DNA methylation in urological malignancies (review).
Three different kinds of alterations in DNA methylation have been observed in urological malignancies. DNA hypermethylation of CpG-rich promoter regions is an important mechanism involved in the inactivation of tumor suppressor and other genes in prostate, renal cell, and bladder carcinoma. Genome-wide hypomethylation is most pronounced in urothelial carcinoma, but also occurs in prostatic cancer. Loss of imprinting may be a primary event in the aetiogenesis of Wilms' tumor and probably contributes to testicular cancer. With respect to alterations in DNA methylation three tumor categories are distinguished: in the development of embryonic tumors, e.g. Wilms' tumor, loss of imprinting is important probably by upsetting the balance between genes promoting or inhibiting proliferation. In tumors with faulty DNA methylation, e.g. renal cell carcinoma, occasional errors in DNA methylation are selected for during tumor development. In tumors with deranged methylation, e. g. in most bladder and prostate carcinomas, the mechanisms establishing methylation patterns are fundamentally disturbed and multiple alterations in DNA methylation are observed. At least one of the enzymes establishing methylation patterns, viz. DNA methyltransferases and demethylases, may be deregulated. Moreover, changes in methyl group metabolism need to be considered. DNA hypermethylation and loss of imprinting act by altering the expression of selected genes, whereas hypomethylation may facilitate transcription and recombination throughout the genome by its effect on the chromatin structure. The combination of all three types of alterations may create genomic instability in tumors with deranged DNA methylation. Regarding a potential clinical use, detection of hypermethylation appears most promising in cancer diagnosis, while parameters reflecting genome-wide hypomethylation may prove useful in the prediction of prognosis. Inhibitors of DNA methylation are being improved and will presumably first be employed against tumors with hypermethylated key tumor suppressor genes.
Schulz
W A
WA
Urologische Klinik, Heinrich-Heine-Universitat, D-40225 Dusseldorf, Germany.
D000818:Animals; D019175:DNA Methylation; D006801:Humans; D014571:Urologic Neoplasms / Q000235:genetics*