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Chromosomal fragile site FRA16D and DNA instability in cancer
M Mangelsdorf1, K Ried, E Woollatt
1Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital, Adelaide, South Australia, Australia.
Abstract:
It has been proposed that common aphidicolin-inducible fragile sites, in general, predispose to specific chromosomal breakage associated with deletion, amplification, and/or translocation in certain forms of cancer. Although this appears to be the case for the fragile site FRA3B and may be the case for FRA7G, it is not yet clear whether this association is a general property of this class of fragile site. The major aim of the present study was to determine whether the FRA16D chromosomal fragile site locus has a role to play in predisposing DNA sequences within and adjacent to the fragile site to DNA instability (such as deletion or translocation), which could lead to or be associated with neoplasia. We report the localization of FRA16D within a contig of cloned DNA and demonstrate that this fragile site coincides with a region of homozygous deletion in a gastric adenocarcinoma cell line and is bracketed by translocation breakpoints in multiple myeloma, as reported previously (Chesi, M., et al., Blood, 91: 4457-4463, 1998). Therefore, given similar findings at the FRA3B and FRA7G fragile sites, it is likely that common aphidicolin-inducible fragile sites exhibit the general property of localized DNA instability in cancer cells.
Insights
Common aphidicolin-inducible fragile sites, like FRA16D, are linked to chromosomal instability and DNA alterations in cancer. This suggests a general role for these fragile sites in neoplastic development.
Area of Science:
- Genetics
- Cancer Biology
- Molecular Oncology
Background:
- Aphidicolin-inducible fragile sites are implicated in cancer-associated chromosomal abnormalities.
- Previous studies suggest FRA3B and FRA7G fragile sites predispose to DNA instability.
- The general role of common fragile sites in cancer development requires further investigation.
Purpose of the Study:
- To investigate the role of the FRA16D fragile site in DNA instability.
- To determine if FRA16D predisposes adjacent DNA sequences to deletions or translocations.
- To assess the association of FRA16D with neoplasia.
Main Methods:
- Localization of the FRA16D fragile site within a DNA contig.
- Analysis of homozygous deletions at the FRA16D locus in gastric adenocarcinoma cells.
- Examination of translocation breakpoints flanking FRA16D in multiple myeloma.
Main Results:
- The FRA16D fragile site was localized to a cloned DNA contig.
- FRA16D was found to coincide with a region of homozygous deletion in gastric cancer cells.
- Translocation breakpoints in multiple myeloma were observed to bracket the FRA16D locus.
Conclusions:
- The FRA16D fragile site is associated with DNA instability in cancer.
- Findings support the hypothesis that common fragile sites contribute to localized DNA instability in cancer cells.
- This instability may play a role in the development or progression of cancer.