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Molecular characterization of FRAXB and comparative common fragile site instability in cancer cells
Martin F Arlt1, Diane E Miller, David G Beer
1Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-0618, USA.
Abstract:
The common fragile site, FRA3B, has been shown to be a site of frequent homozygous deletions in some cancers, resulting in loss of expression of the associated FHIT gene. It has been proposed that FHIT is a tumor suppressor gene that is inactivated as a result of the instability of FRA3B in tumorigenesis. More recently, deletions at other common fragile sites, FRA7G and FRA16D, have been identified in a small number of cancer cell lines. Here, we have mapped and molecularly characterized the frequently observed common fragile site FRAXB, located at Xp22.3. Like other common fragile sites, it spans a large genomic region of approximately 500 kb. Three known genes, including the microsomal steroid sulfatase locus (STS), map within the fragile site region. We examined FRAXB and four other fragile sites (FRA3B, FRA7G, FRA7H, FRA16D), and several associated genes, for deletions and aberrant transcripts in a panel of cancer cell lines and primary tumors. Deletions within FRAXB were seen in 4/27 (14.8%) of the primary tumors and cell lines examined. Three of the 21 (14.3%) cell lines examined were characterized by loss of expression of one or more FRAXB-associated genes. Moreover, all of the fragile sites examined were characterized by genomic deletions within the fragile site regions in one or more tumors or cell lines, including FRAXB, which is not associated with any known tumor suppressor genes or activity. Our results further support the hypothesis that common fragile sites and their associated genes are, in general, unstable in some cancer cells.
Insights
Common fragile sites, like FRAXB, are unstable genomic regions frequently deleted in cancer. These deletions affect associated genes, supporting their general instability in tumorigenesis.
Area of Science:
- Genetics
- Cancer Biology
- Genomic Instability
Background:
- Common fragile sites (CFS) are prone to deletions in cancer.
- The FHIT gene, located at FRA3B, is a proposed tumor suppressor inactivated by deletions.
- Other CFS like FRA7G and FRA16D have also been linked to cancer.
Purpose of the Study:
- To map and characterize the common fragile site FRAXB at Xp22.3.
- To investigate deletions and aberrant transcripts at FRAXB and other CFS in cancer.
- To assess the instability of CFS and their associated genes in tumorigenesis.
Main Methods:
- Mapping and molecular characterization of the FRAXB fragile site.
- Analysis of deletions and aberrant transcripts in cancer cell lines and primary tumors.
- Examination of multiple fragile sites (FRAXB, FRA3B, FRA7G, FRA7H, FRA16D) and associated genes.
Main Results:
- FRAXB spans approximately 500 kb and contains genes including STS.
- Deletions within FRAXB were observed in 14.8% of examined tumors and cell lines.
- Loss of expression of FRAXB-associated genes occurred in 14.3% of cell lines; all examined CFS showed deletions.
Conclusions:
- Common fragile sites are generally unstable in cancer cells.
- FRAXB deletions and associated gene expression loss indicate its role in cancer.
- Genomic instability at CFS contributes to tumorigenesis, even for sites without known tumor suppressors.