TUMOR-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 hum an cancers, However, the genetic events occurring in prostatic oncogen esis are still relatively poorly understood, This is especially so in early-stage tumours, in which mutations of known oncogenes or tumour-s uppressor genes appear to be quite infrequent. Allelic losses of chrom osome arms 7q, 8p, 10, 16q and 18q suggest the involvement of novel su ppressor loci on these chromosomes; allelic losses of chromosome arm 8 p are especially frequent and may be detected even in early-stage tumo urs, We have used a positional approach to seek novel genetic targets in prostate cancer, including allelic-loss mapping of chromosome 8p an d physical mapping of chromosome band 8p22 around the MSR gene. A homo zygous somatic deletion in one prostatic nodal metastasis was mapped i n 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 l ines and some primary colorectal tumours. Characterization of addition al chromosome 8p22 candidates is in progress.