A 6-gene signature identifies four molecular subgroups of neuroblastoma

• Main Authors: Kogner Per, Stallings Raymond, Vermeulen Joëlle, De Preter Katleen, Jörnsten Rebecka, Nethander Maria, Dalevi Daniel, Abel Frida, Maris John, Nilsson Staffan
• Format: Article
• Language: English
• Published: BMC 2011-04-01
• Series: Cancer Cell International
• Online Access: http://www.cancerci.com/content/11/1/9

<p>Abstract</p> <p>Background</p> <p>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 <it>MYCN </it>(MNA) and low expression of the favourable marker <it>NTRK1</it>. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (<it>ALK</it>) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis.</p> <p>Results</p> <p>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 <it>ALK</it>, <it>BIRC5</it>, <it>CCND1</it>, <it>MYCN</it>, <it>NTRK1</it>, and <it>PHOX2B</it>, 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 <it>ALK, BIRC5</it>, and <it>PHOX2B</it>, 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).</p> <p>Conclusions</p> <p>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.</p>