Molecular Genetics of Prostate Cancer
In our program we study the mechanism of genomic instability, the Pten signal transduction pathway and the roles of genes on chromosome arms 8p and 6q in prostate cancer.
The most frequent chromosomal alterations in prostate cancer are deletions
ofparts of chromosome arms 6q, 8p, 10q, 13q, 16q and 17p, and amplification of
8q (see Figure 6 and Trapman et al. 1994; Van Alewijk et al. 1999 for
chromosomearm 8p). Some chromosomal alterations can already be recognized in
pre-cancerous lesions. However, chromosomal alterations are most frequent in
tumor metastases. In a subset of endocrine-therapy resistant prostate cancers,
amplification of the androgen receptor gene, which is located on the X
chromosome, has been found (Koivisto et al. 1997). Out of the many known
traditional oncogenes and tumor suppressor genes, inactivation of P53 at 17p
and PTEN at 10q contribute most frequently to prostate cancer growth (Figure 7)
(Vlietstra et al., 1998).
Figure 6: Analysis of chromosome arm 8p in prostate cancer by allelotyping andComparative Genomic Hybridization.
Figure 7: PTEN alterations in prostate cancer cell lines and xenografts.
Although the various specific chromosomal alterations in prostate cancer are known for over four years, the identification of novel candidate genes based onthe most frequently deleted or amplified chromosomal regions has been disappointing. The failure to detect novel cancer genes might lie in the fact that the traditional concept of alteration of a few genes involved in tumorigenesis is too narrow. A modified, more complex, concept proposes a combination of irreversible mutations in a limited number of genes, with modulated expression of a larger number of genes due to haplo-insufficiency and chromosome gain, and more reversible patterns of altered gene expression because of promoter hypermethylation or chromatin modification.
Figure 6: Analysis of chromosome arm 8p in prostate cancer by allelotyping andComparative Genomic Hybridization.
Figure 7: PTEN alterations in prostate cancer cell lines and xenografts.
Although the various specific chromosomal alterations in prostate cancer are known for over four years, the identification of novel candidate genes based onthe most frequently deleted or amplified chromosomal regions has been disappointing. The failure to detect novel cancer genes might lie in the fact that the traditional concept of alteration of a few genes involved in tumorigenesis is too narrow. A modified, more complex, concept proposes a combination of irreversible mutations in a limited number of genes, with modulated expression of a larger number of genes due to haplo-insufficiency and chromosome gain, and more reversible patterns of altered gene expression because of promoter hypermethylation or chromatin modification.