Cécile Jeanpierre

French Institute of Health and Medical Research, Lutetia Parisorum, Île-de-France, France

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Publications (53)189.25 Total impact

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    ABSTRACT: Renal hypodysplasia (RHD) is a heterogeneous condition encompassing a spectrum of kidney development defects including renal agenesis, hypoplasia, and (cystic) dysplasia. Heterozygous mutations of several genes have been identified as genetic causes of RHD with various severity. However, these genes and mutations are not associated with bilateral renal agenesis, except for RET mutations, which could be involved in a few cases. The pathophysiological mechanisms leading to total absence of kidney development thus remain largely elusive. By using a whole-exome sequencing approach in families with several fetuses with bilateral renal agenesis, we identified recessive mutations in the integrin α8-encoding gene ITGA8 in two families. Itga8 homozygous knockout in mice is known to result in absence of kidney development. We provide evidence of a damaging effect of the human ITGA8 mutations. These results demonstrate that mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease.
    The American Journal of Human Genetics 01/2014; · 11.20 Impact Factor
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    ABSTRACT: BACKGROUND AND OBJECTIVES: Congenital anomalies of the kidney and urinary tract (CAKUT) are a frequent cause of renal failure in children, and their detection in utero is now common with fetal screening ultrasonography. The clinical course of CAKUT detected before birth is very heterogeneous and depends on the level of nephron reduction. The most severe forms cause life-threatening renal failure, leading to perinatal death or the need for very early renal replacement therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study reports the screening of two genes (HNF1B and PAX2) involved in monogenic syndromic CAKUT in a cohort of 103 fetuses from 91 families with very severe CAKUT that appeared isolated by fetal ultrasound examination and led to termination of pregnancy. RESULTS: This study identified a disease-causing mutation in HNF1B in 12 cases from 11 families and a mutation in PAX2 in 4 unrelated cases. Various renal phenotypes were observed, but no case of bilateral agenesis was associated with HNF1B or PAX2 mutations. Autopsy identified extrarenal abnormalities not detected by ultrasonography in eight cases but confirmed the absence of extrarenal defects in eight other cases. A positive family history of renal disease was not significantly more frequent in cases with an identified mutation. Moreover, in cases with an inherited mutation, there was a great phenotypic variability regarding the severity of the renal disease within a single family. CONCLUSIONS: Our results suggest that mutations in genes involved in syndromic CAKUT with Mendelian inheritance are not rare in fetal cases with severe CAKUT appearing isolated at prenatal ultrasound, a finding of clinical importance because of genetic counseling.
    Clinical Journal of the American Society of Nephrology 03/2013; · 5.07 Impact Factor
  • Cécile Jeanpierre
    Medecine sciences: M/S 03/2013; 29(3):254-6. · 0.56 Impact Factor
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    ABSTRACT: The identity of niche signals necessary to maintain embryonic nephron progenitors is unclear. Here we provide evidence that Fgf20 and Fgf9, expressed in the niche, and Fgf9, secreted from the adjacent ureteric bud, are necessary and sufficient to maintain progenitor stemness. Reduction in the level of these redundant ligands in the mouse led to premature progenitor differentiation within the niche. Loss of FGF20 in humans, or of both ligands in mice, resulted in kidney agenesis. Sufficiency was shown in vitro where Fgf20 or Fgf9 (alone or together with Bmp7) maintained isolated metanephric mesenchyme or sorted nephron progenitors that remained competent to differentiate in response to Wnt signals after 5 or 2 days in culture, respectively. These findings identify a long-sought-after critical component of the nephron stem cell niche and hold promise for long-term culture and utilization of these progenitors in vitro.
    Developmental Cell 06/2012; 22(6):1191-207. · 12.86 Impact Factor
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    ABSTRACT: Congenital anomalies of the kidney and urinary tract (CAKUT) are the commonest cause of chronic kidney disease in children. Structural anomalies within the CAKUT spectrum include renal agenesis, kidney hypo-/dysplasia, multicystic kidney dysplasia, duplex collecting system, posterior urethral valves and ureter abnormalities. While most CAKUT cases are sporadic, familial clustering of CAKUT is common, emphasizing a strong genetic contribution to CAKUT origin. Animal experiments demonstrate that alterations in genes crucial for kidney development can cause experimental CAKUT, while expression studies implicate mislocalization and/or aberrant levels of the encoded proteins in human CAKUT. Further insight into the pathogenesis of CAKUT will improve strategies for early diagnosis, follow-up and treatment. Here, we outline a collaborative approach to identify and characterize novel factors underlying human CAKUT. This European consortium will share the largest collection of CAKUT patients available worldwide and undertake multidisciplinary research into molecular and genetic pathogenesis, with extension into translational studies to improve long-term patient outcomes.
    Nephrology Dialysis Transplantation 12/2011; 26(12):3843-51. · 3.37 Impact Factor
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    ABSTRACT: A subset of ciliopathies, including Sensenbrenner, Jeune, and short-rib polydactyly syndromes are characterized by skeletal anomalies accompanied by multiorgan defects such as chronic renal failure and retinitis pigmentosa. Through exome sequencing we identified compound heterozygous mutations in WDR19 in a Norwegian family with Sensenbrenner syndrome. In a Dutch family with the clinically overlapping Jeune syndrome, a homozygous missense mutation in the same gene was found. Both families displayed a nephronophthisis-like nephropathy. Independently, we also identified compound heterozygous WDR19 mutations by exome sequencing in a Moroccan family with isolated nephronophthisis. WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport. We show that IFT144 is absent from the cilia of fibroblasts from one of the Sensenbrenner patients and that ciliary abundance and morphology is perturbed, demonstrating the ciliary pathogenesis. Our results suggest that isolated nephronophthisis, Jeune, and Sensenbrenner syndromes are clinically overlapping disorders that can result from a similar molecular cause.
    The American Journal of Human Genetics 11/2011; 89(5):634-43. · 11.20 Impact Factor
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    ABSTRACT: The RET/GDNF signalling pathway plays a crucial role during development of the kidneys and the enteric nervous system. In humans, RET activating mutations cause multiple endocrine neoplasia, whereas inactivating mutations are responsible for Hirschsprung disease. RET mutations have also been reported in fetuses with renal agenesis, based on analysis of a small series of samples. To characterise better the involvement of RET and GDNF in kidney development defects, a series of 105 fetuses with bilateral defects, including renal agenesis, severe hypodysplasia or multicystic dysplastic kidney, was studied. RET and GDNF coding sequences, evolutionary conserved non-coding regions (ECRs) in promoters, 3'UTRs, and RET intron 1 were analysed. Copy number variations at these loci were also investigated. The study identified: (1) a low frequency (<7%) of potential mutations in the RET coding sequence, with inheritance from the healthy father for four of them; (2) no GDNF mutation; (3) similar allele frequencies in patients and controls for most single nucleotide polymorphism variants, except for RET intron 1 variant rs2506012 that was significantly more frequent in affected fetuses than in controls (6% vs 2%, p=0.01); (4) distribution of the few rare RET variants unidentified in controls into the various 5'-ECRs; (5) absence of copy number variations. These results suggest that genomic alteration of RET or GDNF is not a major mechanism leading to renal agenesis and other severe kidney development defects. Analysis of a larger series of patients will be necessary to validate the association of the RET intron 1 variant rs2506012 with renal development defects.
    Journal of Medical Genetics 07/2011; 48(7):497-504. · 5.70 Impact Factor
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    ABSTRACT: Nephronophthisis is a hereditary nephropathy characterized by interstitial fibrosis and cyst formation. It is caused by mutations in NPHP genes encoding the ciliary proteins, nephrocystins. In this paper, we investigate the function of nephrocystin-4, the product of the nphp4 gene, in vivo by morpholino-mediated knockdown in zebrafish and in vitro in mammalian kidney cells. Depletion of nephrocystin-4 results in convergence and extension defects, impaired laterality, retinal anomalies and pronephric cysts associated with alterations in early cloacal morphogenesis. These defects are accompanied by abnormal ciliogenesis in the cloaca and in the laterality organ. We show that nephrocystin-4 is required for the elongation of the caudal pronephric primordium and for the regulation of cell rearrangements during cloaca morphogenesis. Moreover, depletion of either inversin, the product of the nphp2 gene, or of the Wnt-planar cell polarity (PCP) pathway component prickle2 increases the proportion of cyst formation in nphp4-depleted embryos. Nephrocystin-4 represses the Wnt-β-catenin pathway in the zebrafish cloaca and in mammalian kidney cells in culture. In these cells, nephrocystin-4 interacts with inversin and dishevelled, and regulates dishevelled stability and subcellular localization. Our data point to a function of nephrocystin-4 in a tight regulation of the Wnt-β-catenin and Wnt-PCP pathways, in particular during morphogenesis of the zebrafish pronephros. Moreover, they highlight common signalling functions for inversin and nephrocystin-4, suggesting that these two nephrocystins are involved in common physiopathological mechanisms.
    Human Molecular Genetics 07/2011; 20(13):2611-27. · 7.69 Impact Factor
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    ABSTRACT: Based on characterization of both genomic and expression status of WT1 and CTNNB1 (beta-catenin) in a series of 60 Wilms tumor samples, combined with genome-wide expression profiling of these tumors, normal mature and fetal kidney controls, we show that WT1/beta-catenin expression was a better classifier than WT1/CTNNB1 mutations. We present molecular data supporting that the WNT pathway is involved in both tumor classes, with and without WT1/beta-catenin alterations. In the tumor class with WT1/beta-catenin alterations, we identified overexpression of 14 previously unreported WNT target genes, including TWIST1. We show that the TWIST1 protein was specifically expressed in these tumors, where staining was restricted to the stromal, nuclear beta-catenin positive, component. By comparing the state of the WNT pathway in tumors without WT1/beta-catenin alterations and fetal kidneys we provide evidence that suggests that these tumors have a heightened level of pathway activation. We characterized mutations of the WNT pathway regulator gene WTX in 16% of this tumor class. Moreover, genome-transcriptome correlation analysis allowed us to identify three other WNT pathway regulator genes that could participate in the activation of the WNT pathway: BCL9 (1p36.2), CTNNBIP1 (1p36.2), and CBY1 (22q13.1). These genes thus represent new potential important actors in WT tumorigenesis.
    Genes Chromosomes and Cancer 07/2009; 48(9):816-27. · 3.55 Impact Factor
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    ABSTRACT: Children with WT1 gene-related disorders such as Denys-Drash syndrome (DDS) and Frasier syndrome (FS) are at increased risk of Wilms tumor and end-stage renal disease. We investigated whether Wilms tumors in these patients displayed a specific phenotype or behavior and whether nephron-sparing surgery was beneficial. We retrospectively studied all patients with DDS, FS, or other WT1 mutations treated at our institutions between 1980 and 2007. We identified 20 patients, of whom 18 had benign or malignant tumors. Wilms tumors occurred in 15 patients, being unilateral in 10 and bilateral in 5 (20 tumors). Median age at Wilms tumor diagnosis was 9 months. No patients had metastases. According to the International Society of Pediatric Oncology Working Classification, there were 19 intermediate-risk tumors and one high-risk tumor; no tumor was anaplastic. In patients with nephropathy who underwent unilateral nephrectomy for Wilms tumor or nephron-sparing surgery for bilateral Wilms tumor, mean time to dialysis was 11 or 9 months, respectively. Other tumors included three gonadoblastomas (in two patients), one retroperitoneal soft-tissue tumor, and one transitional cell papilloma of the bladder. Two patients, both with stage I Wilms tumor, died from end-stage renal disease-related complications. The median follow-up time for the 18 survivors was 136 months (range, 17-224 months). Most Wilms tumors in children with WT1-related disorders were early-stage and intermediate-risk tumors, with a young age at diagnosis. In patients without end-stage renal disease, nephron-sparing surgery should be considered for delaying the onset of renal failure.
    Pediatric Blood & Cancer 10/2008; 52(1):55-9. · 2.35 Impact Factor
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    ABSTRACT: The novel continuous cell line WT-Pe.1 was established in vitro from Wilms tumor with histological features of diffuse anaplasia. The cultures grew as poorly differentiated epithelial-like cells with pleomorphic polygonal shapes and formation of typical monolayers. WT-Pe.1 cells were immunoreactive for cytokeratin, vimentin, laminin, villin, CD10, and CD24 proteins. Conventional cytogenetic analysis by RHG-banding revealed a hypotriploid karyotype with numerous abnormalities including ring chromosomes, double-minutes, homogeneous staining regions, radial structures, dicentrics, and several marker chromosomes. Comparative genomic hybridization analysis revealed DNA copy numbers losses on chromosome segments 1p, 3p, 6q, 9q34.1 approximately q34.3, 11q24 approximately q25, 14q12 approximately qter, 16q, 18q, and 22q11 approximately q13; gain of genomic material was localized on chromosome arms 1q, 4p, 6q, and 7p and the entire chromosome 12. With DNA from the original tumor, copy number losses were detected on chromosomes 1p, 14q, 16q, 17q, and 22q and gains were observed on 1q, 4p, 8q, 12p, 12q, and chromosome 14p. Copy number amplifications of distinct loci were found on 1q21.1 and 4p15.3, as well as an elevated copy number of cyclin D2 (CCND2) and cyclin D associated kinase (CDK4) genes on chromosome 12 (confirmed by fluorescence in situ hybridization).
    Cancer genetics and cytogenetics 08/2008; 184(1):22-30. · 1.54 Impact Factor
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    ABSTRACT: Identifying among nephroblastoma those with a high propensity for distant metastases using cell cycle markers: cyclin E as a regulator of progression through the cell cycle and Ki-67 as a tumor proliferation marker, since both are often deregulated in many human malignancies. A staining index (SI) was obtained by immunohistochemistry using anti-cyclin E and anti-Ki-67 antibodies in paraffin sections of 54 postchemotherapy nephroblastoma including 42 nephroblastoma without metastasis and 12 with metastases. Median cyclin E and Ki-67 SI were 46% and 33% in blastemal cells, 30% and 10% in stromal cells, 37% and 29.5% in epithelial cells. The highest values were found for anaplastic nephroblastoma. A correlation between cyclin E and Ki-67 SI was found for the blastemal component and for the epithelial component. Univariate analysis showed prognostic significance for metastases with cyclin E SI in stromal cells, epithelial cells and blastemal cells (p = 0.03, p = 0.01 and p = 0.002, respectively) as well as with Ki-67 SI in blastema (p<10(-4)). The most striking data were that both cyclin E SI and blastemal Ki-67 SI discriminated between patients with metastases and patients without metastasis among intermediate-risk nephroblastoma. Our findings show that a high cyclin E SI in all components of nephroblastoma is correlated with tumor aggressiveness and metastases, and that assessment of its expression may have prognostic value in the categorization of nephroblastoma.
    PLoS ONE 01/2008; 3(5):e2216. · 3.73 Impact Factor
  • Archives De Pediatrie - ARCHIVES PEDIATRIE. 01/2008; 15(5):903-903.
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    ABSTRACT: Wilms tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome is a genetic disorder caused by a deletion of band 11p13, which results in the loss of 1 allele of the Wilms tumor suppressor gene (WT1). It is not classically associated with nephropathies, but increased rates of renal failure are reported. Denys-Drash syndrome (DDS), caused by mutations in the WT1 gene affecting the third or second zinc finger, is characterized by a triad of glomerulopathy progressing rapidly to end-stage renal disease, male hermaphroditism, and Wilms tumor. In patients with DDS, small glomeruli were observed. We reviewed histological findings of nontumoral kidney samples of 7 patients with WAGR syndrome at the time of tumor surgery. Median glomerular diameter was 110 +/- 37 microm in patients with WAGR syndrome versus 125 +/- 18.5 microm in controls (P < 0.0001). The presence of small glomeruli in patients with WAGR syndrome, as in those with DDS, suggests a specific defect of WT1 function in development and a specific role of WT1 allele loss in the development of renal failure in these patients.
    American Journal of Kidney Diseases 06/2007; 49(6):793-800. · 5.29 Impact Factor
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    ABSTRACT: The expression status of the three cyclin D genes (CCND1, CCND2 and CCND3), the two cyclin D-dependent kinase genes (CDK4 and CDK6) and the p16(INK4a) gene was studied in a series of 47 Wilms' tumors, 16 normal mature kidneys and two fetal kidneys. We showed predominant overexpression of CCND2 and CDK4 compared to CCND1/D3 and CDK6 respectively. We found a specific correlation between relapse and CDK4 overexpression, but not CDK6 overexpression. We did not identify any methylation of the p16(INK4a) promoter. This suggests that dysregulation of CCND2 and CDK4 plays a specific role in WT tumorigenesis.
    Cancer Letters 05/2005; 221(1):67-75. · 4.26 Impact Factor
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    ABSTRACT: The WT1 gene plays a role in urogenital and gonadal development. Germline mutations of this gene have been observed in patients with Drash or Frasier syndrome (Sd). The purpose of this report is to compare phenotype and genotype of these patients. Retrospective study of 12 patients treated since 1980 for WT1 gene-related disorders was conducted. End-stage renal disease (ESRD) occurred in 9 patients, mostly because of diffuse mesangial sclerosis (DMS) or focal and segmental glomerular sclerosis (FSGS). Seven patients underwent kidney transplantation, and 2 died. Eleven tumors occurred: 8 Wilms' tumors, one soft tissue tumor, one bladder papilloma, and one gonadoblastoma. Wilms' tumors occurred at a younger age than expected. Eight patients had a 46,XY karyotype. One of these XY patients had female phenotype (Frasier syndrome); she was raised as a girl with bilateral gonadectomy. Seven XY patients had ambiguous phenotype; 4 have been raised as boys and 3 as girls. Four patients had a 46,XX karyotype; they had female genitalia and were raised as girls. WT1 gene analysis was performed in 10 patients and showed heterozygous germline mutations in exon 9 (n = 6), intron 9 (n = 1), exon 3 (n = 1), exon 4 (n = 1), or exon 7 (n = 1). ESRD was secondary to DMS when exon 9 was mutated, and secondary to FSGS when intron 9 was mutated. When exon 3, 4, and 7 were mutated, no nephropathy has been observed. Wilms' tumors occurred with any kind of WT1 mutation except intron 9. Abnormal sexual differentiation has been observed in all XY patients with WT1 mutation, and the most profound inversion of phenotype was observed with mutation in intron 9. Correlation between phenotype and genotype provides better understanding of the role of WT1, and can help the surgeon in the management of these patients.
    Journal of Pediatric Surgery 02/2003; 38(1):124-9; discussion 124-9. · 1.38 Impact Factor
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    ABSTRACT: The study of the gonads of 8 cases of Drash syndrome (6 ambiguous males, 2 females) and of 2 Frasier syndrome shows that WT1 mutations gives a dysgenetic testis which is the cause of the genital ambiguity observed at birth. By contrast the same mutations have no effect on ovary development giving normal females. However intron mutations in KTS with isoforms imbalance of WT1 proteins cause streak gonads with a female phenotype in XY patients. In consequence WT1 mutations are the cause of a spectrum of male genital malformations associated with glomerulonephritis and tumors. The absence of WT1 protein detection in sertoli cells shown by immunohistochemistry for 3 cases suggests an imprinting effect of the normal WT1 allele promotor rather than a low level of protein production. A caryotype is mandatory for a correct diagnosis.
    Arkhiv patologii 01/2003; 65(2):40-4.
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    ABSTRACT: Wilms' tumour (WT) or nephroblastoma is the most frequent kidney cancer in children. In a previous study, we reported alterations to WT1 transcription in 90% of WT tested, with decreased exon 5 +/- isoform ratio being the most frequent alteration (56% of WT). We now report an approach based on cDNA profiling of tumour pools to identify genes likely to be dysregulated in association with a decreased WT1 exon 5 +/- ratio. We compared the expression profiles of pools of tumours classified according to whether this isoform imbalance was present (five tumours) or not (four tumours), using Atlas Cancer cDNA expression arrays. Fourteen of 588 genes tested displayed specific up-regulation (CCND2, PCNA, N-MYC, E2F3, TOP2A, PAK1, DCC and PCDH2) or down-regulation (VEGF, IGFBP5, TIMP3, ARHB, C-FOS and CD9) in the pool of tumours with decreased exon 5 +/- ratio. These results were validated by RT-PCR analysis of four genes (CCND2, PCNA, VEGF and IGFBP5). We extended the analysis of VEGF expression to 51 tumours by real-time RT-PCR and ascertained differential expression of this gene associated with WT1 expression pattern. Moreover, our results suggest that the VEGF expression level may be of prognosis relevance for relapsed patients.
    Oncogene 09/2002; 21(36):5566-73. · 7.36 Impact Factor
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    ABSTRACT: In order to identify genes or pathways involved in Wilms tumor etiology, we used the Atlas Cancer cDNA expression array to compare the gene expression profiles of five tumors, one Wilms tumor cell line (SK-NEP1), and normal mature and fetal kidneys. Of 588 genes tested, 153 had a different expression pattern in tumors compared with mature kidney. Ninety-six genes were differentially expressed in tumors compared with both normal mature and fetal kidney, and 57 genes had expression profiles similar to that of fetal kidney, which may reflect the developmental stage of the tumor cells. Comparison of the expression patterns of tumors shows that only 13% of the differentially expressed genes are constantly up- or downregulated in the five tumors tested, and this provides molecular evidence of tumor heterogeneity. We then confirmed the differential expression by an independent method, using quantitative reverse transcriptase polymerase chain reaction for two of the differentially expressed genes, MMP-14 and cyclin D2. Analysis of expression levels in a panel of 40 tumors showed that 30% overexpressed MMP-14 and 80% overexpressed cyclin D2. Profiling of gene expression using cDNA arrays in a large tumor panel will ultimately lead to the molecular classification of tumors, the identification of prognosis markers, and the design of targeted therapy.
    Pediatric Nephrology 01/2002; 16(12):1113-21. · 2.94 Impact Factor
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    ABSTRACT: Hereditary and sporadic forms of tumors are generally related to germ-line and somatic mutations of the same tumor suppressor gene. Unexpectedly, in Wilms' tumor, somatic mutations of the WT1 gene were found only occasionally in sporadic cases, although constitutional mutations of this gene are clearly associated with predisposition. It has been suggested that abnormal splicing may be another mode of somatic WT1 alteration. However, this idea was based on the analysis of a small series of tumors, precluding accurate evaluation of the frequency of such changes. To investigate WT1 changes at the somatic level in more detail, we analyzed the levels of the four isoform transcripts produced by alternative splicing events in a large series of 50 tumors, normal mature kidneys, and fetal kidneys. We characterized splicing alterations in 63% of sporadic Wilms' tumors. Moreover, taking into account the decreased and increased overall levels of WT1 mRNA, the percentage of sporadic tumors with changes in WT1 expression reached 90%. Whether and how these alterations of expression play a role in the tumorigenic process remain to be evaluated.
    Clinical Cancer Research 11/2000; 6(10):3957-65. · 7.84 Impact Factor

Publication Stats

796 Citations
189.25 Total Impact Points

Institutions

  • 1989–2014
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • University of Toronto
      Toronto, Ontario, Canada
  • 1997–2013
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1993
    • Institut Curie
      Lutetia Parisorum, Île-de-France, France