Frequent loss of sFRP1 expression and sFRP1 promoter methylation in prostate cancer and adjacent histopathologically normal prostate.

3679 Aims : Previous studies have revealed that deletion of chromosome 8p is one of the most common genetic alteration in prostate cancer (PCa). Human secreted frizzled-related protein 1 (sFRP1) is a tumor suppressor located on 8p12-13, acting as a negative regulator of Wnt signaling. Recently, loss of sFRP1 expression was shown in several malignancies, e.g. bladder cancer, breast cancer or renal cell carcinoma. The aim of this study was the investigation of sFRP1 expression in PCa and its correlation to chromosome 8p alterations and to histopathological characteristics of the tumors. Methods : 72 paraffin-embedded archival, organ-confined prostate tumors (ranging from pT1aG1 to pT3cG3, Gleason score range 2-10), and corresponding benign prostatic tissue were analyzed. After microdissection, DNA was isolated. LOH analysis was performed using 3 markers on chromosome 8p. sFRP1 expression was determined using immunohistochemistry and TMA technology. Methylation analysis of the gene promoter was performed using methylation-specific PCR (MS-PCR). Results : LOH was found in 21% (14/67) of informative cases, 1 case showed MSI. Immunhistochemistry revealed a complete loss of sFRP1 protein in 74% (37/50), and a reduced expression in 20% (10/50) of the tumors compared to corresponding benign tissue. MS-PCR showed promoter methylation in 52% (11/21) of investigated PCa samples. Interestingly, promoter methylation was already detectable in 39% (7/18) of corresponding normal prostatic tissue specimens. There was a good correlation between loss of sFRP1 protein and results from MS-PCR (60%). There was no correlation between sFRP1 alterations and histopathological characteristics of the tumors. Conclusions : sFRP1 expression is frequently lost or reduced in PCa. A combination of allelic loss and/or promoter methylation was found to be causative for expression loss. Methylation of sFRP1 promoter region might be an early event in prostate carcinogenesis since it could be detected already in normal prostatic tissue from PCa. patients. Early loss of sFRP1 expression might contribute to an uncontrolled downstream signaling activity (Wnt pathway, MAPK) and to a proliferative advantage of affected cells.