, MDRD-6, CKD-EPI-Creatinine-CystatinC and CKD-EPI-Creatinine equations GFR was not significantly associated with death. Conclusions - Estimated pre-LT renal function is predictive of post-LT survival only when assessed using the CKD-EPI cystatin C equation. This supports the use of Cystatine C and of its related equation for the assessment of renal function before liver transplantation

Cytoplasmic PAR-3 protein expression is associated with adverse prognostic factors in clear cell renal cell carcinoma and independently impacts survival.

International audienceClear cell renal cell carcinomas (ccRCCs) represent 70% of renal cancers, and several clinical and histolopathological factors are implicated in their prognosis. We recently demonstrated that the overexpression of PAR-3 protein encoded by the PARD3 gene could be implicated in renal oncogenesis. The object of this work was to study the association of intratumoral PAR-3 expression with known prognostic parameters and clinical outcome. In this aim, PAR-3 expression was assessed by immunohistochemistry in ccRCC tumors of 101 patients from 2003 to 2005. The immunostaining of PAR-3 was scored either as membranous (mPAR-3) or as both membranous and cytoplasmic (cPAR-3). Cytoplasmic PAR-3 was significantly associated with worse histopathological and clinical prognostic factors: Fuhrman grades 3 and 4, tumor necrosis, sarcomatoid component, adrenal invasion, renal and hilar fat invasion, eosinophilic component, a noninactivated VHL gene, higher tumor grade, lymph node involvement, metastasis, and worse clinical Eastern Cooperative Oncology Group and S classification scores. After multivariate analysis, 2 parameters were independently associated with cPAR-3: necrosis and eosinophilic components. In addition, cPAR-3 patients had shorter overall and progression-free survivals independently from strong prognostic validated factors like metastases. A cytoplasmic expression of PAR-3 is therefore implicated in worse clinical and pathological cancer features in ccRCC and could be useful to identify patients with high-risk tumors

Wild-type VHL Clear Cell Renal Cell Carcinomas Are a Distinct Clinical and Histologic Entity: A 10-Year Follow-up

International audienceBackground: Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor with 50% risk of metastases at initial diagnosis or at follow-up. An inactivation of the tumor-suppressor gene von Hippel-Lindau (VHL) is present in >70% of sporadic cases by two of three different mechanisms: locus deletion, gene mutation, or promoter hypermethylation. Objective: To correlate the complete status of the VHL gene with clinical and pathologic criteria. Design, setting, and participants We retrospectively included 98 patients with ccRCC who underwent surgery between 2002 and 2005. VHL gene deletions (71 of 98; 72.4%), mutations (68 of 98; 69.4%), and promoter hypermethylations (13 of 98; 13.3%) were screened by gene copy analysis, gene sequencing, and methylation-specific multiplex ligation-dependent probe amplification, respectively. Outcome measurements and statistical analysis Relationships between VHL subgroups and the studied criteria were analyzed using chi-square and Student t tests. Survival was analyzed with the log-rank test and Kaplan-Meier curves. Results and limitations: Compared with ccRCCs with two events (66.3%), tumors with no or one genetic event (33.6%) were associated with a higher nuclear grade IV (p = 0.02), metastases (p = 0.04), sarcomatoid component (p = 0.01), dense lymphocyte infiltrate (p = 0.013), and vascular endothelial growth factor overexpression (>30%) (p = 0.003), which was also an independent factor after multivariate analysis. Furthermore, wild-type VHL tumors (no inactivating event, 11.2%) were associated with nodal involvement (p = 0.019), and patients with this type of tumor had a specific survival of 33 mo compared with patients with ccRCCs having one or two VHL inactivating events (107 mo; p = 0.016). The retrospective design with small number of wild-type tumors was a limitation of this work. Conclusions: This long-term study (10-yr clinical follow-up) confirms that ccRCCs with wild-type VHL are highly aggressive tumors that need to be formally identified. Patient summary Among activated VHL tumors, the wild-type subgroup defines an aggressive phenotype with worse survival rates, suggesting that these tumors must be more thoroughly screene

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National audienc

Avancées thérapeutiques dans la prise en charge de l'insuffisance rénale chronique. [Therapeutic advances in the management of chronic renal insufficiency]

International audienc

Facteurs pronostiques de l'infarctus rénal

Soixante-treize infarctus rénaux survenus sur une période de 15 ans ont été analysés de manière rétrospective. Les étiologies étaient principalement la fibrillation atriale et la dissection de l'artère rénale. Un débit de filtration glomérulaire abaissé au diagnostic était le principal risque d'insuffisance rénale à long terme. La nécessité de dialyse au diagnostic était un facteur de risque de mortalité. Le volume de l'infarctus n'apparaissait pas comme un facteur de risque d'insuffisance rénale chronique secondaire.We retrospectively reviewed the course of 73 Acute Renal Infarction in a 15-years period. Etiologies were mainly embolism from atrial fibrillation and renal artery dissection. Low-GFR at diagnosis was the major risk factor for long-term renal insufficiency. Dialysis dependence at diagnosis was a risk factor for mortality. Volume of infarction did not seem to be a risk factor for long-term renal insufficiency.RENNES1-BU Santé (352382103) / SudocSudocFranceF