Survivin mRNA Levels Are Associated With Biology of Disease and Patient Survival in Neuroblastoma: A Report From the Children's Oncology Group

Abstract

Alterations in apoptotic mechanisms favoring cell survival may be vital for modifying tumor behavior. Survivin, an inhibitor of apoptosis, and caspase 8, a proapoptotic enzyme, are key players in cellular apoptotic mechanisms. We investigated whether the levels of survivin and caspase 8 and the ratio between these 2 apoptotic factors correlate with tumor biology and predicts outcome in patients with neuroblastoma. Survivin and caspase 8 levels were quantified in 38 primary tumor specimens and analyzed individually and in relation to each other. High survivin expression and high survivin:caspase 8 ratios were associated with MYCN amplification, unfavorable histology, and high-risk group of disease (P<0.0008). High survivin mRNA levels were associated with worse overall survival (P=0.02) although the median follow up was only 22.6 months with a range of 1 day to 3.3 years. Low caspase 8 expression was associated with stage 4 disease, high-risk group, MYCN amplification, and unfavorable histology. Although the survivin:caspase 8 ratio was associated with these risk factors, the ratio did not improve the predictive value of survivin alone in this small series. Quantifying multiple apoptotic genes in neuroblastoma may supplement current risk stratification. Moreover, categorizing aberrant apoptotic gene expression in neuroblastoma may translate into novel therapeutic targets.

Identification of candidate genes involved in neuroblastoma progression by combining genomic and expression microarrays with survival data

“…We therefore reanalysed the expression of four genes which showed significant copy number dependent expression (PMP22, WSB1, BRCA1 and BIRC5) using real-time PCR. These genes were chosen as they map to distinct regions of chromosome 17 (17p12, 17q11, 17q21 and 17q25, respectively), and because they have been implicated previously in neuroblastoma or other cancers (Chen et al, 2006;Deng, 2006;Miller et al, 2006). Significant correlations were observed between Affymetrix and real-time PCR data for all four genes, r 2 varying from 0.683 for BRCA1 to 0.961 for PMP22 (Supplementary Figure 2S).…”

Repression of BIRC5/Survivin by FOXO3/FKHRL1 Sensitizes Human Neuroblastoma Cells to DNA Damage-induced Apoptosis

“…FKHRL1 is retained in the cytoplasm in NB cells but rapidly translocates into the nucleus upon inhibition of PI3K ( Figure 1, A and B) and represses the antiapoptotic protein Survivin (Figure 3). In primary NB cells, Survivin expression correlates with adverse clinical factors, advanced disease stage (Islam et al, 2000) and is associated with an unfavorable prognosis (Tajiri et al, 2001;Miller et al, 2006). Survivin overexpression was reported to increase proliferation and to protect tumor cells against apoptosis by various stimuli (Ambrosini et al, 1997;Islam et al, 2000).…”

Identification of Novel Prognostic Markers in Relapsing Localized Resectable Neuroblastoma

“…A selected set of 59 genes with prognostic power in at least two independent studies was selected based on published microarray gene-expression studies. This signature contains genes that have previously been linked with NB biology (MYCN, NTRK1, and ODC1) (Hogarty et al, 2008) or have been proposed as positional candidate genes, including CAMTA1 (Henrich et al, 2006) and CHD5 on 1p, BIRC5 (Albino et al, 2008;Miller et al, 2006) on 17q, and CADM1 (IGSF4 ) (Michels et al, 2008;Nowacki et al, 2008) on 11q. Only very few genes are involved in cell-cycle regulation and proliferation as well as in inflammation.…”