Tumour-suppressor genes in prostatic oncogenesis: a positional approach

Genetic alterations, such as mutation, methylation and aneuploidy, are thought to underlie the multistep genesis and progression of many human cancers. However, the genetic events occurring in prostatic oncogenesis are still relatively poorly understood. This is especially so in early-stage tumours, in which mutations of known oncogenes or tumour-suppressor genes appear to be quite infrequent. Allelic losses of chromosome arms 7q, 8p, 10, 16q and 18q suggest the involvement of novel suppressor loci on these chromosomes; allelic losses of chromosome arm 8p are especially frequent and may be detected even in early-stage tumours. We have used a positional approach to seek novel genetic targets in prostate cancer, including allelic-loss mapping of chromosome 8p and physical mapping of chromosome band 8p22 around the MSR gene. A homozygous somatic deletion in one prostatic nodal metastasis was mapped in this region and spanned 730-970 kb. This region was then examined in detail for expressed sequences. One novel gene, called N33, was found to be silenced by a methylation mechanism in most colon cancer cell lines and some primary colorectal tumours. Characterization of additional chromosome 8p22 candidates is in progress.