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Gene Signatures of Progression and Metastasis in Renal Cell Cancer

Authors' Affiliations: ¹ Beth Israel Deaconess Medical Center Genomics Center and Dana-Farber/Harvard Cancer Center Proteomics Core, ² Bioinformatics Core of Beth Israel Deaconess Medical Center Genomics Center and Harvard Medical School, and ³ Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; ⁴ Department of Urology and Pediatric Urology and ⁵ Insititute of Pathology, Johann Wolfgang Goethe University, Frankfurt, Germany; and ⁶ University of California-Los Angeles Kidney Cancer Program, Department of Urology, Jonsson Comprehensive Cancer Center, and David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California

Requests for reprints: Towia A. Libermann, Beth Israel Deaconess Medical Center Genomics Center and Harvard Medical School, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115. Phone: 617-667-3393; Fax: 617-975-5299; E-mail: tliberma{at}bidmc.harvard.edu.

Purpose: To address the progression, metastasis, and clinical heterogeneity of renal cell cancer (RCC).

Experimental Design: Transcriptional profiling with oligonucleotide microarrays (22,283 genes) was done on 49 RCC tumors, 20 non-RCC renal tumors, and 23 normal kidney samples. Samples were clustered based on gene expression profiles and specific gene sets for each renal tumor type were identified. Gene expression was correlated to disease progression and a metastasis gene signature was derived.

Results: Gene signatures were identified for each tumor type with 100% accuracy. Differentially expressed genes during early tumor formation and tumor progression to metastatic RCC were found. Subsets of these genes code for secreted proteins and membrane receptors and are both potential therapeutic or diagnostic targets. A gene pattern ("metastatic signature") derived from primary tumor was very accurate in classifying tumors with and without metastases at the time of surgery. A previously described "global" metastatic signature derived by another group from various non-RCC tumors was validated in RCC.

Conclusion: Unlike previous studies, we describe highly accurate and externally validated gene signatures for RCC subtypes and other renal tumors. Interestingly, the gene expression of primary tumors provides us information about the metastatic status in the respective patients and has the potential, if prospectively validated, to enrich the armamentarium of diagnostic tests in RCC. We validated in RCC, for the first time, a previously described metastatic signature and further showed the feasibility of applying a gene signature across different microarray platforms. Transcriptional profiling allows a better appreciation of the molecular and clinical heterogeneity in RCC.

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