Limiting the location of putative human prostate cancer tumor suppressor genes on chromosome 18q

We studied loss of heterozygosity (LOH) on the long arm of human chromosome 18 in prostate cancer to determine the location of a putative tumor suppressor gene (TSG) and to correlate these losses with the pathological grade and stage of the cancer. Of 48 specimens analysed 17 (35.4%) lost at least one allele on chromosome 18q. All the specimens with allelic losses lost at least one allele within chromosomal region 18q21. Allelic losses picked at D18S51 (19%) and D18S858 (17%). A 0.58 cM DNA segment that includes the D18S858 locus and is flanked by the microsatellite loci D18S41 and D18S381, was lost in eight (47%) of 17 specimens with allelic losses. This segment was designated as a LOH cluster region 1 (LCR 1). Although Smad2 resides within LCR 1, it was not mutated in any of the six prostate cell lines (five prostate cancer cell lines and one immortalized prostate epithelial cell line) analysed, suggesting that it is not a candidate TSG in prostate cancer. A second LCR at 18q21, LCR 2, includes the D18S51 locus and is flanked by the D18S1109 and D18S68 loci, which are separated by 7.64 cM. LCR 2 was lost in six (35%) of the 17 specimens with chromosome 18q losses. These results suggest that chromosome 18q21 may harbor two candidate prostate cancer TSGs. The candidate TSGs DCC and Smad4 are located centromeric to the LCRs. No alleles were lost within or in close proximity to these genes, suggesting that they are not targets for inactivation by allelic losses in prostate cancer. Although there was no obvious correlation between chromosome 18q LOH and the pathological grade or stage, three (37.5%) of eight low-grade cancers and nine (32.1%) of 28 organ-confined cancers lost alleles at 18q21, suggesting that allelic losses are relatively early events in the development of invasive prostate cancer.