A Three-Gene Expression Signature Model for Risk Stratification of Patients with Neuroblastoma

Abstract

Purpose Neuroblastoma is an embryonal tumor with contrasting clinical courses. Despite elaborate stratification strategies, precise clinical risk assessment still remains a challenge. The purpose of this study was to develop a PCR-based predictor model to improve clinical risk assessment of patients with neuroblastoma. Experimental Design The model was developed using real-time PCR gene expression data from 96 samples and tested on separate expression data sets obtained from real-time PCR and microarray studies comprising 362 patients. Results On the basis of our prior study of differentially expressed genes in favorable and unfavorable neuroblastoma subgroups, we identified three genes, CHD5, PAFAH1B1, and NME1, strongly associated with patient outcome. The expression pattern of these genes was used to develop a PCR-based single-score predictor model. The model discriminated patients into two groups with significantly different clinical outcome [set 1: 5-year overall survival (OS): 0.93 ± 0.03 vs. 0.53 ± 0.06, 5-year event-free survival (EFS): 0.85 ± 0.04 vs. 0.042 ± 0.06, both P < 0.001; set 2 OS: 0.97 ± 0.02 vs. 0.61 ± 0.1, P = 0.005, EFS: 0.91 ± 0.8 vs. 0.56 ± 0.1, P = 0.005; and set 3 OS: 0.99 ± 0.01 vs. 0.56 ± 0.06, EFS: 0.96 ± 0.02 vs. 0.43 ± 0.05, both P < 0.001]. Multivariate analysis showed that the model was an independent marker for survival (P < 0.001, for all). In comparison with accepted risk stratification systems, the model robustly classified patients in the total cohort and in different clinically relevant risk subgroups. Conclusion We propose for the first time in neuroblastoma, a technically simple PCR-based predictor model that could help refine current risk stratification systems.

NDPKA is not just a metastasis suppressor – be aware of its metastasis-promoting role in neuroblastoma

“…21 NDPK-A OR NDPK-A S120G ENHANCES NEUROBLASTOMA CELL INVASIVENESS Metastasis-associated cellular processes include decreased cell adhesion as well as increased cell survival, migration, invasion, and colonization. For simplicity here, these cellular processes are collectively termed cell invasiveness.…”

DNA Methylation Fingerprint of Neuroblastoma Reveals New Biological and Clinical Insights

“…Neuroblastoma risk assessment was defined by the International Neuroblastoma Staging System (INSS) [30]. Patients' clinical and biological characteristics are displayed in Supplementary Table 1 [31][32][33].…”

NME1 (NME/NM23 nucleoside diphosphate kinase 1)

“…In neuroblastoma, all studies reported an enhanced expression of NME1 in tumors, correlated, when evaluated, with a poor prognosis (Hailat et al, 1991;Leone et al, 1993b;Chang et al, 1994;Hiyama et al, 2004;Garcia et al, 2012). In accordance with a metastatic promoting role, enhanced NME1 expression in the NB69 neuroblastoma cell line increased cell migration and metastatic potential (Almgren et al, 2004).…”

“…This was observed with cell lines derived from melanoma (Leone et al, 1991) and from breast (Leone et al, 1993a), colon (Suzuki et al, 2004), lung (Nie et al, 2008), liver (She et al, 2010), ovarian (Li et al, 2006), prostate (Andolfo et al, 2011) and oral (Wang YF et al, 2008) carcinomas. In other types of cancers such as neuroblastoma (Leone et al, 1993b;Garcia et al, 2012), hematopoietic malignancies (Yokoyama et al, 1998) and osteosarcoma (Liao et al, 2000), a high tumoral expression was noted which was most often correlated with poor clinical outcome.…”