Individual patient risk stratification of high-risk neuroblastomas using a two-gene score suited for clinical use

Abstract

Several gene expression-based prognostic signatures have been described in neuroblastoma, but none have successfully been applied in the clinic. Here we have developed a clinically applicable prognostic gene signature, both with regards to number of genes and analysis platform. Importantly, it does not require comparison between patients and is applicable amongst highrisk patients. The signature is based on a two-gene score (R-score) with prognostic power in high-stage tumours (stage 4 and/or MYCN-amplified diagnosed after 18 months of age). QPCR-based and array-based analyses of matched cDNAs confirmed cross platform (array-qPCR) transferability. We also defined a fixed cut-off value identifying prognostically differing subsets of high-risk patients on an individual patient basis. This gene expression signature independently contributes to the current neuroblastoma classification system, and if prospectively validated could provide further stratification of high-risk patients, and potential upfront identification of a group of patients that are in need of new/additional treatment regimens.

Hypoxia Predicts Poor Prognosis in Neuroblastoma Patients and Associates with Biological Mechanisms Involved in Telomerase Activation and Tumor Microenvironment Reprogramming

“…The RNA-seq498, Agilent709, and Affymetrix413 data sets were homogeneous on the basis of patient clinical and molecular data and they were used for dissecting the prognostic value of the new NB-hop hypoxia biomarker. Analysis of the gene expression profile of NB primary tumors to find prognostic factors is an active research field, and several prognostic signatures have been reported [5,6,100]. However, a large-scale expression study of NB tumors has not been previously carried out because different technologies used different proprietary annotations to identify transcripts.…”

“…The clinical value of novel prognostic factors is often evaluated in selected groups of patients defined by combination of established NB risk factors [5,6,100]. In this study, we assessed the prognostic value of our biomarker in clinically relevant groups of NB patients whose stratification was not previously reported.…”

The challenge of defining “ultra‐high‐risk” neuroblastoma

“…30 Other single-gene abnormalities identified at diagnosis are associated with unfavorable outcome in unselected groups of NBL patients, including mutations of ALK, 31 ARID1A/1B, 32 or ATRX 33 ; TERT rearrangements 34,35 ; c-MYC expression 36,37 ; and genomic instability as evidenced by increased segmental chromosomal aberrations (SCA) 38 or chromothripsis. 39 [41][42][43][44][45] However, there is little overlap in the genes within each classifier, and a lack of prospective validation to confirm their utility for substratification. In addition, many classifiers are confounded by MYCN status and thus are only applicable to subsets of MYCN-A or non-MYCN-A patients.…”

Intra-Tumour Genetic Heterogeneity and Prognosis in High-Risk Neuroblastoma

“…The International NB Risk Group (INRG) [8] has defined a currently-used prognosis classification according to clinical and biological parameters. Patients classified as high risk NB (HR-NB) have the poorest outcomes, with <50% survival [9]. Adverse prognostic factors include metastatic stage, age ≥18 months at diagnosis, undifferentiated or poorly differentiated histopathology and specific genetic abnormalities, such as MYCN amplification (MNA) and segmental chromosomal aberrations (SCAs) [10].…”