Human Molecular Genetics Advance Access published online on April 6, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi144
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1 ARC Special Research Centre for the Molecular Genetics of Development, ARC-NHMRC Research Network in Genes and Environment in Development, School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide SA 5005, Australia; Centre for Medical Genetics, Women's and Children's Hospital, North Adelaide SA 5006, Australia
* To whom correspondence should be addressed. Neither the molecular basis for common fragile site DNA instability, nor the contribution of this form of chromosomal instability to cancer, are clearly understood. Fragile site FRA16D (16q23.2) is within regions of frequent loss-of-heterozygosity (LOH) in breast and prostate cancers, is associated with homozygous deletions in various adenocarcinomas and t(14;16) chromosomal translocations in multiple myeloma. The FOR (WWOX) gene spans FRA16D and encodes a partner of p53 that also has a role in apoptosis. 53 previously untested cancer cell lines were screened for deletions within the FOR/WWOX gene. Deletions were detected in Co115, KM12C and KM12SM. Homozygous deletions in these and two previously identified tumour cell lines were intragenic on both alleles, indicating a distinct mutation mechanism from that causing LOH. Identical FRA16D deletions in two cell lines (one derived from the primary carcinoma, the other from a secondary metastasis) demonstrate that FRA16D DNA instability can be an early, transient event. Sequence analysis across one deletion locates one endpoint within a polymorphic AT dinucleotide repeat and the other adjacent to an AT-rich mini-satellite repeat implicating AT-rich repeats in FRA16D DNA instability. Another deletion is associated with de novo repetition of the 9bp AT-rich sequence at one of the deletion endpoints. FRA16D deleted cells retain cytogenetic fragile site expression indicating that the deletions are susceptible sites for breakage rather than regions that confer fragility. Most cell lines with FRA16D homozygous deletions also have FRA3B deletions, therefore common fragile sites represent highly susceptible genome-wide targets for a distinct form of mutation.
Article
Common chromosomal fragile site FRA16D mutation in cancer cells
2 Queensland Institute for Medical Research, PO Royal Brisbane Hospital, Queensland 4029, Australia
3 Centre for Medical Genetics, Women's and Children's Hospital, North Adelaide SA 5006, Australia
4 Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria 3050, Australia
5 Department of Paediatrics, The University of Adelaide, Adelaide SA 5005, Australia; Department of Cytogenetics, King Edward Memorial Hospital, Subiaco, WA, Australia
Robert I. Richards, E-mail: robert.richards{at}adelaide.edu.au
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