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Type: Journal article
Title: Common chromosomal fragile site FRA16D mutation in cancer cells
Author: Finnis, M.
Dayan, S.
Hobson, L.
Chenevix-Trench, G.
Friend, K.
Ried, K.
Venter, D.
Woollatt, E.
Baker, E.
Richards, R.
Citation: Human Molecular Genetics, 2005; 14(10):1341-1349
Publisher: Oxford Univ Press
Issue Date: 2005
ISSN: 0964-6906
Organisation: Centre for the Molecular Genetics of Development
Statement of
Merran Finnis, Sonia Dayan, Lynne Hobson, Georgia Chenevix-Trench, Kathryn Friend, Karin Ried, Deon Venter, Erica Woollatt, Elizabeth Baker, and Robert I. Richards
Abstract: Neither the molecular basis for common fragile site DNA instability nor the contribution of this form of chromosomal instability to cancer is 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. Previously untested 53 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 and 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 9 bp 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.
Keywords: Tumor Cells, Cultured
Chromosomes, Human, Pair 16
Chromosome Deletion
Cytogenetic Analysis
Base Sequence
Repetitive Sequences, Nucleic Acid
Loss of Heterozygosity
Chromosome Fragile Sites
Molecular Sequence Data
DOI: 10.1093/hmg/ddi144
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Centre for the Molecular Genetics of Development publications
Molecular and Biomedical Science publications

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