Heterogeneity in the clinical phenotype of TP53 mutations in breast cancerpatients

TP53 mutation is a strong independent marker for survival in breast cancer with some heterogeneity in the clinical phenotype of various types of mutat ions. Based on 315 patients with breast carcinoma, we suggest a new model f or the differentiation of TP53 mutations, Although TP53 mutation in general was associated with aggressive tumor/patient characteristics, missense mut ations outside any conserved or structural domain did not affect the clinic al outcome (risk of disseminated disease and death), In contrast, patients with missense mutations affecting amino acids directly involved in DNA or z inc binding displayed a very aggressive clinical phenotype, Null mutations (including missense mutations disrupting the tetramerization domain) and th e remaining missense mutations displayed an intermediate aggressive clinica l phenotype, When patients with primary early breast cancer were divided in to three groups (wild-type together with missense mutations outside structu ral/conserved domains, null mutations and missense mutations with intermedi ate clinical phenotype, and very aggressive missense mutations), disease-sp ecific survival rates were 89%, 58%, and 35% (5-year actuarial values, P < 0.0001), respectively, In a Cox proportional hazards analysis, separation o f TP53 mutations according to these criteria eliminated the prognostic impo rtance of all investigated classical factors except nodal status.