ERBB3 is a marker of a ganglioneuroblastoma/ganglioneuroma-like expression profile in neuroblastic tumours

Molecular Cancer

Research

Katleen De Preter¹  Cecilia Krona²  Per Kogner²  Baldur Sveinbjörnsson³  John Maris⁴  Raymond L Stallings⁵  Annica Wilzén⁶  Frida Abel⁶  Erik Kristiansson⁷  Daniel Dalevi⁷  Staffan Nilsson⁷  Rogier Versteeg⁸  Ingrid Øra⁹ 

[1] Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium;Childhood Cancer Research Unit, Karolinska Institute, Astrid Lindgren Children’s Hospital, Q6:05, S-171 76, Stockholm, Sweden;Childhood Cancer Research Unit, Karolinska Institute, Astrid Lindgren Children’s Hospital, Q6:05, S-171 76, Stockholm, Sweden;Department of Medical Biology, University of Tromsø, Tromsø, Norway;Children's Hospital of Philadelphia, Division of Oncology, The University of Pennsylvania, Philadelphia, PA, USA;Department of Cancer Genetics, Royal College of Surgeons in Ireland and Children’s Research Centre, Our Lady’s Children’s Hospital, Dublin, Ireland;Department of Clinical Genetics, Institution of Biomedicine, Gothenburg University, Box 413, S- 405 30, Gothenburg, Sweden;Department of Mathematical Statistics, Chalmers University of Technology, Gothenburg, Sweden;Department of Oncogenomics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;Department of Pediatric Oncology, Clinical Sciences, Lund University, Lund, Sweden;

关键词: Microarray;    Expression;    Cancer;    Systems biology;    Oncology;    Network;    Reverse engineering;    Unsupervised;    Clustering;    Cell cycle;    Spindle assembly;    Her-3;    HER3;    ERBB3;    Her-2;    HER2;    ERBB2;    EGFR;    ERBB1;    BIRC5;    Survivin;    MYCN;    N-myc;    ALK;    PHOX2B;    NTRK1;    CCND1;   

DOI  :  10.1186/1476-4598-12-70

 received in 2013-02-14, accepted in 2013-06-25,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundNeuroblastoma (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).MethodsExpression 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.ResultsWe 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.ConclusionsConclusively, 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.

【 授权许可】

Unknown   
© Wilzén et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.