Dominant-negative features of mutant p53 in germline carriers have limited impact on cancer outcomes

摘要

Germline TP53 mutations result in cancer proneness syndromes known as Li-Fraumeni, Li-Fraumeni-like, and nonsyndromic predisposition with or without family history. To explore genotype/phenotype associations, we previously adopted a functional classification of all germline p53 mutant alleles based on transactivation. Severe Deficiency (SD) alleles were associated with more severe cancer proneness syndromes, and a larger number of tumours, compared to Partial Deficiency (PD) alleles. Since mutant p53 can exert Dominant-Negative (DN) effects, we addressed the relationship between DN and clinical manifestations. We reasoned that DN effects might be stronger in familial cancer cases associated with germline p53 mutations, where mutant alleles co-exist with the wild type allele since conception. We examined 104 p53 mutant alleles with single amino acid substitutions described in the IARC germline database for (i) transactivation capability and (ii) capacity to reduce the activity of the wild type allele (i.e., DN effect) using a quantitative yeast-based assay. The functional classifications of p53 alleles were then related to clinical variables. We confirmed that a classification based on transactivation alone can identify familial cancer cases with more severe clinical features. Classification based on DN effects allowed us to highlight similar associations but did not reveal distinct clinical subclasses of SD alleles, except for a correlation with tumour tissue prevalence. We conclude that in carriers of germline p53 mutations transactivation-based classification of p53 alleles appears more important for genotype/phenotype correlations than DN effects and that haplo-insufficiency of the TP53 gene is an important factor in cancer proneness in humans.