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Two-Dimensional Transcriptome Profiling: Identification of Messenger RNA Isoform Signatures in Prostate Cancer from Archived Paraffin-Embedded Cancer Specimens

Departments of ¹ Cellular and Molecular Medicine, ² Pathology, and ³ Surgery, ⁴ San Diego Supercomputer Center, University of California, San Diego, La Jolla; ⁵ Illumina Inc., San Diego, California; ⁶ Department of Medicine, Mudanjiang Medical College, Mudanjiang, China; and ⁷ Departments of Biological Sciences and Computer Science/Informatics, Indiana University South Bend, South Bend, Indiana

Requests for reprints: Xiang-Dong Fu, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651. Phone: 858-534-4937; Fax: 858-534-8549; E-mail: xdfu{at}ucsd.edu or Jian-Bing Fan, Illumina Inc., San Diego, CA 92121. Phone: 858-202-4588; Fax: 858-202-4680; E-mail: jfan{at}illumina.com.

The expression of specific mRNA isoforms may uniquely reflect the biological state of a cell because it reflects the integrated outcome of both transcriptional and posttranscriptional regulation. In this study, we constructed a splicing array to examine 1,500 mRNA isoforms from a panel of genes previously implicated in prostate cancer and identified a large number of cell type–specific mRNA isoforms. We also developed a novel "two-dimensional" profiling strategy to simultaneously quantify changes in splicing and transcript abundance; the results revealed extensive covariation between transcription and splicing in prostate cancer cells. Taking advantage of the ability of our technology to analyze RNA from formalin-fixed, paraffin-embedded tissues, we derived a specific set of mRNA isoform biomarkers for prostate cancer using independent panels of tissue samples for feature selection and cross-analysis. A number of cancer-specific splicing switch events were further validated by laser capture microdissection. Quantitative changes in transcription/RNA stability and qualitative differences in splicing ratio may thus be combined to characterize tumorigenic programs and signature mRNA isoforms may serve as unique biomarkers for tumor diagnosis and prognosis. (Cancer Res 2006; 66(8): 4079-88)

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