Exon-level expression analyses identify MYCN and NTRK1 as major determinants of alternative exon usage and robustly predict primary neuroblastoma outcome

6533b855fe1ef96bd12b14b5

RESEARCH PRODUCT

Exon-level expression analyses identify MYCN and NTRK1 as major determinants of alternative exon usage and robustly predict primary neuroblastoma outcome

A Schramm B Schowe K Fielitz M Heilmann M Martin T Marschall J Köster J Vandesompele J Vermeulen K De Preter J Koster R Versteeg R Noguera F Speleman S Rahmann A Eggert K Morik J H Schulte

subject

Cancer Research Medizin Computational biology Biology exon arrays Bioinformatics N-Myc Proto-Oncogene Protein Exon Neuroblastoma Risk Factors Neuroblastoma Cell Line Tumor Gene expression medicine Humans RNA Messenger Receptor trkA Gene Survival analysis Oncogene Proteins N-Myc Proto-Oncogene Protein Gene Expression Profiling Infant Nuclear Proteins Genetics and Genomics prediction Exons alternative transcript use medicine.disease Prognosis Survival Analysis Gene expression profiling Oncology Child Preschool PAM DNA microarray

description

BACKGROUND: Using mRNA expression-derived signatures as predictors of individual patient outcome has been a goal ever since the introduction of microarrays. Here, we addressed whether analyses of tumour mRNA at the exon level can improve on the predictive power and classification accuracy of gene-based expression profiles using neuroblastoma as a model. METHODS: In a patient cohort comprising 113 primary neuroblastoma specimens expression profiling using exon-level analyses was performed to define predictive signatures using various machine-learning techniques. Alternative transcript use was calculated from relative exon expression. Validation of alternative transcripts was achieved using qPCR- and cell-based approaches. RESULTS: Both predictors derived from the gene or the exon levels resulted in prediction accuracies >80% for both event-free and overall survival and proved as independent prognostic markers in multivariate analyses. Alternative transcript use was most prominently linked to the amplification status of the MYCN oncogene, expression of the TrkA/NTRK1 neurotrophin receptor and survival. CONCLUSION: As exon level-based prediction yields comparable, but not significantly better, prediction accuracy than gene expression-based predictors, gene-based assays seem to be sufficiently precise for predicting outcome of neuroblastoma patients. However, exon-level analyses provide added knowledge by identifying alternative transcript use, which should deepen the understanding of neuroblastoma biology. British Journal of Cancer (2012) 107, 1409-1417. doi:10.1038/bjc.2012.391 www.bjcancer.com (c) 2012 Cancer Research UK

year	journal	country	edition	language
2012-10-01

https://ir.cwi.nl/pub/20760