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Tumour-suppressor genes in prostatic oncogenesis: a positional approach
R Bookstein1, G S Bova, D MacGrogan
1Canji Inc., San Diego, CA 92121, USA.
Abstract:
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.
Insights
Researchers investigated genetic alterations in prostate cancer, identifying a novel gene, N33, on chromosome 8p22. This gene is silenced by methylation in colorectal cancers, suggesting its potential role in oncogenesis.
Area of Science:
- Oncology
- Human Genetics
- Molecular Biology
Background:
- Prostate cancer development involves genetic alterations like mutation, methylation, and aneuploidy.
- Genetic events in prostate oncogenesis, especially in early stages, remain poorly understood.
- Frequent allelic losses on chromosome 8p suggest novel tumor suppressor loci in prostate cancer.
Purpose of the Study:
- To identify novel genetic targets in prostate cancer using a positional approach.
- To investigate allelic loss mapping of chromosome 8p and physical mapping of 8p22.
- To characterize genes within a frequently deleted region on chromosome 8p22.
Main Methods:
- Positional cloning and allelic-loss mapping of chromosome 8p.
- Physical mapping of chromosome band 8p22.
- Detailed examination of expressed sequences within a 730-970 kb homozygous deletion.
- Analysis of gene silencing mechanisms, including methylation.
Main Results:
- A homozygous somatic deletion on chromosome 8p22 was identified in a prostate cancer metastasis.
- A novel gene, N33, was discovered within this deleted region.
- N33 was found to be silenced by methylation in colon cancer cell lines and primary colorectal tumors.
Conclusions:
- Novel genetic alterations, including deletions and gene silencing, are implicated in prostate cancer.
- The N33 gene, silenced by methylation, is a potential target for further investigation in both prostate and colorectal cancers.
- Continued characterization of chromosome 8p22 candidates is crucial for understanding prostate cancer genetics.