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Genetic Clustering of Clear Cell Renal Cell Carcinoma Based on Array-Comparative Genomic Hybridization: Its Association with DNA Methylation Alteration and Patient Outcome

Authors' Affiliations: ¹ Pathology Division, ² Cancer Genomics Project, and ³ Proteome Bioinformatics Project, National Cancer Center Research Institute; ⁴ Urology Division, National Cancer Center Hospital; ⁵ Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan; and ⁶ Department of Pathology II, National Defense Medical College, Tokorozawa, Saitama, Japan

Requests for reprints: Yae Kanai, Pathology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Phone: 81-3-3542-2511; Fax: 81-3-3248-2463; E-mail: ykanai{at}ncc.go.jp.

Purpose: The aim of this study was to clarify genetic and epigenetic alterations occurring during renal carcinogenesis.

Experimental Design: Copy number alterations were examined by array-based comparative genomic hybridization analysis using an array harboring 4,361 bacterial artificial chromosome clones, and DNA methylation alterations on CpG islands of the p16, human MutL homologue 1, von Hippel-Lindau, and thrombospondin 1 genes and the methylated in tumor (MINT-1, MINT-2, MINT-12, MINT-25, and MINT-31) clones were examined in 51 clear cell renal cell carcinomas (RCC).

Results: By unsupervised hierarchical clustering analysis based on copy number alterations, clear cell RCCs were clustered into the two subclasses, clusters A (n = 34) and B (n = 17). Copy number alterations were accumulated in cluster B. Loss of chromosome 3p and gain of 5q and 7 were frequent in both clusters A and B, whereas loss of 1p, 4, 9, 13q, and 14q was frequent only in cluster B. The average number of methylated CpG islands in cluster B was significantly higher than those in cluster A. Clear cell RCCs showing higher histologic grades, vascular involvement, renal vein tumor thrombi, and higher pathologic stages were accumulated in cluster B. The recurrence-free and overall survival rates of patients in cluster B were significantly lower than those of patients in cluster A. Multivariate analysis revealed that genetic clustering was a predictor of recurrence-free survival and was independent of histologic grade and pathologic stage.

Conclusions: This genetic clustering of clear cell RCC is significantly associated with regional DNA hypermethylation and may become a prognostic indicator for patients with RCC.