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Carcinogenesis Advance Access published online on November 26, 2008
Carcinogenesis, doi:10.1093/carcin/bgn268
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genome-wide DNA methylation profiles in both precancerous conditions and clear cell renal cell carcinomas are correlated with malignant potential and patient outcome

Eri Arai1, Saori Ushijima1, Hiroyuki Fujimoto2, Fumie Hosoda3, Tatsuhiro Shibata3, Tadashi Kondo4, Sana Yokoi5, Issei Imoto5, Johji Inazawa5, Setsuo Hirohashi1 and Yae Kanai1,*

1 Pathology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
3 Cancer Genomics Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan
4 Proteome Bioinformatics Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan
2 Urology Division, National Cancer Center Hospital, Tokyo 104-0045, Japan
5 Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

* To whom correspondence should be addressed. Pathology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Tel: 81-3-3542-2511; Fax: 81-3-3248-2463; E-mail: ykanai{at}ncc.go.jp.

To clarify genome-wide DNA methylation profiles during multistage renal carcinogenesis, bacterial artificial chromosome (BAC) array-based methylated CpG island amplification (BAMCA) was performed. Non-cancerous renal cortex tissue obtained from patients with clear cell renal cell carcinomas (RCCs) (N) was at the precancerous stage where DNA hypomethylation and DNA hypermethylation on multiple BAC clones were observed. By unsupervised hierarchical clustering analysis based on BAMCA data for their N, 51 patients with clear cell RCCs were clustered into two subclasses, Clusters AN (n=46) and BN (n=5). Clinicopathologically aggressive clear cell RCCs were accumulated in Cluster BN, and the overall survival rate of patients in Cluster BN was significantly lower than that of patients in Cluster AN. By unsupervised hierarchical clustering analysis based on BAMCA data for their RCCs, 51 patients were clustered into two subclasses, Clusters AT (n=43) and BT (n=8). Clinicopathologically aggressive clear cell RCCs were accumulated in Cluster BT, and the overall survival rate of patients in Cluster BT was significantly lower than that of patients in Cluster AT. Multivariate analysis revealed that belonging to Cluster BT was an independent predictor of recurrence. Cluster BN was completely included in Cluster BT, and the majority of the BAC clones that significantly discriminated Cluster BN from Cluster AN, also discriminated Cluster BT from Cluster AT. In individual patients, DNA methylation status in N was basically inherited by the corresponding clear cell RCC. DNA methylation alterations in the precancerous stage may generate more malignant clear cell RCCs and determine patient outcome.

Key Words: DNA methylation • bacterial artificial chromosome array-based methylated CpG island amplification • precancerous condition • clear cell renal cell carcinoma • prognostication

Received September 1, 2008; revised November 12, 2008; accepted November 20, 2008.


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