CG ISLAND METHYLATION CHANGES NEAR THE GSTP1 GENE IN PROSTATIC INTRAEPITHELIAL NEOPLASIA

Prostate intraepithelial neoplasia (PLN) is a purported prostate cance r precursor lesion and a candidate biomarker for efficacy assessment i n prostate cancer chemoprevention trials. Loss of expression of the pi -class glutathione S-transferase enzyme GSTP1, which is associated wit h the hypermethylation of deoxycytidine residues in the 5'-regulatory CG island region of the GSTP1 gene, is a near-universal finding in hum an prostate cancer. GSTP1 expression was assessed by immunohistochemis try in 60 high-grade PIN samples adjacent to and distant from prostate adenocarcinoma, Whereas abundant enzyme polypeptide expression was ev ident in all normal prostatic tissues, all samples of high-grade PIN a nd adenocarcinoma were completely devoid of GSTP1. DNA from 10 high-gr ade PIN lesions was analyzed for GSTP1 CG island methylation changes u sing a PCR technique targeting a polymorphic (ATAAA)(n) repeat sequenc e in the promoter region of the GSTP1 gene. Somatic GSTP1 CG island me thylation changes were detected in DNA from 7 of the 10 PIN lesions. A llele discrimination was possible for 5 of the 10 DNA samples: 2 of th e 5 samples exhibited DNA methylation changes at both alleles; whereas 3 samples displayed no DNA methylation changes at either allele. GSTP 1 CG island methylation changes were present in each of the five homoz ygous samples. Hypermethylation of the 5'-regulatory region of the GST P1 gene may serve as an important molecular genetic biomarker for both prostate cancer and PIN. The finding of frequent GSTP1 methylation ch anges in PIN and prostate cancer supports a role for PIN lesions as a prostate cancer precursor and may provide insight to the molecular pat hogenesis of prostate cancer.