title: Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes.
abstract: 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 TP53 mutant alleles based on transactivation. Severe deficiency (SD) alleles were associated with more severe cancer proneness syndromes, and a larger number of tumors, compared with partial deficiency (PD) alleles. Because 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 TP53 mutations, where mutant alleles coexist 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 tumor tissue prevalence. We conclude that in carriers of germline TP53 mutations transactivation-based classification of TP53 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.
authors.affiliation: Molecular Mutagenesis and DNA Repair Unit, Department of Epidemiology and Prevention, National Cancer Research Institute (IST), Largo Rosanna Benzi, 10, Genova 16132, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Monti
authors.forename: Chiara
authors.initials: C
authors.lastname: Perfumo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bisio
authors.forename: Yari
authors.initials: Y
authors.lastname: Ciribilli
authors.forename: Paola
authors.initials: P
authors.lastname: Menichini
authors.forename: Debora
authors.initials: D
authors.lastname: Russo
authors.forename: David M
authors.initials: DM
authors.lastname: Umbach
authors.forename: Michael A
authors.initials: MA
authors.lastname: Resnick
authors.forename: Alberto
authors.initials: A
authors.lastname: Inga
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fronza
mesh_terms: D000483:Alleles; D016158:Genes, p53 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D010641:Phenotype; D011230:Precancerous Conditions / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53