Chromosome 17/17q gain and unaltered profiles in high resolution array‐CGH are prognostically informative in neuroblastoma

Abstract

The prognostic relevance of chromosome 17 gain in neuroblastoma is still discussed. This investigation specifies the frequency, type, size, and transcriptional relevance in a large patient cohort. Primary tumor material of 202 patients was analyzed using high-resolution oligonucleotide array-based comparative genomic hybridization (aCGH) and correlated with clinical and survival data. A subset (n = 145) was correlated for differentially expressed genes (DEG) by microarray analysis. Chromosome 17 aCGH analysis showed numerical gain in 94/202 patients (47%), partial gain in 93/202 patients (46%), and no gain in 15/202 patients (7%). The frequency of partial gain was higher in stage 4 neuroblastoma (stage 1 15%; stage 2 12%; stage 3 16%; stage 4S 7%; and stage 4 50%). Overall survival (OS) was superior in patients with numerical gain compared with patients with partial gain or no gain (5-y-OS: 0.95 ± 0.02 vs. 0.63 ± 0.05 vs. 0.60 ± 0.13; P < 0.001). Gene expression analysis demonstrated 95/130 DEGs between tumors with numerical or partial chromosome/no gain. Only one DEG (CCKBR) was detected comparing tumors with partial gain and those with no gain. In patients with partial gain, the distribution of breakpoints did not correlate with stage and 11q status, but with MYCN amplification and 1p status. The "best" breakpoints in cases with partial 17q gain were at 42.5 Mb for event-free and 26.6 Mb for OS. Numerical gain of chromosome 17 is associated with a better prognosis than partial and no gain. The group of tumors with partial gain was similar to the group without gain with respect to stage distribution, outcome, and gene expression profile.

MYCNoverexpression is associated with unbalanced copy number gain, altered nuclear location, and overexpression of chromosome arm 17q genes in neuroblastoma tumors and cell lines

“…Previous studies have, however, been confounded by the fact that numerical versus no gain of chromosome 17 was not distinguished in the nonunbalanced gain patient group; this has led to mixed conclusions as to whether the copy number status of chromosome 17 provides any prognostic value in MYCN ‐nonamplified patients. Our findings provide further support for the hypothesis that neuroblastomas with numerical gain of chromosome 17 have a better prognosis when compared with those with no gain, initially proposed by Theissen et al (). In our study, the majority of neuroblastomas with unbalanced gain of 17q are MYCN amplified and have high MYCN expression.…”

“…Theissen et al () found that neuroblastomas with numerical gain of chromosome 17 have a better prognosis when compared with those with partial or no gain, a distinction not made in previous studies (Spitz et al, ). Tumors with partial or no gain of chromosome 17 also had very similar gene expression profiles (Theissen et al, ). These findings suggest that although neuroblastomas with no gain of chromosome 17 are genetically distinct from those with partial chromosome 17 gain, these types of tumors may share similar oncogene regulation, such as MYCN, resulting in similar gene expression profiles and prognosis.…”

“…The unbalanced gain of 17q is the most frequent chromosome aberration in neuroblastoma (Brinkschmidt et al, 1997;Lastowska et al, 1997b;Plantaz et al, 1997) and is an independent prognostic factor of poor outcome (Caron, 1995;Lastowska et al, 1997a;Bown et al, 1999;Vandesompele et al, 2005). Theissen et al (2014) found that neuroblastomas with numerical gain of chromosome 17 have a better prognosis when compared with those with partial or no gain, a distinction not made in previous studies (Spitz et al, 2003). Tumors with partial or no gain of chromosome 17 also had very similar gene expression profiles (Theissen et al, 2014).…”

Predicting clinical outcome of neuroblastoma patients using an integrative network-based approach

“…All clinical descriptors are binary and are available for all 498 patients. The original data have been described previously [7, 15–18]. The two expression datasets contain pre-processed profiles for 498 samples, corresponding to 498 patients.…”

Neuroblastoma: Molecular Pathogenesis and Therapy

“…Likewise, structural genomic changes have not been linked to NB tumorigenesis. For example, 1p deletion, MYCN amplification, or gain of 17q may identify subtypes of neuroblastoma and impact survival (28, 29), yet there is no common neuroblastoma-specific genomic alteration, LOH or genetic translocation uniformly ascribed to all high-risk neuroblastoma tumors. Thus, this extensive molecular heterogeneity supports the concept that neuroblastoma represents a spectrum of disease.…”