Showing papers by "Katleen De Preter published in 2007"

Human fetal neuroblast and neuroblastoma transcriptome analysis confirms neuroblast origin and highlights neuroblastoma candidate genes

Abstract: Background: Neuroblastoma tumor cells are assumed to originate from primitive neuroblasts giving rise to the sympathetic nervous system. Because these precursor cells are not detectable in postnatal life, their transcription profile has remained inaccessible for comparative data mining strategies in neuroblastoma. This study provides the first genome-wide mRNA expression profile of these human fetal sympathetic neuroblasts. To this purpose, small islets of normal neuroblasts were isolated by laser microdissection from human fetal adrenal glands. Results: Expression of catecholamine metabolism genes, and neuronal and neuroendocrine markers in the neuroblasts indicated that the proper cells were microdissected. The similarities in expression profile between normal neuroblasts and malignant neuroblastomas provided strong evidence for the neuroblast origin hypothesis of neuroblastoma. Next, supervised feature selection was used to identify the genes that are differentially expressed in normal neuroblasts versus neuroblastoma tumors. This approach efficiently sifted out genes previously reported in neuroblastoma expression profiling studies; most importantly, it also highlighted a series of genes and pathways previously not mentioned in neuroblastoma biology but that were assumed to be involved in neuroblastoma pathogenesis. Conclusion: This unique dataset adds power to ongoing and future gene expression studies in neuroblastoma and will facilitate the identification of molecular targets for novel therapies. In addition, this neuroblast transcriptome resource could prove useful for the further study of human sympathoadrenal biogenesis.

ArrayCGH-based classification of neuroblastoma into genomic subgroups

Abstract: High-resolution array comparative genomic hybridization (arrayCGH) profiling was performed on 75 primary tumors and 29 cell lines to gain further insight into the genetic heterogeneity of neuroblastoma and to refine genomic subclassification. Using a novel data-mining strategy, three major and two minor genomic subclasses were delineated. Eighty-three percent of tumors could be assigned to the three major genomic subclasses, corresponding to the three known clinically and biologically relevant subsets in neuroblastoma. The remaining subclasses represented (1) tumors with no/few copy number alterations or an atypical pattern of aberrations and (2) tumors with 11q13 amplification. Inspection of individual arrayCGH profiles showed that recurrent genomic imbalances were not exclusively associated with a specific subclass. Of particular notice were tumors with numerical imbalances typically observed in subtype 1 neuroblastoma, in association with genomic features of subtype 2A or 2B. A search for prognostically relevant genomic alterations disclosed 1q gain as a predictive marker for therapy failure within the group of subtype 2A and 2B tumors. In cell lines, a high incidence of 6q loss was observed, with a 3.87-5.32 Mb region of common loss within 6q25.1-6q25.2. Our study clearly illustrates the importance of genomic profiling in relation to tumor behavior in neuroblastoma. We propose that genome-wide assessment of copy number alterations should ideally be included in the genetic workup of neuroblastoma. Further multicentric studies on large tumor series are warranted in order to improve therapeutic stratification in conjunction with other features such as age at diagnosis, tumor stage, and gene expression signatures.

Erratum: Human fetal neuroblast and neuroblastoma transcriptome analysis confirms neuroblast origin and highlights neuroblastoma candidate genes (Genome Biology)

Abstract: A correction to Human fetal neuroblast and neuroblastoma transcriptome analysis confirms neuroblast origin and highlights neuroblastoma candidate genes by K De Preter, J Vandesompele, P Heimann, N Yigit, S Beckman, A Schramm, A Eggert, RL Stallings, Y Benoit, M Renard, A De Paepe, G Laureys, S Påhlman and F Speleman. Genome Biology 2006 7:R84

A detailed inventory of DNA copy number alterations in four commonly used Hodgkin’s lymphoma cell lines

Abstract: Background and Objectives Classical Hodgkin’s lymphoma (cHL) is a common malignant lymphoma characterized by the presence of large, usually multinucleated malignant Hodgkin and Reed Sternberg (HRS) cells which are thought to be derived from germinal center B-cells. In cHL, the HRS cells constitute less than 1% of the tumor volume; consequently the profile of genetic aberrations in cHL is still poorly understood. Design and Methods In this study, we subjected four commonly used cHL cell lines to array comparative genomic hybridization (aCGH) in order to delineate known chromosomal aberrations in more detail and to search for small hitherto undetected genomic imbalances. Results The aCGH profiles of the four cell lines tested confirmed the complex patterns of rearrangements previously demonstrated with multicolor fluorescence in situ hybridization and chromosomal CGH (cCGH). Importantly, aCGH allowed a much more accurate delineation of imbalances as compared to previous studies performed at a chromosomal level of resolution. Furthermore, we detected 35 hitherto undetected aberrations including a homozygous deletion of chromosomal region 15q26.2 in the cell line HDLM2 encompasing RGMA and CHD2 and an amplification of the STAT6 gene in cell line L1236 leading to STAT6 overexpression. Finally, in cell line KM-H2 we found a 2.35 Mb deletion at 16q12.1 putatively defining a small critical region for the recurrent 16q deletion in cHL. This region contains the CYLD gene, a known suppressor gene of the NF-κB pathway. Interpretation and Conclusions aCGH was performed on four cHL cell lines leading to the improved delineation of known chromosomal imbalances and the detection of 35 hitherto undetected aberrations. More specifically, our results highlight STAT6 as a potential transcriptional target and identified RGMA , CHD2 and CYLD as candidate tumor suppressors in cHL.

Identification of 2 putative critical segments of 17q gain in neuroblastoma through integrative genomics

Abstract: Partial gain of chromosome arm 17q is the most frequent genetic change in neuroblastoma (NB) and constitutes the strongest independent genetic factor for adverse prognosis. It is assumed that 1 or more genes on 17q contribute to NB pathogenesis by a gene dosage effect. In the present study, we applied chromosome 17 tiling path BAC arrays on a panel of 69 primary tumors and 28 NB cell lines in order to reduce the current smallest region of gain and facilitate identification of candidate dosage sensitive genes. In all tumors and cell lines with 17q gain, large distal segments were consistently present in extra copies and no interstitial gains were observed. In addition to these large regions of distal gain with breakpoints proximal to coordinate 44.3 Mb (17q21.32), smaller regions of gain (distal to coordinate 60 Mb at 17q24.1) were found superimposed on the larger region in a minority of cases. Positional gene enrichment analysis for 17q genes overexpressed in NB showed that dosage sensitive NB oncogenes are most likely located in the gained region immediately distal to the most distal breakpoint of the 2 breakpoint regions. Interestingly, comparison of gene expression profiles between primary tumors and normal fetal adrenal neuroblasts revealed 2 gene clusters on chromosome 17q that are overexpressed in NB, i.e. a region on 17q21.32 immediately distal to the most distal breakpoint (in cases with single regions of gain) and 17q24.1, a region coinciding with breakpoints leading to superimposed gain.

High resolution tiling-path BAC array deletion mapping suggests commonly involved 3p21-p22 tumor suppressor genes in neuroblastoma and more frequent tumors.

Abstract: The recurrent loss of 3p segments in neuroblastoma suggests the implication of 1 or more tumor suppressor genes but thus far few efforts have been made to pinpoint their detailed chromosomal position. To achieve this goal, array-based comparative genomic hybridization was performed on a panel of 23 neuroblastoma cell lines and 75 primary tumors using a tiling-path bacterial artificial chromosome array for chromosome 3p. A total of 45 chromosome 3 losses were detected, including whole chromosome losses, large terminal deletions and interstitial deletions. The latter, observed in cell lines as well as a number of distal deletions detected in primary tumors, allowed us to demarcate 3 minimal regions of loss of 3.6 Mb [3p21.31-p21.2, shortest regions of overlap (SRO)1], 1.4 Mb (3p22.3-3p22.2, SRO2) and 3.8 Mb (3p25.3-p25.1, SRO3) in size. The present data significantly extend previous findings and now firmly establish critical regions on 3p implicated in neuroblastoma. Interestingly, the 2 proximal regions coincide with previously defined SROs on 3p21.3 in more frequent tumors including lung and breast cancer. As such, similar tumor suppressor genes may play a critical role in development or progression of a variety of neoplasms, including neuroblastoma.