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A 6-gene signature identifies four molecular subgroups of neuroblastoma

Journal article
Authors Frida Abel
Daniel Dalevi
Maria Nethander
Rebecka Jörnsten
Katleen De Preter
Joëlle Vermuelen
Raymond Stallings
Per Kogner
John Maris
Staffan Nilsson
Published in Cancer Cell International
Volume 11
Issue 9
ISSN 1475-2867
Publication year 2011
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Department of Mathematical Sciences, Mathematical Statistics
Language en
Links dx.doi.org/10.1186/1475-2867-11-9
https://gup.ub.gu.se/file/77880
Keywords EXPRESSION-BASED CLASSIFICATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; TUMOR-SUPPRESSOR GENE; ACTIVATING MUTATIONS; ONCOLOGY GROUP; MESSENGER-RNA; COPY scigloo.NUMBER; ALK KINASE; AMPLIFICATION; PROGRESSION
Subject categories Medical and Health Sciences

Abstract

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.

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