Spectrum of p53 tumor suppressor gene mutations and breast cancer survival

Context. p53 mutation is associated with poor prognosis in breast cancer patients. Mutations in different structural and functional domains of p53 have different effects on its biological activities. Nevertheless, few studies have examined the full spectrum of p53 gene mutations in relation to breast cancer survival. Objective. To evaluate the prognostic significance of the types, localizations, and multiplicity of p53 gene mutations in breast cancer patients. Design, setting, and participants. Prospective cohort study of a consecutive series of 271 women with histologically confirmed primary breast cancer who underwent breast resection at the Jackson Memorial Hospital, Miami, FL, between 1984 and 1986. Main outcome measures. Ten year overall and breast-cancer- specific deaths. Results. After adjustment for tumor stage, treatment regimen, and the number of mutations, patients with p53 mutations had significantly greater breast-cancer-specific mortality than did patients without p53 mutations (hazard ratio = 2.86; 95% confidence interval: 1.15-7.11). Further analysis of mutation characteristics showed that patients with the following mutations had significantly poorer breast cancer disease-free survival: silent/missense mixed mutations (7.95; 1.28-49.62), nonsense mutations (9.43; 1.29-69.12), transitions (3.79; 1.46-9.88), mutations in which guanine changed (3.32; 1.01-10.35), and mutations on exon 7 (6.46; 1.78-23.45). Conclusions. Breast-cancer-specific and all-cause mortality are increased in female breast cancer patients with the following p53 mutation characteristics: silent and missense mixed mutations, transitional mutations, mutations in which guanine changed, mutations on exon 7, or multiple mutations occurring within 60 codons. These findings indicate that not just p53 mutation per se but the full spectrum (i.e., different types, locations, and numbers) of p53 mutation needs to be examined when it is used as a prognostic marker of survival in breast cancer patients.