Abstract
Transcript variants play a critical role in diversifying gene expression. Alternative splicing is a major mechanism for generating transcript variants. A number of genes have been implicated in breast cancer pathogenesis with their aberrant expression of alternative transcripts. In this study, we performed genome-wide analyses of transcript variant expression in breast cancer. With RNA-Seq data from 105 patients, we characterized the transcriptome of breast tumors, by pairwise comparison of gene expression in the breast tumor versus matched healthy tissue from each patient. We identified 2839 genes, ~10 % of protein-coding genes in the human genome, that had differential expression of transcript variants between tumors and healthy tissues. The validity of the computational analysis was confirmed by quantitative RT-PCR assessment of transcript variant expression from four top candidate genes. The alternative transcript profiling led to classification of breast cancer into two subgroups and yielded a novel molecular signature that could be prognostic of patients’ tumor burden and survival. We uncovered nine splicing factors (FOX2, MBNL1, QKI, PTBP1, ELAVL1, HNRNPC, KHDRBS1, SFRS2, and TIAR) that were involved in aberrant splicing in breast cancer. Network analyses for the coordinative patterns of transcript variant expression identified twelve “hub” genes that differentiated the cancerous and normal transcriptomes. Dysregulated expression of alternative transcripts may reveal novel biomarkers for tumor development. It may also suggest new therapeutic targets, such as the “hub” genes identified through the network analyses of transcript variant expression, or splicing factors implicated in the formation of the tumor transcriptome.
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Acknowledgments
We thank the Tissue Bank core facility of the Sylvester Comprehensive Cancer Center at the University of Miami for assistance in obtaining breast tumor samples and paired normal controls. Research reported in this publication was partially supported by NIGMS/NIH R01GM104975 and NSF grant CCF-1319981 (to XC), and the Bankhead Coley Cancer Research Program 09BN-05 and NCI/NIH R21CA178675 (to ZC).
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Wen, J., Toomer, K.H., Chen, Z. et al. Genome-wide analysis of alternative transcripts in human breast cancer. Breast Cancer Res Treat 151, 295–307 (2015). https://doi.org/10.1007/s10549-015-3395-2
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DOI: https://doi.org/10.1007/s10549-015-3395-2