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1209177A.Pdf Oncogene (2006) 25, 1571–1583 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc ONCOGENOMICS Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primaryglioma cell lines G Roversi1, R Pfundt2, RF Moroni1, I Magnani1, S van Reijmersdal2, B Pollo3, H Straatman4, L Larizza1 and EFPM Schoenmakers2 1Department of Biology and Genetics, University of Milan, Milan, Italy; 2Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 3Istituto Neurologico Besta, Milan, Italy and 4Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Identification of genetic copynumber changes in glial further identification of novel genetic elements, which may tumors is of importance in the context of improved/refined provide us with molecular tools for the improved diagnostic, prognostic procedures and therapeutic deci- diagnostics and therapeutic decision-making in these sion-making. In order to detect recurrent genomic copy tumors. number changes that might playa role in glioma Oncogene (2006) 25, 1571–1583. doi:10.1038/sj.onc.1209177; pathogenesis and/or progression, we characterized 25 published online 24 October 2005 primaryglioma cell lines including 15 non glioblastoma (non GBM) (I–III WHO grade) and 10 GBM (IV WHO Keywords: glioma; array-based CGH; copy number grade), byarraycomparative genomic hybridization, changes; chromosome 19 using a DNA microarraycomprising approx. 3500 BACs covering the entire genome with a 1 Mb resolution and additional 800 BACs covering chromosome 19 at tiling path resolution. Combined evaluation bysingle clone and whole chromosome analysis plus ‘moving average (MA) Introduction approach’ enabled us to confirm most of the genetic abnormalities previouslyidentified to be associated with Gliomas are the most frequently occurring primary glioma progression, including þ 1q32, þ 7, À10, À22q, brain tumors in humans, and can be subdivided into PTEN and p16 loss, and to disclose new small genomic three histological subtypes, that is, astrocytoma, oligo- regions, some correlating with grade malignancy. Grade dendroglioma and mixed oligoastrocytoma (OA), each I–III gliomas exclusivelyshowed losses at 3p26 (53%), characterized by a different grade of malignancy 4q13–21 (33%) and 7p15–p21 (26%), whereas only according to the WHO classification (Kleihues and GBMs exhibited 4p16.1 losses (40%). Other recurrent Cavenee, 2000). Despite recent technical improvements imbalances, such as losses at 4p15, 5q22–q23, 6p23–25, in radiological and pathological diagnostic procedures, 12p13 and gains at 11p11–q13, were shared bydifferent as well as the increasing knowledge on glioma biology glioma grades. Three intervals with peak of loss could be and genetics, the possibilities for effective treatment and further refined for chromosome 10 byour MA approach. prognosis remain poor, especially for patients affected Data analysis of full-coverage chromosome 19 highlighted by glioblastoma (GBM) (the most aggressive astrocytic two main regions of copynumber gain, never described form), who have an average survival of o1 year after before in gliomas, at 19p13.11 and 19q13.13–13.2. The diagnosis (Simpson et al., 1993). At the other side of the well-known 19q13.3 loss of heterozygosity area in gliomas prognostic spectrum, oligodendroglial tumors exhibiting was not frequentlyaffected in our cell lines. Genomic loss of chromosomal arms 1p and/or 19q show a better hotspot detection facilitated the identification of response to chemotherapy and, consequently, a better ONCOGENOMICS small intervals resulting in positional candidate genes prognosis (Cairncross et al., 1998; Ino et al., 2001; such as PRDM2 (1p36.21), LRP1B (2q22.3), ADARB2 Jeuken et al., 2004). (10p15.3), BCCIP (10q26.2) and ING1 (13q34) for losses Difficulties in clinical management (e.g. treatment and and ECT2 (3q26.3), MDK, DDB2, IG20 (11p11.2) for prognosis) are related to the complex identity of gains. These data increase our current knowledge about gliomas, which impairs a clearcut classification needed cryptic genetic changes in gliomas and may facilitate the for discrimination between different tumor subtypes. Limitations of the actual diagnostic criteria are pointed out by data on both the different combinations of Correspondence: Professor L Larizza, Department of Biology and genetic lesions in tumors sharing similar histology, grade Genetics for Medical Sciences, University of Milan, Via Viotti 3/5, and intratumor genetic heterogeneity (Noble and Milano 20133, Italy. E-mail: [email protected] Dietrich, 2004). For these reasons, there is a growing Received 7 April 2005; revised 9 August 2005; accepted 9 September awareness that genome-wide and high-resolution genetic 2005; published online 24 October 2005 analyses will contribute to the improvement of the Array-based CGH in glioma cell lines G Roversi et al 1572 current WHO classification by constructing a more progression to GBM. Besides the confirmatory copy objective molecular taxonomy of gliomas (Mischel et al., number alterations previously identified in gliomas, we 2004). also identified several genomic intervals containing For this purpose, over the last decade molecular novel candidate genes involved in gliomagenesis and/ approaches including mutation screening, comparative or progression recurrently found to be affected. Further genomic hybridization (CGH) and loss of heterozygo- clinical validation of these intervals by dedicated sity (LOH) analyses have led to the identification of the approaches might enable their inclusion among the most frequently recurring genomic imbalances correlat- genetic markers useful for a prognostic classification of ing to each WHO subtype (Koschny et al., 2002; gliomas, and is expected to ultimately lead to improved Shapiro, 2002; Kitange et al., 2003) and to the clinical decision-making. identification of several genes acting in pathways involved in glioma development, either in the initiation stages (p53 and Ras by PDGF-NF1) or in malignant Results progression (Rb-CDKN2-CDK4) (Zhu and Parada, 2002; Collins, 2004). Deletion of 19q is of particular Recurrent genomic imbalances interest, as it is shared by all three glioma subtypes, Aiming at the detection of recurrent genomic copy occurring in approximately 75% of oligodendroglioma, number changes involved in glioma genesis and/or 45% of mixed OA and 40% of astrocytoma (von progression, we characterized 15 grade I–III gliomas Deimling et al., 1992, 1994), where it is associated with (defined as ‘non-GBMs’) and 10 GBMs primary cell the transition from low-grade to anaplasic tumors lines (Supplementary Table A) by aCGH on a 3.5k (Ohgaki et al., 1995; Ritland et al., 1995; Smith et al., whole genome plus full-coverage chromosome 19 BAC 1999). Furthermore, similarly to oligodendroglioma, array. Figure 1 depicts all the autosome ideograms combined LOH of 1p and 19q was found to define a (except chromosome 19, which is shown separately and small subset of GBM patients with a significantly better in more detail in Figure 3) with the corresponding copy survival, even if their tumors are not morphologically number changes identified in each cell line by the distinguishable from the bulk of GBMs (Schmidt et al., combined application of two statistical approaches: the 2002). whole chromosome association analysis and the ‘moving A candidate tumor suppressor region has been average (MA)’ algorithm. Whole chromosome associ- assigned by LOH studies to 19q13.3, but no prime ation analysis defines entirely gained or lost chro- positional functional candidate gene in this band has yet mosomes (Hackett et al., 2003), whereas the ‘MA been identified (Hartmann et al., 2002). We postulated a algorithm’ allowed us to cluster gained or lost clones possible role for the novel serine threonine kinase gene with aberrant average ratios in consecutive areas of copy MARK4, which maps at the centromeric boundary of number changes (Schraders et al., 2005). For more the 19q13.3 LOH region, and which is overexpressed defined regions affecting at least four cases of partial and duplicated in three GBM cell lines (Beghini et al., chromosomal arm imbalance, the smallest regions of 2003). overlap (SROs), defined as the minimal regions of In order to improve our current knowledge on both deletion/gain overlap, were also determined as shown in gross and subtle genetic changes involved in glioma Table 1, where detailed clone information as well as the initiation and progression, we interrogated 25 primary physical location (Mb positions) of the encompassing cell lines at the whole genome level by array-based and flanking clones is also provided. comparative genomic hybridization (array-CGH or Figure 1 and Table 1 show genomic imbalance aCGH) at a 1 Mb resolution. Since chromosome 19 is affecting either specifically GBMs or non-GBMs of particular interest in the context of clinical decision- or, alternatively, both. The most frequent changes making, a full genomic chromosome 19 tiling path was exclusive for GBMs involve complete or partial gain also present on our arrays (our current resolution on of chromosome 7 (70%), loss of chromosomes 10 chromosome 19 is in theory around 50 kb, and in (100%) and 22 (40%) (Kitange et al., 2003), which practice around 100 kb). are known to be involved in glioma progression, as Few high-resolution aCHG studies on gliomas are well as gain at 1q32 (Riemenschneider
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