Hypermethylation of chromosome 17P locus D17S5 in human prostate tissue.

PURPOSE: Under normal conditions genomic CpG islands are not methylated. Hypermethylation of a CpG island in the 5' regulatory region of a gene has the capacity to silence gene transcription. Recently, hypermethylation of a CpG island at D17S5 on chromosome 17P13.3 has been shown to be a frequent tumor-specific event. When it has been observed, hypermethylation of D17S5 occurs solely in neoplastic tissues. Consequently, it has been hypothesized that hypermethylation of D17S5 may be an important carcinogenic event in the organs in which it occurs (colon, kidney, and brain). In this study we examine D17S5 hypermethylation in DNA from the prostate, a gland which is unique in that it undergoes hyperplastic or neoplastic growth or both in virtually all aging men. MATERIALS AND METHODS: The methylation sensitive restriction enzyme Notl, a cDNA probe specific for the D17S5 locus, and Southern blotting were used to assay for hypermethylation of D17S5 in DNA derived from normal, benign hyperplastic and malignant prostate tissues. RESULTS: We find that methylation of Notl restriction sites at D17S5 is a very common occurrence in prostate cancers (25 of 26 cases examined). Surprisingly, we found that methylation of these sites at D17S5 also occurred in histologically normal prostate and benign hyperplastic (BPH) tissue from glands which both did and did not contain cancer. In contrast, seminal vesicle, an androgen-dependent male sex accessory tissue that rarely undergoes pathological overgrowth, was devoid of hypermethylation at this locus. CONCLUSIONS. These data demonstrate that hypermethylation of D17S5 is a tissue-specific event in prostate DNA, and we hypothesize that methylation of this and/or related loci may play a role in the extreme predilection of this gland to neoplastic growth.

p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3.

For several human tumour types, allelic loss data suggest that one or more tumour suppressor genes reside telomeric to the p53 gene at chromosome 17p13.1. In the present study we have used a new strategy, involving molecular analysis of a DNA site hypermethylated in tumour DNA, to identify a candidate gene in this region (17p13.3). Our approach has led to identification of HIC-1 (hypermethylated in cancer), a new zinc-finger transcription factor gene which is ubiquitously expressed in normal tissues, but underexpressed in different tumour cells where it is hypermethylated. Multiple characteristics of this gene, including the presence of a p53 binding site in the 5' flanking region, activation of the gene by expression of a wild-type p53 gene and suppression of G418 selectability of cultured brain, breast and colon cancer cells following insertion of the gene, make HIC-1 gene a strong candidate for a tumour suppressor gene in region 17p13.3.