ERBB3 is a marker of a ganglioneuroblastoma/ganglioneuroma-like expression profile in neuroblastic tumours.
Artikel i vetenskaplig tidskrift, 2013

Background Neuroblastoma (NB) tumours are commonly divided into three cytogenetic subgroups. However, by unsupervised principal components analysis of gene expression profiles we recently identified four distinct subgroups, r1-r4. In the current study we characterized these different subgroups in more detail, with a specific focus on the fourth divergent tumour subgroup (r4). Methods Expression microarray data from four international studies corresponding to 148 neuroblastic tumour cases were subject to division into four expression subgroups using a previously described 6-gene signature. Differentially expressed genes between groups were identified using Significance Analysis of Microarray (SAM). Next, gene expression network modelling was performed to map signalling pathways and cellular processes representing each subgroup. Findings were validated at the protein level by immunohistochemistry and immunoblot analyses. Results We identified several significantly up-regulated genes in the r4 subgroup of which the tyrosine kinase receptor ERBB3 was most prominent (fold change: 132–240). By gene set enrichment analysis (GSEA) the constructed gene network of ERBB3 (n = 38 network partners) was significantly enriched in the r4 subgroup in all four independent data sets. ERBB3 was also positively correlated to the ErbB family members EGFR and ERBB2 in all data sets, and a concurrent overexpression was seen in the r4 subgroup. Further studies of histopathology categories using a fifth data set of 110 neuroblastic tumours, showed a striking similarity between the expression profile of r4 to ganglioneuroblastoma (GNB) and ganglioneuroma (GN) tumours. In contrast, the NB histopathological subtype was dominated by mitotic regulating genes, characterizing unfavourable NB subgroups in particular. The high ErbB3 expression in GN tumour types was verified at the protein level, and showed mainly expression in the mature ganglion cells. Conclusions Conclusively, this study demonstrates the importance of performing unsupervised clustering and subtype discovery of data sets prior to analyses to avoid a mixture of tumour subtypes, which may otherwise give distorted results and lead to incorrect conclusions. The current study identifies ERBB3 as a clear-cut marker of a GNB/GN-like expression profile, and we suggest a 7-gene expression signature (including ERBB3) as a complement to histopathology analysis of neuroblastic tumours. Further studies of ErbB3 and other ErbB family members and their role in neuroblastic differentiation and pathogenesis are warranted.

genetics expression analysis systems biology tumor neuroblastoma

Författare

Annica Wilzén

Göteborgs universitet

Cecilia Krona

Karolinska universitetssjukhuset

Baldur Sveinbjörnsson

Karolinska universitetssjukhuset

Universitetet i Tromso

Erik Kristiansson

Chalmers, Matematiska vetenskaper, matematisk statistik

Göteborgs universitet

Daniel Dalevi

Chalmers, Data- och informationsteknik, Datavetenskap

Ingrid Ora

Lunds universitet

Katleen De Preter

Center for Medical Genetics

Raymond L Stallings

Our Lady's Hospital for Sick Children

John Maris

University of Pennsylvania

Rogier Versteeg

Universiteit Van Amsterdam

Staffan Nilsson

Göteborgs universitet

Chalmers, Matematiska vetenskaper, matematisk statistik

Per Kogner

Karolinska universitetssjukhuset

Frida Abel

Göteborgs universitet

Molecular Cancer

1476-4598 (ISSN)

Vol. 12 artikel nr 70- 70

Ämneskategorier

Medicinska grundvetenskaper

DOI

10.1186/1476-4598-12-70

PubMed

23835063