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Inactivation of Cyclin D2 Gene in Prostate Cancers by Aberrant Promoter Methylation

Hamon Center for Therapeutic Oncology Research [A. P., U. G. S., M. S., R. M., J. D. M., A. F. G.], The Simmons Cancer Center [E. P. F.], and Departments of Pathology [U. G. S., A. F. G.], Urology [J-T. H.], Internal Medicine [J. D. M.], and Pharmacology [J. D. M.], The University of Texas Southwestern Medical Center, Dallas, Texas 75390

ABSTRACT

Purpose: Loss or abnormal expression of Cyclin D2, a crucial cell cycle-regulatory gene, has been described in human cancers; however, data for prostate tumors are lacking. We investigated the epigenetic silencing of Cyclin D2 gene in prostate cancers and correlated the data with clinicopathological features.

Experimental Design: Cyclin D2 promoter methylation was analyzed in 101 prostate cancer samples by methylation-specific PCR. In addition, we analyzed 32 nonmalignant prostate tissue samples, which included 24 samples of benign disease, benign prostatic hypertrophy, or prostatitis and 7 normal tissues adjacent to cancer. The methylation status of Cyclin D2 was correlated with the methylation of nine other tumor suppressor genes published previously from our laboratory on the same set of samples (R. Maruyama et al., Clin. Cancer Res., 8: 514–519, 2002). The methylation index was determined as a reflection of the methylated fraction of the genes examined.

Results: The frequency of methylation of Cyclin D2 promoter was significantly higher in prostate cancers (32%) than in nonmalignant prostate tissues (6%; P = 0.004), and it was not age related. Aberrant methylation was present at insignificant levels in peripheral blood lymphocytes (8%). We also compared methylation of cyclin D2 with methylation of nine tumor suppressor genes [published previously from our laboratory (R. Maruyama et al., Clin. Cancer Res., 8: 514–519, 2002)] studied in the same set of samples. The concordances between methylation of Cyclin D2 and the methylation of RARß, GSTP1, CDH13, RASSF1A, and APC were statistically significant, whereas methylation of P16, DAPK, FHIT, and CDH1 were not significant. The differences in methylation index between malignant and nonmalignant tissues for all 10 genes were statistically significant (P < 0.0001). Among clinicopathological correlations, the high Gleason score group had significantly greater methylation frequency of Cyclin D2 (42%; P = 0.004). Although the high preoperative serum prostate-specific antigen (PSA) group did not have significantly greater methylation frequency, methylation of Cyclin D2 had higher mean PSA value. Also, the prostate cancers in the high Gleason score group had high mean values of PSA.

Conclusions: Our results indicate that methylation of Cyclin D2 in prostate cancers correlates with clinicopathological features of poor prognosis. These findings are of biological and potential clinical importance.

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