Detection of genomic deletions of the TP53 gene in the Li-Fraumeni syndrome. G. Bougeard^1,2, S. Vasseur¹, C. Martin¹, L. Brugières³, A. Chompret⁴, B. Bressac-De Paillerets⁵, P. Jonveaux⁶, H. Sobol⁷, L. Gladieff⁸, P. Gesta⁹, S. Baert-Desurmont^1,2, T. Frebourg^1,2. 1) Department of Genetics, Rouen University Hospital, F-76000 France; 2) Inserm U614, Faculty of Medicine, Rouen, F-76000 France; 3) Department of Pediatric Oncology; Gustave Roussy Institute, Villejuif, F-94800 France; 4) Department of Oncogenetics - Gustave Roussy Institute, Villejuif, F-94800 France; 5) Department of Genetics - Gustave Roussy Institute, Villejuif, F-94800 France; 6) Department of Medical Genetics - Nancy University Hospital, F-54000 France; 7) Marseille Cancer Institute, Molecular Oncology Department, UMR599 Inserm and Paoli-Calmettes Institute, Marseille, France; 8) Department of Oncogenetics - Claudius Regaud Institute, Toulouse, F-31000 France; 9) Department of Oncology - Niort Hospital, F-79000 France.
   Absence of detectable germline mutation of the TP53 gene in a fraction of families with Li-Fraumeni syndrome (LFS) led us to screen for TP53 genomic rearrangements, using QMPSF (Quantitative Multiplex PCR of Short Fluorescent fragments), families without detectable point mutation. We recently reported the first case of a complete heterozygous germline deletion of TP53, removing all the exons, in a large French family. The screening for TP53 rearrangements has now been integrated into the routine diagnosis of LFS, using a QMPSF assay which explores the 11 exons and the promoter of the TP53 gene. Analysis, using both sequencing and QMPSF, of 259 families suspected to present a LFS according to the Chompret criteria allowed us to identify a TP53 germline alteration in 52 families (20%). We identified 3 large genomic deletions, indicating that TP53 rearrangements represent about 6% of the TP53 alterations. In 2 distinct families, we identified 2 deletions removing exon 1 and the promoter but respecting the 10 coding exons. These results constitute a definitive argument demonstrating that the LFS results from a haploinsufficiency at the TP53 locus and suggest that screening for TP53 rearrangements should be integrated in the LFS molecular diagnosis.