Luis Jaime Castro-Vega, M.D., Ph.D. - Paris - Cardiovascular Research Center - Postdoctoral Fellow

Luis Jaime Castro-Vega

M.D., Ph.D.

Paris - Cardiovascular Research Center

Postdoctoral Fellow

Paris | France

Main Specialties: Oncology

Additional Specialties: Molecular Oncology

Luis Jaime Castro-Vega, M.D., Ph.D. - Paris - Cardiovascular Research Center - Postdoctoral Fellow

Luis Jaime Castro-Vega

M.D., Ph.D.

Introduction

Primary Affiliation: Paris - Cardiovascular Research Center - Paris , France

Specialties:

Additional Specialties:

Publications

22Publications

1227Reads

199Profile Views

Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma.

J Med Genet 2019 Aug 15;56(8):513-520. Epub 2019 Mar 15.

Genetics department, Assistance Publique-Hôpitaux de Paris, Hôpitaleuropéen Georges Pompidou, F-75015, Paris, France.

Background: Knowing the genetic status of patients affected by paragangliomas and pheochromocytomas (PPGL) is important for the guidance of their management and their relatives. Our objective was to improve the diagnostic performances of PPGL genetic testing by next-generation sequencing (NGS).

Methods: We developed a custom multigene panel, which includes 17?PPGL genes and is compatible with both germline and tumour DNA screening. The NGS assay was first validated in a retrospective cohort of 201 frozen tumour DNAs and then applied prospectively to 623 DNAs extracted from leucocytes, frozen or paraffin-embedded PPGL tumours.

Results: In the retrospective cohort, the sensitivity of the NGS assay was evaluated at 100% for point and indels mutations and 86% for large rearrangements. The mutation rate was re-evaluated from 65% (132/202) to 78% (156/201) after NGS analysis. In the prospective cohort, NGS detected not only germline and somatic mutations but also co-occurring variants and mosaicism. A mutation was identified in 74% of patients for whom both germline and tumour DNA were available.

Conclusion: The analysis of 824 DNAs from patients with PPGL demonstrated that NGS assay significantly improves the performances of PPGL genetic testing compared with conventional methods, increasing the rate of identified mutations and identifying rare genetic mechanisms.

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http://dx.doi.org/10.1136/jmedgenet-2018-105714DOI Listing
August 2019
11 Reads
6.335 Impact Factor

Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma.

Theranostics 2019 9;9(17):4946-4958. Epub 2019 Jul 9.

Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through models, and define specific therapeutic options according to tumor genomic features. : We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized . : A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients' liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, =4.67·10), and was found associated with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated a repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. : Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients' management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors.

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http://dx.doi.org/10.7150/thno.35458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691382PMC
July 2019
8.000 Impact Factor

Emerging molecular markers of metastatic pheochromocytomas and paragangliomas.

Ann Endocrinol (Paris) 2019 Jun 11;80(3):159-162. Epub 2019 Apr 11.

Inserm, UMR970, équipe labellisée Ligue Contre le Cancer, Paris-Cardiovascular Research Center, 75015 Paris, France; Faculté de médecine, PRES Sorbonne Paris-Cité, Paris-Descartes University, 75006 Paris, France. Electronic address:

Metastatic pheochromocytoma/paraganglioma (PPGL) represents a major clinical challenge due to limitations in accurate diagnostic tools and effective treatments. Currently, patients classified at high-risk by means of clinical, biochemical and genetic criteria, require a lifelong monitoring, while it remains difficult to determine the metastatic potential of PPGL only on the basis of histopathological features. Thus, tumor molecular markers that improve the risk stratification of these patients are needed. In the past few years, we have witnessed an unprecedented molecular characterization of PPGL, which led to the emergence of promising candidate biomarkers predictive of metastatic behavior. Here, we briefly discuss these breakthroughs and provide some insights for the prospective implementation of molecular markers of metastatic PPGL in the clinical setting in years to come.

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http://dx.doi.org/10.1016/j.ando.2019.04.003DOI Listing
June 2019
61 Reads
1.444 Impact Factor

Telomerase Activation and ATRX Mutations Are Independent Risk Factors for Metastatic Pheochromocytoma and Paraganglioma.

Clin Cancer Res 2019 Jan 9;25(2):760-770. Epub 2018 Oct 9.

INSERM, UMR970, Paris-Cardiovascular Research Center, Equipe Labellisée par la Ligue contre le Cancer, Paris, France.

Purpose: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors. Whereas most PPGLs are benign, up to 20% may become metastatic with - and -mutated tumors showing the higher risk. We aimed at determining the contribution of immortalization mechanisms to metastatic progression. Immortalization mechanisms were investigated in 200 tumors. To identify telomerase (+) tumors, we analyzed genomic alterations leading to transcriptional activation of comprising promoter mutations, hypermethylation and gain copy number. To identify tumors that activated the alternative lengthening of telomere (ALT) mechanism, we combined analyses of telomere length by slot blot, telomere heterogeneity by telomere FISH, and mutations by next-generation sequencing. Univariate/multivariate and metastasis-free survival (MFS) and overall survival (OS) analyses were carried out for assessment of risk factors and clinical outcomes.

Results: Only 37 of 200 (18.5%) tumors achieved immortalization. Telomerase activation occurred in 12 metastatic tumors and was prevalent in -mutated paragangliomas ( = 2.42e-09). ALT features were present in 25 tumors, mostly pheochromocytomas, regardless of metastatic status or molecular group ( = 0.169), yet mutations were found preferentially in -mutated metastatic tumors ( = 0.0014). Telomerase activation and mutations were independent factors of poor prognosis: MFS (hazard ratio, 48.2 and 33.1; = 6.50E-07 and 1.90E-07, respectively); OS (hazard ratio, 97.4 and 44.1; = 4.30E-03 and 2.00E-03, respectively) and were associated with worse MFS and OS (log-rank tests < 0.0001).

Conclusions: Assessment of telomerase activation and mutations could be used to identify metastatic PPGLs, particularly in tumors at high risk of progression.

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http://dx.doi.org/10.1158/1078-0432.CCR-18-0139DOI Listing
January 2019
111 Reads
10.199 Impact Factor

Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier Gene Confer a Predisposition to Metastatic Paragangliomas.

Cancer Res 2018 04 5;78(8):1914-1922. Epub 2018 Feb 5.

INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; Equipe labellisée Ligue contre le Cancer.

Comprehensive genetic analyses have identified germline and gene mutations as predominant causes of metastatic paraganglioma and pheochromocytoma. However, some suspicious cases remain unexplained. In this study, we performed whole-exome sequencing of a paraganglioma exhibiting an -like molecular profile in the absence of or mutations and identified a germline mutation in the gene, which encodes the mitochondrial 2-oxoglutarate/malate carrier. Germline mutations were identified in six other patients, five of whom had metastatic disease. These mutations were associated with loss of heterozygosity, suggesting that acts as a tumor-suppressor gene. Pseudohypoxic and hypermethylator phenotypes comparable with those described in - and -related tumors were observed both in tumors with mutated and in immortalized mouse chromaffin knockout cells generated by CRISPR-Cas9 technology. These data show that is a novel paraganglioma susceptibility gene for which loss of function correlates with metastatic presentation. A gene encoding a mitochondrial carrier is implicated in a hereditary cancer predisposition syndrome, expanding the role of mitochondrial dysfunction in paraganglioma. .

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http://dx.doi.org/10.1158/0008-5472.CAN-17-2463DOI Listing
April 2018
32 Reads
9.329 Impact Factor

Primary mediastinal large B-cell lymphoma: transcriptional regulation by miR-92a through FOXP1 targeting.

Oncotarget 2017 Mar;8(10):16243-16258

Université-Paris-Diderot, Sorbonne-Paris-Cité, Laboratoire de Pathologie, UMR-S-1165, Paris, France.

Background: Primary mediastinal large B-cell lymphoma (PMBL) shares pathological features with diffuse large B-cell lymphoma (DLBCL), and molecular features with classical Hodgkin lymphoma (cHL). The miR-17~92 oncogenic cluster, located at chromosome 13q31, is a region that is amplified in DLBCL.

Methods: Here we compared the expression of each member of the miR-17~92 oncogenic cluster in samples from 40 PMBL patients versus 20 DLBCL and 20 cHL patients, and studied the target genes linked to deregulated miRNA in PMBL.

Results: We found a higher level of miR-92a in PMBL than in DLBCL, but not in cHL. A combination of in silico prediction and transcriptomic analyses enabled us to identify FOXP1 as a main miR-92a target gene in PMBL, a result so far not established. This was confirmed by 3'UTR, and RNA and protein expressions in transduced cell lines. In vivo studies using the transduced cell lines in mice enabled us to demonstrate a tumor suppressor effect of miR-92a and an oncogenic effect of FOXP1.A higher expression of miR-92a and the down-regulation of FOXP1 mRNA and protein expression were also found in human samples of PMBL, while miR-92a expression was low and FOXP1 was high in DLBCL.

Conclusions: We concluded to a post-transcriptional regulation by miR-92a through FOXP1 targeting in PMBL, with a clinico-pathological relevance for better characterisation of PMBL.

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http://dx.doi.org/10.18632/oncotarget.12988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369960PMC
March 2017
125 Reads
6.359 Impact Factor

The MITF, p.E318K Variant, as a Risk Factor for Pheochromocytoma and Paraganglioma.

J Clin Endocrinol Metab 2016 12 28;101(12):4764-4768. Epub 2016 Sep 28.

INSERM (L.J.C.-V., S.R.K., N.K., A.B., L.A., N.B.-N., J.F., A.-P.G.-R.), UMR970, Paris-Cardiovascular Research Center, F-75015, Paris, France; Université Paris Descartes (L.J.C.-V., S.R.K., N.B., A.B., L.A., N.B.-N., J.F., A.-P.G.-R.), PRES Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France; Service de Génétique, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (N.B., C.S., A.-P.G.-R.), F-75015, Paris, France; Unité Hypertension artérielle (L.A.), Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, F-75015, Paris, France; Département de Cancérologie endocrinienne and Université Paris-Saclay (A.B., M.S.), Gustave Roussy, Villejuif, F-94805, France; Université Paris 13 (P.G.), Equipe de Recherche en Epidémiologie Nutritionnelle (EREN), Centre d'Epidémiologie et Statistiques Sorbonne Paris Cité, INSERM (U1153), Inra (U1125), Cnam, COMUE Sorbonne Paris Cité, Bobigny; INSERM (B.B.-d.P.), U1186, Université Paris-Sud, Université Paris-Saclay, Villejuif, F-94805, France; Département de Biopathologie (B.B.-d.P.), Gustave Roussy, Villejuif, F-94805, France; and Rare Adrenal Cancer Network COMETE (L.A., A.-P.G.-R.), F-75006, Paris, France.

Context: The microphthalmia-associated transcription factor (MITF) regulates the survival, proliferation, and differentiation of neural crest-derived lineages. Recent studies reported an increased risk of melanoma in individuals carrying the rare variant MITF, p.E318K (rs149617956). Whether this variant plays a role in other neural crest-derived tumors is unknown.

Objective: In the present study, we aimed at determining the prevalence of the MITF, p.E318K variant, in a well-characterized French cohort of pheochromocytomas/paragangliomas (PCC/PGL).

Design And Methods: Genomic DNA from 555 unrelated patients with PCC/PGL was genotyped for the p.E318K variant in MITF using Sanger sequencing.

Main Outcome Measure: The prevalence of the mutation in the PCC/PGL cohort was compared with a population-based sample of 2348 ethnically matched controls.

Results: We identified seven carriers (five patients with sporadic PCCs, two with PGLs). The prevalence of the MITF, p.E318K variant, was higher in the PCC/PGL cohort than in controls, and appears to be a significant risk factor (odds ratio, 3.19; 95% confidence interval, 1.34-7.59; P = .005). Noteworthy, two patients were homozygous for the p.E318K risk allele, a patient with metastatic PCC and an SDHB-mutated patient with PGL.

Conclusion: Our results indicate that the germline variant MITF, p.E318K is associated with an increased risk of other neural crest-derived tumors such as PCC/PGL.

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http://dx.doi.org/10.1210/jc.2016-2103DOI Listing
December 2016
36 Reads
6.209 Impact Factor

PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance.

PLoS Genet 2016 Oct 28;12(10):e1006367. Epub 2016 Oct 28.

INSERM, UMR970 Paris Cardiovascular Research Center (PARCC), Paris F-75015, FRANCE.

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10-4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10-10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10-4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development. We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.

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http://dx.doi.org/10.1371/journal.pgen.1006367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085032PMC
October 2016
89 Reads
5.540 Impact Factor

Meta-analysis of Telomere Length in Alzheimer's Disease.

J Gerontol A Biol Sci Med Sci 2016 08 18;71(8):1069-73. Epub 2016 Apr 18.

College of Sciences, University of Texas at San Antonio.

Background: Alzheimer's disease (AD) is a common and severe neurodegenerative disorder. Human telomeres are fundamental for the maintenance of genomic stability and play prominent roles in both cellular senescence and organismal aging. Regulation of telomere length (TL) is the result of the complex interplay between environmental and genetic factors. Alterations in TL are increasingly being studied as a possible risk factor for AD, and published studies on TL in AD show discrepant results, highlighting the need for a meta-analysis.

Methods: In the current study, we carried out a meta-analysis of published studies of TL in AD patients and healthy controls. PubMed, Web of Science and Google Scholar databases (from inception to September 2015) were used to identify relevant articles reporting TL in humans with AD, from which we retrieved data such as sample size, experimental methods, and mean TL for cases and controls. A random-effects model was used for meta-analytical procedures.

Results: The meta-analysis included 13 primary studies and demonstrated a significant difference in TL between 860 AD patients and 2,022 controls, with a standardized mean difference of -0.984 (confidence interval: -1.433 to -0.535; p value: <.001).

Conclusions: Our results show a consistent evidence of shorter telomeres in AD patients and highlight the importance of the analysis of epigenomic markers associated with neurodegeneration and with the risk for common and severe neurological diseases, such as AD.

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http://dx.doi.org/10.1093/gerona/glw053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945891PMC
August 2016
57 Reads
5.416 Impact Factor

Telomere length in Parkinson's disease: A meta-analysis.

Exp Gerontol 2016 Mar 7;75:53-5. Epub 2016 Jan 7.

College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA.

Parkinson's disease (PD) is a common and severe movement disorder. Differences in telomere length (TL) have been reported as possible risk factors for several neuropsychiatric disorders, including PD. Results from published studies for TL in PD are inconsistent, highlighting the need for a meta-analysis. In the current work, a meta-analysis of published studies for TL in PD was carried out. PubMed, Web of Science and Google Scholar databases were used to identify relevant articles that reported TL in groups of PD patients and controls. A random-effects model was used for meta-analytical procedures. The meta-analysis included eight primary studies, derived from populations of European and Asian descent, and did not show a significant difference in TL between 956 PD patients and 1284 controls (p value: 0.246). Our results show that there is no consistent evidence of shorter telomeres in PD patients and suggest the importance of future studies on TL and PD that analyze other populations and also include assessment of TL from different brain regions.

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http://dx.doi.org/10.1016/j.exger.2016.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786001PMC
March 2016
60 Reads
3.485 Impact Factor

Rethinking pheochromocytomas and paragangliomas from a genomic perspective.

Oncogene 2016 Mar 1;35(9):1080-9. Epub 2015 Jun 1.

INSERM, UMR970, Paris-Cardiovascular Research Center, Paris, France.

Pheochromocytomas (PCC) and paragangliomas (PGL) are rare neuroendocrine tumors of neural crest origin. These tumors are caused by germline or somatic mutations in known susceptibility genes in up to 70% of cases. Over the past few years, the emergence of high-throughput technologies has enabled the unprecedented characterization of genomic alterations in PCC/PGL, and has improved our understanding of the molecular mechanisms that distinguish the different tumor subtypes. Integrated genomic analyses have shown that the mutation status of PCC/PGL susceptibility genes strongly correlates with multi-omics data. These observations not only emphasize the role of the long-standing susceptibility genes as the main drivers of PCC/PGL tumorigenesis, but also illustrate the functional interdependence between genomic and epigenomic alterations. In this review, we discuss the genomic landscape underlying PCC/PGL, its functional consequences for tumorigenesis and tumor progression, and the potential clinical relevance of this knowledge for the application of precision medicine for patients with PCC/PGL.

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http://dx.doi.org/10.1038/onc.2015.172DOI Listing
March 2016
17 Reads
8.459 Impact Factor

From Nf1 to Sdhb knockout: Successes and failures in the quest for animal models of pheochromocytoma.

Mol Cell Endocrinol 2016 Feb 27;421:40-8. Epub 2015 Jun 27.

INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France. Electronic address:

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors characterized by a high frequency of hereditary forms. Based on transcriptome classification, PPGL can be classified in two different clusters. Cluster 1 tumors are caused by mutations in SDHx, VHL and FH genes and are characterized by a pseudohypoxic signature. Cluster 2 PPGL carry mutations in RET, NF1, MAX or TMEM127 genes and display an activation of the MAPK and mTOR signaling pathways. Many genetically engineered and allografted mouse models have been generated these past 30 years to investigate the mechanisms of PPGL tumorigenesis and test new therapeutic strategies. Among them, only Cluster 2-related models have been successful while no Cluster 1-related knockout mouse was so far reported to develop a PPGL. In this review, we present an overview of existing, successful or not, PPGL models, and a description of our own experience on the quest of Sdhb knockout mouse models of PPGL.

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http://dx.doi.org/10.1016/j.mce.2015.06.027DOI Listing
February 2016
94 Reads
4.405 Impact Factor

Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism.

Nat Commun 2015 Nov 2;6:8784. Epub 2015 Nov 2.

Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.

The tricarboxylic acid (TCA) cycle is a central metabolic pathway responsible for supplying reducing potential for oxidative phosphorylation and anabolic substrates for cell growth, repair and proliferation. As such it thought to be essential for cell proliferation and tissue homeostasis. However, since the initial report of an inactivating mutation in the TCA cycle enzyme complex, succinate dehydrogenase (SDH) in paraganglioma (PGL), it has become clear that some cells and tissues are not only able to survive with a truncated TCA cycle, but that they are also able of supporting proliferative phenotype observed in tumours. Here, we show that loss of SDH activity leads to changes in the metabolism of non-essential amino acids. In particular, we demonstrate that pyruvate carboxylase is essential to re-supply the depleted pool of aspartate in SDH-deficient cells. Our results demonstrate that the loss of SDH reduces the metabolic plasticity of cells, suggesting vulnerabilities that can be targeted therapeutically.

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http://dx.doi.org/10.1038/ncomms9784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632646PMC
November 2015
49 Reads
12.353 Impact Factor

Deciphering the molecular basis of invasiveness in Sdhb-deficient cells.

Oncotarget 2015 Oct;6(32):32955-65

INSERM, UMR970, Paris Cardiovascular Research Centre, F-75015 Paris, France.

Metastatic pheochromocytomas and paragangliomas (PPGL) are malignant neuroendocrine tumors frequently associated with germline mutations in the SDHB gene. SDHB-mutated PPGL display a hypermethylator phenotype associated with hallmarks of epithelial-to-mesenchymal transition (EMT). In the present study, we report the characterization of a unique model of Sdhb knockout in mouse chromaffin cells. Sdhb deficient cells exhibit a metastatic phenotype as highlighted by increased individual cell migration (characterized by faster motility and increased persistence) as well as high invasive and adhesion abilities. This phenotype is associated with the modulation of Twist1, Twist2, Tcf3, Snai1, N-cadherin or Krt19 expression, reflecting an EMT-like reprogramming of cells. Krt19 is epigenetically silenced in Sdhb-deficient cells and re-expressed after treatment by the demethylating agent decitabine. Krt19 rescue by lentiviral transduction in Sdhb-deficient cells and Krt19 inhibition by RNA interference in wild-type cells were performed. Both studies revealed the involvement of KRT19 in the invasive phenotype by modulating collective and individual migration and cell/extra-cellular matrix adhesion properties. These findings underline the role of hypermethylation and EMT in the in vitro acquisition of metastatic properties, following SDHB loss of function.

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http://dx.doi.org/10.18632/oncotarget.5106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741742PMC
October 2015
44 Reads
6.359 Impact Factor

The senescent microenvironment promotes the emergence of heterogeneous cancer stem-like cells.

Carcinogenesis 2015 Oct 13;36(10):1180-92. Epub 2015 Jul 13.

UMR3244, Telomeres and Cancer Laboratory, "Labellisé Ligue", Institut Curie, Paris 75248, France, UPMC University, Paris 75005, France,

There is a well-established association between aging and the onset of metastasis. Although the mechanisms through which age impinges upon the malignant phenotype remain uncharacterized, the role of a senescent microenvironment has been emphasized. We reported previously that human epithelial cells that undergo telomere-driven chromosome instability (T-CIN) display global microRNA (miR) deregulation and develop migration and invasion capacities. Here, we show that post-crisis cells are not able to form tumors unless a senescent microenvironment is provided. The characterization of cell lines established from such tumors revealed that these cells have acquired cell autonomous tumorigenicity, giving rise to heterogeneous tumors. Further experiments demonstrate that explanted cells, while displaying differences in cell differentiation markers, are all endowed of enhanced stem cell properties including self-renewal and multilineage differentiation capacity. Treatments of T-CIN+ cells with senescence-conditioned media induce sphere formation exclusively in cells with senescence-associated tumorigenicity, a capacity that depends on miR-145 repression. These results indicate that the senescent microenvironment, while promoting further transdifferentiations in cells with genome instability, is able to propel the progression of premalignant cells towards a malignant, cell stem-like state.

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http://dx.doi.org/10.1093/carcin/bgv101DOI Listing
October 2015
84 Reads
5.334 Impact Factor

The High Expression of the microRNA 17-92 Cluster and its Paralogs, and the Downregulation of the Target Gene PTEN, Is Associated with Primary Cutaneous B-Cell Lymphoma Progression.

J Invest Dermatol 2015 Jun 29;135(6):1659-1667. Epub 2015 Jan 29.

Inserm U1165, Institut Universitaire d'Hématologie, Hôpital Saint Louis, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, Paris, France; AP-HP, Hôpital Saint-Louis, Department of Pathology, Paris, France.

The oncogenic microRNA (miR) 17-92 cluster has a causative role in the lymphomagenesis of nodal B-cell lymphomas, by activating proliferation and inhibiting apoptosis. Here we analyzed primary cutaneous B-cell lymphomas for the miR-17-92 cluster and its paralogs miR-106a-363 and miR-106b-25. In 22 primary cutaneous diffuse large B-cell lymphomas, leg type (PCLBCL-LT) compared with 22 primary cutaneous follicle center lymphomas (PCFCLs), we found that miR-20a and miR-106a were overexpressed. Multivariate Cox analysis showed that higher miR-20a and miR-20b expression levels were associated with shorter disease-free and overall survival, independently from histological type. Gene expression profiling also showed a downregulation of 8 candidate target genes of miR-20a, miR-20b, and miR-106a in PCLBCL-LT compared with PCFCL. Among the candidate target genes, PTEN, NCOA3, and CAPRIN2 were confirmed to be underexpressed in PCLBCL-LT using quantitative reverse transcriptase-PCR on CD20-positive laser-microdissected tumor cells. In multivariate Cox analysis, lower PTEN mRNA expression level was associated with shorter disease-free survival (DFS), independently from the histological type. Altogether, this molecular and bioinformatic study of 44 patient skin biopsy samples showed that the oncogenic miR-17-92 cluster and its paralogs were involved in cutaneous B-cell lymphoma progression, and that the downregulation of the target gene PTEN was associated with shorter DFS.

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http://dx.doi.org/10.1038/jid.2015.27DOI Listing
June 2015
35 Reads
7.216 Impact Factor

Relative telomere length is associated with a functional polymorphism in the monoamine oxidase A gene in a South American sample.

J Genet 2015 Jun;94(2):305-8

Laboratory of Neuropsychiatric Genetics, Biomedical Sciences Research Group, School of Medicine,Universidad Antonio Nariño, 110231 Bogotá,

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June 2015
21 Reads
1.093 Impact Factor

Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas.

Nat Commun 2015 Jan 27;6:6044. Epub 2015 Jan 27.

1] INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France [3] Department of Genetics, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015 Paris, France [4] Rare Adrenal Cancer Network COMETE, F-75006 Paris, France.

Pheochromocytomas and paragangliomas (PCCs/PGLs) are neural crest-derived tumours with a very strong genetic component. Here we report the first integrated genomic examination of a large collection of PCC/PGL. SNP array analysis reveals distinct copy-number patterns associated with genetic background. Whole-exome sequencing shows a low mutation rate of 0.3 mutations per megabase, with few recurrent somatic mutations in genes not previously associated with PCC/PGL. DNA methylation arrays and miRNA sequencing identify DNA methylation changes and miRNA expression clusters strongly associated with messenger RNA expression profiling. Overexpression of the miRNA cluster 182/96/183 is specific in SDHB-mutated tumours and induces malignant traits, whereas silencing of the imprinted DLK1-MEG3 miRNA cluster appears as a potential driver in a subgroup of sporadic tumours. Altogether, the complete genomic landscape of PCC/PGL is mainly driven by distinct germline and/or somatic mutations in susceptibility genes and reveals different molecular entities, characterized by a set of unique genomic alterations.

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http://dx.doi.org/10.1038/ncomms7044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354166PMC
January 2015
97 Reads
12.353 Impact Factor

Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas.

Hum Mol Genet 2014 May 13;23(9):2440-6. Epub 2013 Dec 13.

INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015, Paris, France.

Malignant pheochromocytoma (PCC) and paraganglioma (PGL) are mostly caused by germline mutations of SDHB, encoding a subunit of succinate dehydrogenase. Using whole-exome sequencing, we recently identified a mutation in the FH gene encoding fumarate hydratase, in a PCC with an 'SDH-like' molecular phenotype. Here, we investigated the role of FH in PCC/PGL predisposition, by screening for germline FH mutations in a large international cohort of patients. We screened 598 patients with PCC/PGL without mutations in known PCC/PGL susceptibility genes. We searched for FH germline mutations and large deletions, by direct sequencing and multiplex ligation-dependent probe amplification methods. Global alterations in DNA methylation and protein succination were assessed by immunohistochemical staining for 5-hydroxymethylcytosine (5-hmC) and S-(2-succinyl) cysteine (2SC), respectively. We identified five pathogenic germline FH mutations (four missense and one splice mutation) in five patients. Somatic inactivation of the second allele, resulting in a loss of fumarate hydratase activity, was demonstrated in tumors with FH mutations. Low tumor levels of 5-hmC, resembling those in SDHB-deficient tumors, and positive 2SC staining were detected in tumors with FH mutations. Clinically, metastatic phenotype (P = 0.007) and multiple tumors (P = 0.02) were significantly more frequent in patients with FH mutations than those without such mutations. This study reveals a new role for FH in susceptibility to malignant and/or multiple PCC/PGL. Remarkably, FH-deficient PCC/PGLs display the same pattern of epigenetic deregulation as SDHB-mutated malignant PCC/PGL. Therefore, we propose that mutation screening for FH should be included in PCC/PGL genetic testing, at least for tumors with malignant behavior.

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http://dx.doi.org/10.1093/hmg/ddt639DOI Listing
May 2014
31 Reads
6.393 Impact Factor

Estrogen-dependent dynamic profile of eNOS-DNA associations in prostate cancer.

PLoS One 2013 3;8(5):e62522. Epub 2013 May 3.

Department of Experimental Oncology, National Cancer Institute Regina Elena, Rome, Italy.

In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ER?) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ? 55% of them in extragenic DNA regions and an intriguing involvement of the 5' domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa.

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0062522PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3643940PMC
November 2013
18 Reads
3.234 Impact Factor

The heterochromatic chromosome caps in great apes impact telomere metabolism.

Nucleic Acids Res 2013 May 21;41(9):4792-801. Epub 2013 Mar 21.

Telomeres and Cancer laboratory, 'Equipe Labellisée Ligue contre le Cancer', UMR3244, Institut Curie, 26 rue d'Ulm, 75248 Paris, France.

In contrast with the limited sequence divergence accumulated after separation of higher primate lineages, marked cytogenetic variation has been associated with the genome evolution in these species. Studying the impact of such structural variations on defined molecular processes can provide valuable insights on how genome structural organization contributes to organismal evolution. Here, we show that telomeres on chromosome arms carrying subtelomeric heterochromatic caps in the chimpanzee, which are completely absent in humans, replicate later than telomeres on chromosome arms without caps. In gorilla, on the other hand, a proportion of the subtelomeric heterochromatic caps present in most chromosome arms are associated with large blocks of telomere-like sequences that follow a replication program different from that of bona fide telomeres. Strikingly, telomere-containing RNA accumulates extrachromosomally in gorilla mitotic cells, suggesting that at least some aspects of telomere-containing RNA biogenesis have diverged in gorilla, perhaps in concert with the evolution of heterochromatic caps in this species.

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http://dx.doi.org/10.1093/nar/gkt169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3643582PMC
May 2013
17 Reads
11.561 Impact Factor

Telomere crisis in kidney epithelial cells promotes the acquisition of a microRNA signature retrieved in aggressive renal cell carcinomas.

Carcinogenesis 2013 May 27;34(5):1173-80. Epub 2013 Jan 27.

UMR3244, Telomeres and Cancer Laboratory, Institut Curie, 26 rue d'Ulm, Paris 75248, France.

Telomere shortening is a major source of chromosome instability (CIN) at early stages during carcinogenesis. However, the mechanisms through which telomere-driven CIN (T-CIN) contributes to the acquisition of tumor phenotypes remain uncharacterized. We discovered that human epithelial kidney cells undergoing T-CIN display massive microRNA (miR) expression changes that are not related to local losses or gains. This widespread miR deregulation encompasses a miR-200-dependent epithelial-to-mesenchymal transition (EMT) that confers to immortalized pre-tumoral cells phenotypic traits of metastatic potential. Remarkably, a miR signature of these cells, comprising a downregulation of miRs with conserved expression in kidney, was retrieved in poorly differentiated aggressive renal cell carcinomas. Our results reveal an unanticipated connection between telomere crisis and the activation of the EMT program that occurs at pre-invasive stages of epithelial cancers, through mechanisms that involve miR deregulation. Thus, this study provides a new rational into how telomere instability contributes to the acquisition of the malignant phenotype.

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http://carcin.oxfordjournals.org/content/34/5/1173.full.pdf
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http://www.carcin.oxfordjournals.org/cgi/doi/10.1093/carcin/
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http://dx.doi.org/10.1093/carcin/bgt029DOI Listing
May 2013
138 Reads
5.334 Impact Factor

Top co-authors

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Paris-Cardiovascular Research Center

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Alexandre Buffet
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France; and Université Paris Descartes (J.F.

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Laurence Amar

Université Paris Descartes

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Nelly Burnichon
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Paris Descartes University

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Jerome Bertherat
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