Abstract 795: Transcriptome instability as a common characteristic of solid cancers.

Abstract

Abstract Analogous to the genomic types of instability describing cancer genomes, we recently proposed transcriptome instability as a genome-wide, pre-mRNA splicing related characteristic of colorectal cancer (Sveen et al., Genome Medicine, 2011). Here, we explore transcriptome instability in several major solid cancer types. We have analyzed exon microarray data from ten cancer datasets (555 samples; seven cancer types) and four normal tissue types (93 samples; paired samples from colonic mucosa, lung, prostate and the stomach) for variation in relative amounts of aberrant exon usage, based on alternative splicing scores calculated by the FIRMA algorithm. Most major solid cancer types (breast, cervical, colorectal (two datasets), lung, and prostate (two datasets) cancer) showed large variations in aberrant exon usage amounts among the samples, and these amounts were strongly associated with splicing factor expression levels. Thus, we consider these cancer types to exhibit transcriptome instability. Non-random associations with splicing factor (n = 280) expression levels were shown by separation of samples according to aberrant exon usage amounts upon unsupervised hierarchical clustering analyses, and by stronger correlations between aberrant exon usage amounts and splicing factor expression levels than expected by chance (compared with random gene sets and permutations of the aberrant exon usage amounts; P < 0.001). In comparisons across healthy tissue types and paired cancer and normal datasets, we observed tissue- and cancer-specific patterns in splicing factor correlations. Interestingly, in comparisons across cancer types with transcriptome instability (but not across cancer datasets that did not show transcriptome instability; gastric cancer, a second lung cancer dataset, and neuroblastoma), the non-random associations between aberrant exon usage amounts and splicing factor expression remained intact, indicating a failure to adhere to tissue specificity. Thus, we consider transcriptome instability to be a common feature of most major solid cancer types, and this deviant splicing pattern is associated with splicing factor expression levels. Citation Format: Anita Sveen, Bjarne Johannessen, Manuel R. Teixeira, Ragnhild A. Lothe, Rolf I. Skotheim. Transcriptome instability as a common characteristic of solid cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 795. doi:10.1158/1538-7445.AM2013-795