Molecular detection of prostate cancer in urine by GSTP1 hypermethylation

Novel approaches for the early detection and management of prostate cancer are urgently needed. Clonal genetic alterations have been used as targets f or the detection of neoplastic cells in bodily fluids from many cancer type s. A similar strategy for molecular diagnosis of prostate cancer requires a common and/or early genetic alteration as a specific target for neoplastic prostate cells. Hypermethylation of regulatory sequences at the glutathion e S-transferase pi (GSTP1) gene locus is found in the majority (> 90%) of p rimary prostate carcinomas, but not in normal prostatic tissue or other nor mal tissues. We hypothesized that urine from prostate cancer patients might contain shed neoplastic cells or debris amenable to DNA analysis. Matched specimens of primary tumor, peripheral blood lymphocytes (normal control), and simple voided urine were collected from 28 patients with prostate cance r of a clinical stage amenable to cure. Genomic DNA was isolated from the s amples, and the methylation status of GSTP1 was examined in a blinded manne r using methylation-specific PCR. Decoding of the results revealed that 22 of 28 (79%) prostate tumors were positive for GSTP1 methylation. In 6 of 22 (27%) cases, the corresponding urine-sediment DNA was positive for GSTP1 m ethylation, indicating the presence of neoplastic DNA in the urine. Further more, there was no case where urine-sediment DNA harbored methylation when the corresponding tumor was negative. Although we only detected GSTP1 methy lation in under one-third of voided urine samples, we have demonstrated tha t molecular diagnosis of prostate neoplasia in urine is feasible. Larger st udies focusing on carcinoma size, location in the prostate, and urine colle ction techniques, as well as more sensitive technology, may lead to the use ful application of GSTP1 hypermethylation in prostate cancer diagnosis and management.