Team Publications Diversity and Plasticity of Childhood Tumors (Depict)
Total Page：16
File Type：pdf, Size：1020Kb
Team Publications Diversity and Plasticity of Childhood Tumors (DePiCT) Year of publication 2005 Franck Bourdeaut, Delphine Trochet, Isabelle Janoueix-Lerosey, Agnès Ribeiro, Anne Deville, Carole Coz, Jean-François Michiels, Stanislas Lyonnet, Jeanne Amiel, Olivier Delattre (2005 Jun 14) Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. Cancer letters : 51-8 Summary Hereditary predisposition to neuroblastoma accounts for less than 5% of neuroblastomas and is probably heterogeneous. Recently, a predisposition gene has been mapped to 16p12-p13, but has not yet been identified. Occurrence of neuroblastoma in association with congenital central hypoventilation and Hirschsprung’s disease suggests that genes, involved in the development of neural-crest-derived cells, may be altered in these conditions. The recent identification of PHOX2B as the major disease-causing gene in congenital central hypoventilation prompted us to test it as a candidate gene in familial neuroblastoma. We report a family with three first-degree relatives with neuroblastic tumours (namely two ganglioneuromas and one neuroblastoma) in one branch and two siblings with Hirschsprung’s disease in another branch. A constitutional R100L PHOX2B mutation was identified in all three patients affected with tumours. We also report a germline PHOX2B mutation in one patient treated for Hirschsprung’s disease who subsequently developed a multifocal neuroblastoma in infancy. Both mutations disrupt the homeodomain of the PHOX2B protein. No loss of heterozygosity at the PHOX2B locus was observed in the tumour, suggesting that haplo-insufficiency, gain of function or dominant negative effects may account for the oncogenic effects of these mutations. These observations identify PHOX2B as the first predisposing gene to hereditary neuroblastic tumours. Gudrun Schleiermacher, Franck Bourdeaut, Valérie Combaret, Gaelle Picrron, Virginie Raynal, Alain Aurias, Agnes Ribeiro, Isabelle Janoueix-Lerosey, Olivier Delattre (2005 Mar 1) Stepwise occurrence of a complex unbalanced translocation in neuroblastoma leading to insertion of a telomere sequence and late chromosome 17q gain. Oncogene : 3377-84 Summary In neuroblastoma, the most frequent genetic alterations are unbalanced translocations involving chromosome 17. To gain insights into these rearrangements, we have characterized a previously identified der(1)t(1;17) of the CLB-Bar cell line. The 17q breakpoint was mapped by FISH. Subsequently, a rearranged fragment was identified by Southern analysis, cloned in a lambda vector and sequenced. The chromosome rearrangement is more complex than expected due to the presence of an interstitial 4p telomeric sequence between chromosome 1p and 17q. Three different genes, which may play a role in neuroblastoma development, are disrupted by the translocation breakpoints. INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1 Team Publications Diversity and Plasticity of Childhood Tumors (DePiCT) Indeed, the 3’UTR of the PIP5K2B gene on chromosome 17q is directly fused to the (TTAGGG)n repeat of the chromosome 4p telomere, and the (1;4) fusion disrupts the MACF1 (microtubule-actin crosslinking factor 1) and POLN genes, respectively. Interestingly, the (1;4) fusion was present at diagnosis and at relapse, whereas the (4;17) fusion was detected at relapse only, leading to a secondary 17q gain confirmed by array CGH therefore indicating that 17q gain may not be a primary event in neuroblastoma. Finally, screening of a panel of neuroblastoma cell lines identified interstitial telomeric sequences in three other cases, suggesting that this may be a recurrent mechanism leading to unbalanced translocations in neuroblastoma. Marie-Françoise Rousseau-Merck, Laurence Fiette, Agnès Klochendler-Yeivin, Olivier Delattre, Alain Aurias (2005 Feb 22) Chromosome mechanisms and INI1 inactivation in human and mouse rhabdoid tumors. Cancer genetics and cytogenetics : 127-33 Summary The human rhabdoid tumorigenesis orchestrated by INI1 inactivation is associated with specific rearrangements of chromosome 22 that correlate with preferential anatomic tumor locations. A literature review revealed significant correlations between an apparently normal karyotype and kidney tumors, monosomy 22 and cerebral tumors, and chromosome 22 translocations and tumors at other anatomic sites. In the mouse rhabdoid tumor model, specifically in the four tumors that we tested for loss of heterozygosity, neither partial deletion nor monosomy of chromosome 10 could be detected. In contrast to the human data, the only chromosome mechanism involved in the 18 mouse tumors studied appears to be a mitotic recombination or a nondisjunction-duplication. Additionally, and despite mouse tumor incidence across a variety of sites, no rhabdoid tumor could be observed in the mouse kidney. These data suggest that the chromosome mechanisms for INI1 inactivation and the selective cell survival pressure differ in human and mouse. Year of publication 2004 Alexandre Prieur, Franck Tirode, Pinchas Cohen, Olivier Delattre (2004 Jul 30) EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Molecular and cellular biology : 7275-83 Summary Ewing tumors are characterized by abnormal transcription factors resulting from the oncogenic fusion of EWS with members of the ETS family, most commonly FLI-1. RNA interference targeted to the junction between EWS and FLI-1 sequences was used to INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2 Team Publications Diversity and Plasticity of Childhood Tumors (DePiCT) inactivate the EWS/FLI-1 fusion gene in Ewing cells and to explore the resulting phenotype and alteration of the gene expression profile. Loss of expression of EWS/FLI-1 resulted in the complete arrest of growth and was associated with a dramatic increase in the number of apoptotic cells. Gene profiling of Ewing cells in which the EWS/FLI-1 fusion gene had been inactivated identified downstream targets which could be grouped in two major functional clusters related to extracellular matrix structure or remodeling and regulation of signal transduction pathways. Among these targets, the insulin-like growth factor binding protein 3 gene (IGFBP-3), a major regulator of insulin-like growth factor 1 (IGF-1) proliferation and survival signaling, was strongly induced upon treating Ewing cells with EWS/FLI-1-specific small interfering RNAs. We show that EWS/FLI-1 can bind the IGFBP-3 promoter in vitro and in vivo and can repress its activity. Moreover, IGFBP-3 silencing can partially rescue the apoptotic phenotype caused by EWS/FLI-1 inactivation. Finally, IGFBP-3-induced Ewing cell apoptosis relies on both IGF-1-dependent and -independent pathways. These findings therefore identify the repression of IGFBP-3 as a key event in the development of Ewing’s sarcoma. Isabelle Janoueix-Lerosey, Eugene Novikov, Marta Monteiro, Nadège Gruel, Gudrun Schleiermacher, Béatrice Loriod, Catherine Nguyen, Olivier Delattre (2004 Jun 15) Gene expression profiling of 1p35-36 genes in neuroblastoma. Oncogene : 5912-22 Summary Deletion of the chromosome 1p36 region is a frequent abnormality in neuroblastoma. To gain further insights into the role of this alteration in oncogenesis, we have constructed a specific cDNA microarray representing most known genes and ESTs from the 1p35-36 region and analysed the expression profiles of 15 neuroblastoma cell lines and 28 neuroblastoma tumours. Hierarchical clustering using expression levels of 320 cDNAs from 1p35-36 separated localized or 4S cases without 1p deletion from advanced stages and cell lines. Supervised learning classification enabled to predict reliably the status of chromosome 1p according to its expression profile. Around 15% of the genes or ESTs presented a significantly decreased expression in samples with 1p deletion as compared to 1p-normal samples suggesting that 1p deletion results in a gene dosage effect on a subset of genes critical for the development of 1p-deleted neuroblastoma. Several genes presumed to have functions in neural differentiation (CDC42, VAMP3, CLSTN1), signal transduction in neural cells (GNB1) and cell cycle regulation (STMN1, RPA2, RBAF600, FBXO6, MAD2L2) exhibited a decreased expression in samples presenting 1p deletion. The identification of such genes provides baseline information for further studies to elucidate how these genes could individually or collectively play a critical role in neuroblastoma tumorigenesis. Souhila Medjkane, Eugene Novikov, Isabella Versteege, Olivier Delattre (2004 May 20) The tumor suppressor hSNF5/INI1 modulates cell growth and actin cytoskeleton organization. Cancer research : 3406-13 INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 3 Team Publications Diversity and Plasticity of Childhood Tumors (DePiCT) Summary hSNF5/INI1, which encodes a component of the ATP-dependent chromatin remodeling hSWI- SNF complex, is a tumor suppressor gene mutated in malignant rhabdoid tumors. We have developed a tetracycline-based hSNF5/INI1-inducible system in a hSNF5/INI1-deficient malignant rhabdoid tumor cell line and studied time course variation of 22,000 genes/expressed sequence tags upon hSNF5/INI1 induction. A total of 482 responsive genes were identified and further clustered into 9 groups of coregulated genes. Among genes with early and strong inductions, the use of a fusion protein with the hormone-binding domain of the estrogen receptor