Evaluation of tumor suppressor genes on chromosome 8p

Carcinogenesis is driven by the gain of function of oncogenes and the loss of function of so-called tumor suppressor genes (TSGs). Recently, we and others could show that a loss of genetic material on the short arm of chromosome 8 occurs in ovarian cancer frequently. This observation is a strong indicator that this chromosomal region harbours potential TSGs which might play a causative role in ovarian cancer. In the previous years, we have carefully mapped smallest regions of overlap (SRO) in this region and have isolated bacterial artificial chromosomes (BAC) from human DNA libraries to physically cover one SRO on 8p21-22. Consequently, we have used powerful molecular genetic and bioinformatic tools to isolate potential coding sequences. Now, we are working on potential genes predicted by bioinformatic tools from sequences of the region available from the Human Genome Project, on expressed sequence tags (ESTs) mapping to the region and on exons isolated by exon trapping. The evaluation of upcoming TSG candidate genes is challenging since the demonstration of mutations or other forms of inactivation like methylation in the relevant genes is labour intensive. One option is to search systematically for homozygous deletions (HD). HD are usually smaller than regions where one allel is lost and are -most of the time- a prerequisite for the successful isolation of a TSG by reducing the number of potential candidate genes which have to be screened. While we are developing new high-throughput-tools to define regions of homozygous loss by chip technology (microarray CGH), we were lucky by identifying a region of homozygous loss in a pancreatic carcinoma cell line. Covering a region of only 685 kilo bases it will be relatively straightforward to isolate and characterize a defined number of genes from this comparatively small area. Besides the search for novel genes, we are also working candidate genes mapping to the more extended region like the receptors for TNF-related apoptosis inducing ligand (TRAIL). In combination, these approaches should shed light on the underlying cause for the frequent loss of genetic material from 8p21-22 in human tumours, leading to the identification of novel genes involved in oncogenesis, a better understanding of tumorigenesis and ultimatively to better diagnostic and therapeutic options for patients with ovarian cancer.

Carcinogenesis is driven by the gain of function of oncogenes and the loss of function of so-called tumor suppressor genes (TSGs). Recently, we and others could show that a loss of genetic material on the short arm of chromosome 8 occurs in ovarian cancer frequently. This observation is a strong indicator that this chromosomal region harbours potential TSGs which might play a causative role in ovarian cancer. In the previous years, we have carefully mapped smallest regions of overlap (SRO) in this region and have isolated bacterial artificial chromosomes (BAC) from human DNA libraries to physically cover one SRO on 8p21-22. Consequently, we have used powerful molecular genetic and bioinformatic tools to isolate potential coding sequences. Now, we are working on potential genes predicted by bioinformatic tools from sequences of the region available from the Human Genome Project, on expressed sequence tags (ESTs) mapping to the region and on exons isolated by exon trapping. The evaluation of upcoming TSG candidate genes is challenging since the demonstration of mutations or other forms of inactivation like methylation in the relevant genes is labour intensive. One option is to search systematically for homozygous deletions (HD). HD are usually smaller than regions where one allel is lost and are -most of the time- a prerequisite for the successful isolation of a TSG by reducing the number of potential candidate genes which have to be screened. While we are developing new high-throughput-tools to define regions of homozygous loss by chip technology (microarray CGH), we were lucky by identifying a region of homozygous loss in a pancreatic carcinoma cell line. Covering a region of only 685 kilo bases it will be relatively straightforward to isolate and characterize a defined number of genes from this comparatively small area. Besides the search for novel genes, we are also working candidate genes mapping to the more extended region like the receptors for TNF-related apoptosis inducing ligand (TRAIL). In combination, these approaches should shed light on the underlying cause for the frequent loss of genetic material from 8p21-22 in human tumours, leading to the identification of novel genes involved in oncogenesis, a better understanding of tumorigenesis and ultimatively to better diagnostic and therapeutic options for patients with ovarian cancer.