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Open Access Highly Accessed Primary research

A 6-gene signature identifies four molecular subgroups of neuroblastoma

Frida Abel1*, Daniel Dalevi2, Maria Nethander3, Rebecka Jörnsten2, Katleen De Preter4, Joëlle Vermeulen4, Raymond Stallings5, Per Kogner6, John Maris7 and Staffan Nilsson2

Author Affiliations

1 Department of Clinical Genetics, Gothenburg University, Gothenburg, Sweden

2 Department of Mathematical Statistics, Chalmers University of Technology, Gothenburg, Sweden

3 Genomics Core Facility, Gothenburg University, Gothenburg, Sweden

4 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

5 Department of Cancer Genetics, Royal College of Surgeons in Ireland and Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland

6 Childhood Cancer Research Unit, Karolinska Institute, Astrid Lindgren Children's Hospital Q6:05, S-171 76 Stockholm, Sweden

7 Children's Hospital of Philadelphia, Division of Oncology, The University of Pennsylvania, Philadelphia, PA

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Cancer Cell International 2011, 11:9  doi:10.1186/1475-2867-11-9

Published: 14 April 2011

Abstract

Background

There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB); Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA) and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis.

Results

The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples). Four distinct clusters were identified by Principal Components Analysis (PCA) in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples) using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p < 0.05, one-way ANOVA test). PCA clusters p1, p2, and p3 were found to correspond well to the postulated subtypes 1, 2A, and 2B, respectively. Remarkably, a fourth novel cluster was detected in all three independent data sets. This cluster comprised mainly 11q-deleted MNA-negative tumours with low expression of ALK, BIRC5, and PHOX2B, and was significantly associated with higher tumour stage, poor outcome and poor survival compared to the Type 1-corresponding favourable group (INSS stage 4 and/or dead of disease, p < 0.05, Fisher's exact test).

Conclusions

Based on expression profiling we have identified four molecular subgroups of neuroblastoma, which can be distinguished by a 6-gene signature. The fourth subgroup has not been described elsewhere, and efforts are currently made to further investigate this group's specific characteristics.