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Transcriptome instability in colorectal cancer identified by exon microarray analyses: Associations with splicing factor expression levels and patient survival

Anita Sveen12, Trude H Ågesen12, Arild Nesbakken23, Torleiv O Rognum4, Ragnhild A Lothe12 and Rolf I Skotheim12*

Author Affiliations

1 Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, PO Box 4953 Nydalen, NO-0424 Oslo, Norway

2 Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, PO Box 1072 Blindern, NO-0316 Oslo, Norway

3 Department of Gastrointestinal Surgery, Aker University Hospital, Oslo University Hospital, PO Box 4959 Nydalen, NO-0424 Oslo, Norway

4 Institute of Forensic Medicine, University of Oslo, PO Box 1072 Blindern, NO-0316 Oslo, Norway

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Genome Medicine 2011, 3:32  doi:10.1186/gm248

Published: 27 May 2011

Abstract

Background

Colorectal cancer (CRC) is a heterogeneous disease that, on the molecular level, can be characterized by inherent genomic instabilities; chromosome instability and microsatellite instability. In the present study we analyze genome-wide disruption of pre-mRNA splicing, and propose transcriptome instability as a characteristic that is analogous to genomic instability on the transcriptome level.

Methods

Exon microarray profiles from two independent series including a total of 160 CRCs were investigated for their relative amounts of exon usage differences. Each exon in each sample was assigned an alternative splicing score calculated by the FIRMA algorithm. Amounts of deviating exon usage per sample were derived from exons with extreme splicing scores.

Results

There was great heterogeneity within both series in terms of sample-wise amounts of deviating exon usage. This was strongly associated with the expression levels of approximately half of 280 splicing factors (54% and 48% of splicing factors were significantly correlated to deviating exon usage amounts in the two series). Samples with high or low amounts of deviating exon usage, associated with overall transcriptome instability, were almost completely separated into their respective groups by hierarchical clustering analysis of splicing factor expression levels in both sample series. Samples showing a preferential tendency towards deviating exon skipping or inclusion were associated with skewed transcriptome instability. There were significant associations between transcriptome instability and reduced patient survival in both sample series. In the test series, patients with skewed transcriptome instability showed the strongest prognostic association (P = 0.001), while a combination of the two characteristics showed the strongest association with poor survival in the validation series (P = 0.03).

Conclusions

We have described transcriptome instability as a characteristic of CRC. This transcriptome instability has associations with splicing factor expression levels and poor patient survival.