Chromosome instability in neuroblastoma

Abstract

Neuroblastoma is a neural crest-derived tumor that accounts for 7-10% of all malignancies in children and ~15% of all childhood cancer-associated mortalities. Approximately 50% of patients are characterized as high-risk (HR) and have an overall survival of <40% at 5 years from diagnosis. HR patients with unfavorable prognosis exhibit several structural copy number variations (CNVs), whereas localized tumors belonging to patients in the low- and intermediate-risk classes, have favorable outcomes and display several numerical CNVs. Taken together these results are indicative of chromosome instability (CIN) in neuroblastoma tumor cells. The present review discusses multiple aspects of CIN including methods of measuring CIN, CIN targeting as a therapeutic strategy in cancer and the effects of CIN in neuroblastoma development and aggressiveness with particular emphasis on the CIN gene signature associated with HR neuroblastoma patients.

Keywords: chromosome instability; chromosome instability signature; neuroblastoma; tumorigenesis.

Figure 1.

Schematic presenting the causes of chromosome missegregation in mitosis.

Figure 2.

Unsupervised clustering of 45 genes with CIN70 in NB. The heatmap of the unsupervised clustering presents 30 genes with differential expression between NB-high risk patients (stages 2, 3, 4, and 4S with MYCN gene amplification; stage 4 patients with an age at diagnosis >12 months) and low/intermediate-risk patients (stage 1, 2, 3, 4S without MYCN gene amplification). Above the heatmap are the indicated patient clinical features and the patients' stage. Black bars represent unfavorable scores and light gray bars represent favorable scores for ‘Status of Disease’ and ‘Outcome’. Black bars for the ‘Age at Diagn.’ identify cases with ages over 60 months at diagnosis. Black bars for ‘MYCN’ identify cases with amplification of MYCN gene. On the left of the panel is a key of the staging colors applied. On the right of the panel are the 45 genes out of CIN70. CIN, chromosome instability; NB, neuroblastoma; MYCN, neuroblastoma MYC oncogene; St., stage.