A 6-gene signature identifies four molecular subgroups of neuroblastoma
Artikel i vetenskaplig tidskrift, 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.

ONCOLOGY GROUP

COPY NUMBER

TUMOR-SUPPRESSOR GENE

MESSENGER-RNA

ACUTE LYMPHOBLASTIC-LEUKEMIA

AMPLIFICATION

ACTIVATING MUTATIONS

PROGRESSION

EXPRESSION-BASED CLASSIFICATION

ALK KINASE

Författare

Frida Abel

Göteborgs universitet

Daniel Dalevi

Chalmers University of Technology

Maria Nethander

Göteborgs universitet

Rebecka Jörnsten

Chalmers University of Technology

Katleen De Preter

Center for Medical Genetics

Joëlle Vermuelen

Center for Medical Genetics

Raymond L Stallings

Our Lady's Hospital for Sick Children

Per Kogner

Karolinska universitetssjukhuset

John Maris

University of Pennsylvania

Staffan Nilsson

Göteborgs universitet

Chalmers, Matematiska vetenskaper, matematisk statistik

Cancer Cell International

1475-2867 (ISSN)

Vol. 11 9

Ämneskategorier

MEDICIN OCH HÄLSOVETENSKAP

DOI

10.1186/1475-2867-11-9

PubMed

21492432