Li-Fraumeni Syndrome

Abstract

Li-Fraumeni syndrome (LFS) is a classic cancer predisposition disorder that is commonly associated with germline mutations of the p53 tumor suppressor gene. Examination of the wide spectrum of adult-onset and childhood cancers and the distribution of p53 mutations has led to a greater understanding of cancer genotype-phenotype correlations. However, the complex LFS phenotype is not readily explained by the simple identification of germline p53 mutations in affected individuals. Recent work has identified genetic events that modify the LFS phenotype. These include intragenic polymorphisms, mutations/polymorphisms of genes in the p53 regulatory pathway, as well as more global events such as aberrant copy number variation and telomere attrition. These genetic events may, in part, explain the breadth of tumor histiotypes within and across LFS families, the apparent accelerated age of onset within families, and the range of clinical outcomes among affected family members. This review will examine the clinical and genetic definitions of LFS and offer insight into how lessons learned from the study of this rare disorder may inform similar questions in other familial cancer syndromes.

Germline copy number variation of genes involved in chromatin remodelling in families suggestive of Li-Fraumeni syndrome with brain tumours

“…4 In families fulfilling the Chompret criteria, the TP53 mutation detection rate can be estimated to 25% 6 and the sensitivity and specificity of these criteria have been estimated to 82% and 58%, respectively. [6][7][8] In the context of molecular diagnostic of LFS, our laboratory has performed in 41000 index cases of French families suggestive of LFS, mostly fulfilling the Chompret criteria, extensive analysis of the TP53 gene.…”

“…151623) is a Mendelian predisposition to cancer affecting children and adults, and characterised by a wide tumour spectrum. [1][2][3][4] The heterogeneity of the clinical presentation has led to the elaboration of the Chompret criteria in order to facilitate the clinical recognition of the syndrome. [5][6][7] These criteria correspond to (i) a proband with a tumour belonging to the narrow LFS tumour spectrum (eg., soft tissue sarcoma, osteosarcoma, brain tumour, premenopausal breast cancer, adrenocortical carcinoma, leukaemia and lung bronchoalveolar cancer) diagnosed before age 46 years, and at least one first-or second-degree relative with an LFS tumour (except breast cancer, if proband is affected by breast cancer) before age 56 years or with multiple tumours; or (ii) a proband with multiple tumours, two of which belong to the narrow LFS tumour spectrum (except multiple primary breast cancers) and the first of which occurred before age 46 years; or (iii) a patient with adrenocortical carcinoma or a choroid plexus carcinoma, irrespective of family history.…”

Protéger et sévir : p53, métabolisme et suppression tumorale

“…Le maintien de la stabilité chromosomique fait vraisemblablement partie des fonctions conservatrices responsables de la suppression tumorale constitutive [43]. L'efficacité de la suppression tumorale constitutive pourrait varier selon les espèces, en relation avec leur longévité et leur résis-tance au stress oxydant, et serait, par exemple, plus robuste chez l'homme que chez la souris [5,44]. Notons d'ailleurs que p53 diverge beaucoup plus rapidement que p63 ou p73 au cours de l'évolution des vertébrés [45].…”

“…mise hors circuit définitive de ses fonctions destructrices, voire, par un effet dominant négatif, de celles de p63 et p73, tout en préservant (ou en exagérant) éventuellement certaines fonctions conservatrices bénéfiques aux tumeurs [1,9,25,43,47]. De plus, des allèles de p53 fréquemment associés aux cancers humains présentent de nouvelles propriétés (mutants néomorphes) participant activement à la transformation (Figure 4) [1,4,5]. Ainsi, plusieurs mutations ponctuelles altèrent ou inversent les fonctions métaboliques de p53 : les mutants correspondants promeuvent l'effet Warburg et/ou la voie du méva-lonate et la synthèse des acides gras, ce qui contribue à leur effet tumorigène [48][49][50] (Tableau II) (Figure 5).…”

“…La mutation germinale d'une copie de p53 est associée au syndrome de Li-Fraumeni, caractérisé par une prédisposition à développer de nombreux types de cancers. Dans les tumeurs des patients ayant hérité d'un allèle nul de p53, l'autre allèle (normal) est invariablement perdu [5]. Chez la souris, l'invalidation homozygote ou même (dans une moindre mesure) hétérozygote de p53 conduit à une impressionnante accélération de la survenue des tumeurs [1,2].…”