To clarify genome-wide DNA methylation profiles during multistage urothelial carcinogenesis, bacterial artificial chromosome (BAC) array-based methylated CpG island amplification (BAMCA) was performed in 18 normal urothelia obtained from patients without urothelial carcinomas (UCs) (C), 17 noncancerous urothelia obtained from patients with UCs (N), and 40 UCs. DNA hypo-and hypermethylation on multiple BAC clones was observed even in N compared to C. Principal component analysis revealed progressive DNA methylation alterations from C to N, and to UCs. DNA methylation profiles in N obtained from patients with invasive UCs were inherited by the invasive UCs themselves, that is DNA methylation alterations in N were correlated with the development of more malignant UCs. The combination of DNA methylation status on 83 BAC clones selected by Wilcoxon test was able to completely discriminate N from C, and diagnose N as having a high risk of carcinogenesis, with 100% sensitivity and specificity. The combination of DNA methylation status on 20 BAC clones selected by Wilcoxon test was able to completely discriminate patients who suffered from recurrence after surgery from patients who did not. The combination of DNA methylation status for 11 BAC clones selected by Wilcoxon test was able to completely discriminate patients with UCs of the renal pelvis or ureter who suffered from intravesical metachronous UC development from patients who did not. Genome-wide alterations of DNA methylation may participate in urothelial carcinogenesis from the precancerous stage to UC, and DNA methylation profiling may provide optimal indicators for carcinogenetic risk estimation and prognostication. (Cancer Sci 2010; 101: 231-240) I t is known that DNA hypomethylation results in chromosomal instability as a result of changes in chromatin structure, and that DNA hypermethylation of CpG islands silences tumorrelated genes in cooperation with histone modification in human cancers.(1-5) Accumulating evidence suggests that alterations of DNA methylation are involved even in the early and the precancerous stages.(6,7) On the other hand, in patients with cancers, aberrant DNA methylation is significantly associated with poorer tumor differentiation, tumor aggressiveness, and poorer patient outcome.(6,7) Therefore, alterations of DNA methylation may play a significant role in multistage carcinogenesis.With respect to urothelial carcinogenesis, we have reported accumulation of DNA methylation on C-type CpG islands in a cancer-specific but not age-dependent manner, and protein overexpression of DNA methyltransferase (DNMT) 1, a major DNMT, even in noncancerous urothelia with no apparent histological changes obtained from patients with urothelial carcinomas (UCs). (8,9) Moreover, accumulation of DNA methylation on C-type CpG islands associated with DNMT1 protein overexpression was more frequently evident in aggressive nodular invasive UCs (8)(9)(10) resulting in poorer patient outcome than in superficial papillary UCs, which usually remain noninvasi...
Epigenetic mechanisms such as histone modification play key roles in the pathogenesis of multiple myeloma (MM). We previously showed that EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, and G9, a H3K9 methyltransferase, are potential therapeutic targets in MM. Moreover, recent studies suggest EZH2 and G9a cooperate to regulate gene expression. We therefore evaluated the antitumor effect of dual EZH2 and G9a inhibition in MM. A combination of an EZH2 inhibitor and a G9a inhibitor strongly suppressed MM cell proliferation in vitro by inducing cell cycle arrest and apoptosis. Dual EZH2/G9a inhibition also suppressed xenograft formation by MM cells in vivo. In datasets from the Gene Expression Omnibus, higher EZH2 and EHMT2 (encoding G9a) expression was significantly associated with poorer prognoses in MM patients. Microarray analysis revealed that EZH2/G9a inhibition significantly upregulated interferon (IFN)-stimulated genes and suppressed IRF4-MYC axis genes in MM cells. Notably, dual EZH2/G9a inhibition reduced H3K27/H3K9 methylation levels in MM cells and increased expression of endogenous retrovirus (ERV) genes, which suggests that activation of ERV genes may induce the IFN response. These results suggest that dual targeting of EZH2 and G9a may be an effective therapeutic strategy for MM.
Objective: The aim of this study was to clarify the prognostic value and clinical reliability of the 2004 World Health Organization classification system of non-muscle-invasive bladder cancer. Methods: Between January 1995 and November 2010, 153 patients were diagnosed with nonmuscle-invasive bladder cancer. We used a substage system that discerns T1-microinvasive (T1m, 42 patients) and T1-extensive-invasive (T1e, 37 patients) cancers. Results: There were 2 (1.3%), 89 (58.2%) and 62 (40.5%) cases of Grade 1 -3 urothelial carcinoma, respectively, on the basis of the 1973 World Health Organization classification system. Of these, 37 (24.2%) and 116 (75.8%) were graded as low and high on the basis of the 2004 World Health Organization classification system. All of the cases with progression (15 patients) were diagnosed as high grade at the time of primary transurethral resection of the bladder tumor. Based on the Kaplan -Meier analysis, the 2004 World Health Organization classification system accurately predicted tumor recurrence (P ¼ 0.029) and progression (P ¼ 0.031). The 5-year recurrence-free survival rates in patients with low-grade and high-grade tumors were 68.7 and 47.1%, and the 5-year progression-free survival rates were 100 and 89.0%, respectively. In the high-grade T1 cases, the substage (T1m or T1e) was a significant predictor of tumor recurrence (P ¼ 0.001) and progression (P ¼ 0.020). Conclusions:The 2004 World Health Organization classification system accurately predicts the risk of recurrence in primary non-muscle-invasive bladder cancer cases and has the same accuracy when predicting the risk of progression as the 1973 World Health Organization classification. Furthermore, the substaging system for high-grade T1 tumors is useful in predicting both recurrence and progression.
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