Syndrome de Li-Fraumeni

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Les altérations des gènes de la famille TP53, de la prédisposition génétique aux cancers aux anomalies de l'embryogénèse

Le syndrome de Li-Fraumeni (LFS), touchant l'enfant et l'adulte jeune, représente l'une des prédispositions génétiques aux cancers les plus dévastatrices et se caractérise par un large spectre de tumeurs à développement précoce, en particulier des sarcomes, des corticosurrénalomes et des cancers du sein préménopausiques. Ce syndrome résulte généralement de mutations du gène TP53, mais dans certaines familles l'altération sous?jacente reste indéterminée. Dans un premier temps nous avons recherché ces altérations et mis au point une nouvelle technique de QMPSF (quantitative multiplex PCR of short fluorescent fragments) qui a permis de détecter la disparition d'une copie de TP53 dans une grande famille française. Cette découverte permettra d'adapter la prise en charge de ces patients. Cette technique a aussi permis de détecter une altération homozygote du gène MSH2 à l'origine du développement de tumeurs infantiles, mettant en avant l'importance de considérer l'hypothèse d'une altération homozygote des gènes de réparation de l'ADN dans les familles présentant des tumeurs précoces du système nerveux central et des tumeurs hématologiques. Dans une seconde partie nous avons analysé TP63, homologue de TP53, qui s'est avéré ne pas être impliqué dans le LFS mais dans le développement embryonnaire. Nous avons détecté des mutations de TP63 dans différents syndromes malformatifs de type EEC (Ectrodactyly, Ectodermal dysplasia and Cleft lip/palate), montrant en particulier que les altérations de TP63 sont à l'origine d'un large spectre de symptomes. Nous avons testé in vitro l'effet de ces mutations sur l'interaction entre TP53 et TP63 et avons montré que la plupart des mutations de TP63 lèvent l'effet transdominant négatif des isoformes ?Np63 sur TP53 et que cet effet transdominant négatif ne passerait pas par une compétition pour les séquences cibles de TP53. Les gènes de la famille TP53 semblent donc impliqués à la fois dans des voies de développement et de cancérisationThe Li-Fraumeni syndrome (LFS), affecting children and young adults, represents one of the most devastating genetic predispositions to cancers and is characterised by a wide spectrum of early onset malignancies including sarcomas, adrenocortical tumours, and premenopausal breast cancers. This syndrome results generally from TP53 gene mutations, however in a fraction of LFS families the underlying alteration remains indeterminate. First we searched for these alterations and we developped a new QMPSF (quantitative multiplex PCR of short fluorescent fragments) method which allowed us to detect the loss of one copy of TP53 in a large french family. This discovery will allow to adapt the medical treatment of these patients. This method allowed us to detect a homozygous alteration of MSH2 in children tumors, indicating that the presence of homozygous mutations of the different MMR genes must be considered in families with early-onset CNS tumors and hematological malignancies. Second, we analyzed TP63, a TP53 homolog not involved in the LFS but in the embryonic development. We detected TP63 mutations in different EEC-like syndromes (Ectrodactyly, Ectodermal dysplasia and Cleft lip/palate), indicating that TP63 alterations are the cause of a large spectrum of symptoms. We tested in vitro the effect of these mutations on the interaction between TP53 and TP63 and we showed that most of TP63 mutations remove the transdominant negative effect of ?Np63 isoforms on TP53 and that this transdominant negative effect does not act through a competition for the TP53 response elements. Therefore, the TP53 family genes seem involved in development and cancerROUEN-BU Sciences (764512102) / SudocSudocFranceF

The Rapp–Hodgkin syndrome results from mutations of the TP63 gene

International audienceThe Rapp-Hodgkin syndrome (RHS, MIM 129400) corresponds to a rare form of anhydrotic ectodermal dysplasia, which shares some features with the ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome (EEC, MIM 604292) resulting from TP63 mutations. We report here, in two unrelated patients with RHS, the identification of two distinct TP63 mutations, corresponding to a novel frameshift mutation (1709DelA, exon 14) located downstream the sterile alpha motif (SAM) domain and to a missense mutation (R279H, exon 7) within the DNA binding domain. Functional analysis of the R279H mutation, which had previously been reported in several EEC families, shows that this mutation disrupted the dominant negative activity of the DeltaNp63alpha and gamma isoforms on the transcriptional activity of TP53. This report shows, on a molecular basis, that RHS is also an EEC-like syndrome resulting from mutations of the TP63 gene, and highlights the wide phenotypic spectrum associated to TP63 mutations

TP63 gene mutation in ADULT syndrome.

International audienceTP63 gene mutations have recently been shown to be disease causing in EEC and SHFM. Two other overlapping syndromes with ectrodactyly as a major feature, have been mapped to chromosome 3q27 close by the TP63 locus, namely the LMS and ADULT syndromes. Here, we report on a missense TP63 gene mutation in an isolated ADULT syndrome case. This finding widens the spectrum of abnormalities to be ascribed to TP63 gene in human and emphasise on the variable roles of the different Tp63 isotypes

Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage

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A new genotoxicity assay based on p53 target gene induction

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MSI detection and its pitfalls in CMMRD syndrome in a family with a bi-allelic MLH1 mutation

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The MDM2 285G–309G haplotype is associated with an earlier age of tumour onset in patients with Li-Fraumeni syndrome

International audienceIn the Li-Fraumeni syndrome (LFS) resulting from germline TP53 mutations, the MDM2 SNP309G allele has been shown to be associated with an earlier age of tumour onset, however the significance of this association is controversial. The 285C variation, also located in the MDM2 promoter, has been shown to reduce the strength of Sp1 binding to MDM2 promoter, antagonizing the effect of the 309G variation. In this study, we investigated the interaction of the MDM2 SNP285 and 309 in a large series of 195 LFS patients. Although we observed a lower mean age of tumour onset in patients with MDM2 SNP309 T/G or G/G genotype (23.1 years) than in patients with T/T genotype (27.3 years), the difference was not statistically significant. In contrast, patients with the 285-309 G-G haplotype develop tumours 5 years earlier than patients harbouring other haplotypes (p = 0.044). This result shows that the MDM2 285-309 G-G is a higher risk haplotype in patients with germline TP53 mutations. This study confirms that the MDM2 309G variation is deleterious when its effect is not neutralized by the 285C variation and illustrates the interfering effects of SNPs located within a gene acting as modifier factor in a Mendelian disease