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A Molecular Classification of Papillary Renal Cell Carcinoma

Departments of ¹ Pathology and ² Urology, Feinberg School of Medicine, Northwestern University; Department of ³ Pathology and ⁴ Medical Oncology, University of Chicago, Chicago, Illinois; ⁵ Laboratory of Cancer Genetics and ⁶ Bioinformatics Program, Van Andel Research Institute; ⁷ Department of Urology, Spectrum Health Hospital, Grand Rapids, Michigan; Departments of ⁸ Urology and ⁹ Pathology, University of California, Los Angeles, California; ¹⁰ Department of Urology, University of Tokushima, Tokushima, Japan; ¹¹ Department of Pathology, Singapore General Hospital; ¹² Department of Medical Oncology, National Cancer Center; ¹³ Department of Medicine, Alexandra Hospital, Singapore, Singapore; ¹⁴ Department of Radiation Oncology, Baylor College of Medicine and The Methodist Hospital; ¹⁵ Genitourinary Oncology Program, The Methodist Hospital, Houston, Texas; Departments of ¹⁶ Pathology and ¹⁷ Urology, Johns Hopkins University, Baltimore, Maryland; and ¹⁸ Department of Medical Oncology, Nevada Cancer Institute, Reno, Nevada

Requests for reprints: Bin Tean Teh, 333 Bostwick Avenue Northeast, Grand Rapids, MI 49503. Phone: 616-234-5350; Fax: 616-234-5115; E-mail: bin.teh{at}vai.org.

Despite the moderate incidence of papillary renal cell carcinoma (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphologic classification of PRCC into type 1 and 2 tumors has been recently proposed, but its biological relevance remains uncertain. We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analyses. Comparative genomic microarray analysis was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples with 15 independent tumors. We identified two highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to three histologic subtypes: type 1, low-grade type 2, and mixed type 1/low-grade type 2 tumors. The second class, with poor survival, corresponded to high-grade type 2 tumors (n = 11). Dysregulation of G₁-S and G₂-M checkpoint genes were found in class 1 and 2 tumors, respectively, alongside characteristic chromosomal aberrations. We identified a seven-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in class 1 tumors and of topoisomerase II in class 2 tumors. We report two molecular subclasses of PRCC, which are biologically and clinically distinct and may be readily distinguished in a clinical setting.

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