Abstract
The absence of detectable germline TP53 mutations in a fraction of families with Li–Fraumeni syndrome (LFS) has suggested the involvement of other genes, but this hypothesis remains controversial. The density of Alu repeats within the TP53 gene led us to search genomic rearrangements of TP53 in families without detectable TP53 mutation. To this aim, we adapted the quantitative multiplex PCR of short fluorescent fragments (QMPSF) method to the analysis of the 11 exons of TP53. We analysed 98 families, either fulfilling (six families) or partially meeting (92 families) the criteria for LFS, and in which classical methods had failed to reveal TP53 alterations. We identified, in a large family fulfilling the criteria for LFS, a complete heterozygous deletion of TP53. Additional QMPSF analyses indicated that this deletion, which partially removed the centromeric FLJ10385 locus, covered approximately 45 kb. This deletion was shown to result from a complex rearrangement involving two distinct Alu-mediated recombinations. We conclude that TP53 germline rearrangements occur as rare events, but must be considered in LFS families without detectable point TP53 mutation.
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Acknowledgements
We are grateful to Mario Tosi for a critical review of the manuscript and to Qin Wang for providing DNA samples. This work was supported by l'Association pour la Recherche sur le Cancer, la Fondation pour la Recherche Médicale and la Ligue Nationale contre le Cancer. G Bougeard was supported by a grant from le Ministère de la Recherche.
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Bougeard, G., Brugières, L., Chompret, A. et al. Screening for TP53 rearrangements in families with the Li–Fraumeni syndrome reveals a complete deletion of the TP53 gene. Oncogene 22, 840–846 (2003). https://doi.org/10.1038/sj.onc.1206155
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DOI: https://doi.org/10.1038/sj.onc.1206155
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