http://repub.eur.nl/res/aut/5282/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/21486/ 2010-11-02T00:00:00Z http://repub.eur.nl/res/pub/19698/ 2010-07-01T00:00:00Z Relapse is the most common cause of treatment failure in pediatric acute lymphoblastic leukemia (ALL) and is often difficult to predict. To explore the prognostic impact of recurrent DNA copy number abnormalities on relapse, we performed high-resolution genomic profiling of 34 paired diagnosis and relapse ALL samples. Recurrent lesions detected at diagnosis, including PAX5, CDKN2A and EBF1, were frequently absent at relapse, indicating that they represent secondary events that may be absent in the relapse-prone therapy-resistant progenitor cell. In contrast, deletions and nonsense mutations in IKZF1 (IKAROS) were highly enriched and consistently preserved at the time of relapse. A targeted copy number screen in an unselected cohort of 131 precursor B-ALL cases, enrolled in the dexamethasone-based Dutch Childhood Oncology Group treatment protocol ALL9, revealed that IKZF1 deletions are significantly associated with poor relapse-free and overall survival rates. Separate analysis of ALL9-treatment subgroups revealed that non-high-risk (NHR) patients with IKZF1 deletions exhibited a ∼12-fold higher relative relapse rate than those without IKZF1 deletions. Consequently, IKZF1 deletion status allowed the prospective identification of 53% of the relapse-prone NHR-classified patients within this subgroup and, therefore, serves as one of the strongest predictors of relapse at the time of diagnosis with high potential for future risk stratification.Leukemia advance online publication, 6 May 2010; doi:10.1038/leu.2010.87. http://repub.eur.nl/res/pub/24298/ 2009-12-01T00:00:00Z FBXW7 (alias CDC4) is a p53-dependent tumor suppressor gene that exhibits mutations or deletions in a variety of human tumors. Mutation or deletion of the FBXW7 gene has been associated with an increase in chromosomal instability and cell cycle progression. In addition, the FBXW7 protein has been found to act as a component of the ubiquitin proteasome system and to degrade several oncogenic proteins that function in cellular growth regulatory pathways. By using a rapid breakpoint cloning procedure in a case of renal cell cancer (RCC), we found that the FBXW7 gene was disrupted by a constitutional t(3;4)(q21;q31). Subsequent analysis of the tumor tissue revealed the presence of several anomalies, including loss of the derivative chromosome 3. Upon screening of a cohort of 29 independent primary RCCs, we identified one novel pathogenic mutation, suggesting that the FBXW7 gene may also play a role in the development of sporadic RCCs. In addition, we screened a cohort of 48 unrelated familial RCC cases with unknown etiology. Except for several known or benign sequence variants such as single nucleotide polymorphisms (SNPs), no additional pathogenic variants were found. Previous mouse models have suggested that the FBXW7 gene may play a role in the predisposition to tumor development. Here we report that disruption of this gene may predispose to the development of human RCC. http://repub.eur.nl/res/pub/36876/ 2007-09-01T00:00:00Z Recent studies have revealed a new type of variation in the human genome encompassing relatively large genomic segments (∼100 kb-2.5 Mb), commonly referred to as copy number variation (CNV). The full nature and extent of CNV and its frequency in different ethnic populations is still largely unknown. In this study we surveyed a set of 12 CNVs previously detected by array-CGH. More than 300 individuals from five different ethnic populations, including three distinct European, one Asian and one African population, were tested for the occurrence of CNV using multiplex ligation-dependent probe amplification (MLPA). Seven of these loci indeed showed CNV, i.e., showed copy numbers that deviated from the population median. More precise estimations of the actual genomic copy numbers for (part of) the NSF gene locus, revealed copy numbers ranging from two to at least seven. Additionally, significant inter-population differences in the distribution of these copy numbers were observed. These data suggest that insight into absolute DNA copy numbers for loci exhibiting CNV is required to determine their potential contribution to normal phenotypic variation and, in addition, disease susceptibility. Copyright http://repub.eur.nl/res/pub/3025/ 1991-01-01T00:00:00Z The human excision-repair gene ERCC3 was cloned after DNA-mediated gene transfer to the uv-sensitive Chinese hamster ovary mutant cell line 27-1, a member of complementation group 3 of the excision-defective rodent cell lines. The ERCC3 gene specifically corrects the DNA repair defect of xeroderma pigmentosum (XP) complementation group B, which displays the clinical symptoms of XP as well as of another rare excision-repair disorder, Cockayne syndrome. The gene encodes a presumed DNA and chromatin binding helicase, involved in early steps of the excision-repair pathway. ERCC3 was previously assigned to human chromosome 2 (L.H. Thompson, A.V. Carrano, K. Sato, E.P. Salazar, B.F. White, S.A. Stewart, J.L. Minkler, and M.J. Siciliano (1987) Somat. Cell Genet. 13: 539-551). Here we report its subchromosomal localization in the q21 region of chromosome 2 via somatic cell hybrids containing a translocated chromosome 2 and in situ hybridization with fluorescently labeled ERCC3 probes. http://repub.eur.nl/res/pub/2387/ 1985-01-01T00:00:00Z We have isolated the gene coding for human Thy-1. Introduction of this gene into HeLa cells by DNA-mediated transfer results in the expression of Thy-1 antigen on the cell surface. Chromosomal mapping of the Thy-1 gene by hybridization to metaphase chromosomes and Southern blots of DNA from hybrid cells indicate that the Thy-1 gene is located on the long arm of chromosome 11. http://repub.eur.nl/res/pub/37548/ 1983-09-28T00:00:00Z During the last two decades evidence for a close association between the presence of specific chromosomal abnormalities and the occurrence of several types of cancers and leukemias has accumulated. The Philadelphia (Ph 1) translocation, present in about 90% of the patients with chronic myeloid leukemia (CML), is one of the most typical and best documented examples of such an aberration. Usually this translocation involves chromosome 9 and 22: t(9;22)(q34;q11). The translocation products are designated 9q+ and 22q-. Variant translocations involving an array of translocation sites different from 9 have been described as well, but chromosome 22 is always involved. So far, no clear indications were found for the possible role played by this highly specific chromosomal aberration in the etiology of CML. Moreover, results concerning the exact nature of the Ph1 translocation, obtained by different investigators using different techniques, appeared to be contradictory. In this thesis the application of somatic cell hybridization and gene segregation analyses to these questions has been described. Rodent cells (fibroblasts) were fused with human Ph1 positive leucocytes and, subsequently, hybrid cell 1 ines were isolated. These hybrids appeared to segregate human chromosomes, including the Ph1 translocation products. The segregation of genes, previously assigned to the regions of the chromosomal breakpoints, was studied together with the segregation of the relevant human (translocation) chromosomes. Several genes on chromosome 22 were found to be translocated to the 9q+ chromosome which confirmed, on a molecular level, the translocation of chromosome 22 materia] to chromosome 9. Another gene on chromosome 22 (immunoglobulin A 1 ight chain) stayed on the Ph1 chromosome (22q-). One gene on chromosome 9 (c-abl) appeared to be translocated to 22q-. This latter result provided unequivocal evidence for reciprocity of the Ph 1 translocation. No apparent differences in chromosomal breakpoints could be revealed in the different CML patients used for analysis and no evidence was found for loss of chromosomal material {genes) as a result of the Ph 1 translocation. The clonal origin of the Ph 1 translocation in CML was confirmed using a chromosome 9 encoded polymorphic enzyme (AKI).