Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification

Abstract

Whereas neuroblastoma (NB) with MYCN amplification presents a poor prognosis, no single marker allows to reliably predict outcome in tumours without MYCN amplification. We report here an extensive analysis of 147 NB samples at diagnosis, without MYCN amplification, by chromosomal comparative genomic hybridisation (CGH), providing a comprehensive overview of their genomic imbalances. Comparative genomic hybridisation profiles showed gains or losses of entire chromosomes (type 1) in 71 cases, whereas partial chromosome gains or losses (type 2), including gain involving 17q were observed in 68 cases. Atypical profiles were present in eight cases. A type 1 profile was observed more frequently in localised disease (Po0.0001), and in patients of less than 12 months at diagnosis (Po0.0001). A type 2 genomic profile was associated with a higher risk of relapse in the overall population (logrank test; Po0.0001), but also in the subgroup of patients with localised disease (log-rank test, P ¼ 0.007). In multivariate analysis, the genomic profile was the strongest independent prognostic factor. In conclusion, the genomic profile is of prognostic impact in patients without MYCN amplification, making it a help in the management of low-stage NB. Further studies using higher-resolution CGH are needed to better characterise atypical genomic alterations.

The neuroblastoma and ganglion components of nodular ganglioneuroblastoma are genetically similar: evidence against separate clonal origins

“…Moreover, these regions of gain have also been reported in other array studies on neuroblastoma. 23,24,[28][29][30]38 Thus, although our results suggest there may be a genetic profile characteristic of nodular ganglioneuroblastoma, it would not appear to distinguish this subtype of neuroblastoma from others. In our series, there was no correlation between the total number of copy number alterations or specific gains and losses and histologic prognostic categories (favorable vs unfavorable) or patient outcome.…”

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

“…These tumours almost always show whole chromosome gains with few, if any, segmental chromosome aberrations and without gene amplifications. The DNA content is usually in the near-triploid (penta/ hexaploid) range (Ambros et al, 1995(Ambros et al, , 1996Brodeur, 2003;George et al, 2007;Mosse et al, 2007;Schleiermacher et al, 2007). This is also the case for the neuroblastic/ganglionic cell population in Schwann cell stroma-rich tumours, whereas the Schwann cell population itself has a diploid DNA content (Ambros et al, 1996;Bourdeaut et al, 2008).…”

“…Other chromosomal aberrations (and a diploid DNA content) have been assumed to predict unfavourable tumour behaviour, including deletion at the chromosomal region 1p36.3 or 11q23, (Maris et al, 1995;Caron et al, 1996b;Attiyeh et al, 2005) as well as unbalanced gain of the long arm of chromosome 17 (17q21 to 17qter; Caron, 1995;Bown et al, 1999;Spitz et al, 2003). In addition, some studies have shown that deletions on chromosome 3p, 4p, 9p, and 12p also have prognostic significance (Caron et al, 1996a;Thompson et al, 2001;Schleiermacher et al, 2007). As 11q deletions are inversely associated with MYCN amplification, this aberration has emerged as a powerful biomarker of outcome in cases without MYCN amplification (Attiyeh et al, 2005).…”

“…(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.…”

“…Locoregional tumours are commonly hyperdiploid; diploidy is more common in advanced-stage tumours. A number of studies have shown that in patients o18 months of age with metastatic disease, hyperdiploidy in combination with a non-amplified MYCN gene and the lack of specific segmental chromosome aberrations (such as 11q deletion) are predictive of a favourable outcome (George et al, 2005;Schleiermacher et al, 2007). However, in patients o18 months of age with metastatic disease with diploid, MYCN non-amplified tumours have a statistically significantly worse outcome.…”