Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype.

TLDR

A publicly accessible IARC TP53 Database was established to compile data from families with germ‑line TP53 mutations and Li‑Fraumeni/Li‑Fraumeni‑like syndromes, incorporating published literature and available online at http://www.iarc.fr/p53. Analysis of 265 families identified genotype‑phenotype correlations, including earlier breast cancer onset in TP53 mutation carriers, distinct missense mutations associated with brain and adrenal tumors, and null mutations linked to earlier brain tumor onset, underscoring clinical implications for genetic testing and surveillance.

Abstract

A database has been created to collect information on families carrying a germ-line mutation in the TP53 gene and on families affected with Li-Fraumeni syndromes [Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL)]. Data from the published literature have been included. The database is available online at http://www.iarc.fr/p53, as part of the IARC TP53 Database. The analysis of the 265 families/individuals that have been included thus far has revealed several new findings. In classical LFS families with a germ-line TP53 mutation (83 families), the mean age of onset of breast cancer was significantly lower than in LFS families (16 families) without a TP53 mutation (34.6 versus 42.5 years; P = 0.0035). In individuals with a TP53 mutation, a correlation between the genotype and phenotype was found. Brain tumors were associated with missense TP53 mutations located in the DNA-binding loop that contact the minor groove of DNA (P = 0.01), whereas adrenal gland carcinomas were associated with missense mutations located in the loops opposing the protein-DNA contact surface (P = 0.003). Finally, mutations likely to result in a null phenotype (absence of the protein or loss of function) were associated with earlier onset brain tumors (P = 0.004). These observations have clinical implications for genetic testing and tumor surveillance in LFS/LFL families.