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Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families
  1. Gaëlle Bougeard (gaelle.bougeard{at}univ-rouen.fr)
  1. Inserm U614, Faculty of Medicine, and Department of Genetics, University Hospital, Rouen, France
    1. Richard Sesboüé (richard.sesboue{at}univ-rouen.fr)
    1. Inserm U614, Faculty of Medicine, and Department of Genetics, University Hospital, Rouen, France
      1. Stéphanie Baert-Desurmont (stephanie.baert-desurmont{at}chu-rouen.fr)
      1. Inserm U614, Faculty of Medicine, and Department of Genetics, University Hospital, Rouen, France
        1. Stéphanie Vasseur
        1. Inserm U614, Faculty of Medicine, and Department of Genetics, University Hospital, Rouen, France
          1. Cosette Martin
          1. Inserm U614, Faculty of Medicine, and Department of Genetics, University Hospital, Rouen, France
            1. Julie Tinat
            1. Inserm U614, Faculty of Medicine, and Department of Genetics, University Hospital, Rouen, France
              1. Laurence Brugières
              1. Department of Pediatric Oncology, Institut Gustave Roussy, Villejuif, France
                1. Agnès Chompret
                1. Department of Medicine, Institut Gustave Roussy, Villejuif, France
                  1. Brigitte Bressac-de Paillerets
                  1. Department of Genetics, Institut Gustave Roussy, Villejuif, France
                    1. Dominique Stoppa-Lyonnet
                    1. Department of Genetics, Institut Curie, Paris, France
                      1. Catherine Bonaïti-Pellié
                      1. Inserm U535, Villejuif, France
                        1. Thierry Frebourg (frebourg{at}chu-rouen.fr)
                        1. Inserm U614, Faculty of Medicine, and Department of Genetics, University Hospital, Rouen, France
                          1. The French LFS working group
                          1. The French LFS working group, France

                            Abstract

                            We have performed an extensive analysis of TP53 in 474 French families suggestive of LFS, including 232 families fulfilling the Chompret criteria. We identified a germline alteration of TP53 in 82 families (17%), in 67/232 of the families fulfilling the Chompret criteria (29%) and in 15/242 which did not fulfil these criteria (6%). Most of the alterations corresponded to missense mutations (67%) and we identified in 4 families genomic deletions removing, the entire TP53 locus, the promoter and the non coding exon 1, or exons 2-10. These results represent a definitive argument demonstrating that LFS results from TP53 haplo-deficiency. The mean ages of tumour onset were significantly different between patients harbouring TP53 missense mutations and other types of alterations, missense mutations being associated with a 9-year earlier tumour onset. These results confirm that missense mutations not only inactivate p53 but also have an additional oncogenic effect. Germline alterations of TP53 that lead exclusively to loss of function are therefore associated with a later age of tumour onset and the presence of such mutations should be considered in atypical LFS families with tumours diagnosed after 40 years.

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