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.

Copy number defects of G1‐Cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis

“…S1). Moreover, the CCND1 gene sporadically showed high level amplification, which is in line with our previous findings (Molenaar et al, 2003;Michels et al, 2007). In our cohort of 82 neuroblastomas, we identified two primary tumors with high level amplification of the 11q13 region including the CCND1 gene (Supporting Information Fig.…”

“…Several of these events have been reported before. We and others have reported sporadic cases of CCND1 amplification (Molenaar et al, 2003;Michels et al, 2007). CDK4 amplifications in neuroblastoma have been identified before but only in established cell lines (Van Roy et al, 1995;FAn et al, 1999).…”

International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee

“…(Cohn et al, 2009). Recent publications clearly show the potential of comprehensive genome-wide approaches to further refine the prognostic accuracy of somatically acquired chromosomal alterations, (Vandesompele et al, 2005;Michels et al, 2007;Mosse et al, 2007;Schleiermacher et al, 2007;Tomioka et al, 2008). These studies have shown that in tumours without MYCN amplification, segmental chromosome aberrations are associated with clinically aggressive disease.…”

“…Chip-based technologies have also been used to molecularly classify neuroblastoma tumours (Bilke et al, 2005;George et al, 2005;Selzer et al, 2005;Spitz et al, 2006;Stallings et al, 2006;Lastowska et al, 2007;Michels et al, 2007;Mosse et al, 2007;Tomioka et al, 2008). Comparative genomic hybridisation has reached a high coverage of the target sequences and become more widely used.…”

Cyclin D1 is a direct transcriptional target of GATA3 in neuroblastoma tumor cells

“…We have previously reported high-level genomic amplification of the Cyclin D1 gene in 5 out of 202 neuroblastoma tumors and cell lines. Others also reported recurrent high-level genomic amplifications of the 11q13 region encompassing the Cyclin D1 gene (Molenaar et al, 2003;Michels et al, 2007). These clonal events clearly pointed to a crucial function for Cyclin D1 in neuroblastoma tumor genesis, but could not explain the overexpression of Cyclin D1 in about 75% of the remaining neuroblastomas, that showed Cyclin D1 expression levels reaching equal or even higher levels compared to tumors with genomic amplification.…”