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Mutations in residues of TP53 that directly contact DNA predict poor outcome in human primary breast cancer.

Abstract：

:The tumour-suppressor gene TP53 is frequently mutated in breast tumours, and the majority of the mutations are clustered within the core domain, the region involved in DNA binding. We searched for alterations in this central domain of the TP53gene in 222 human breast cancer specimens using polymerase chain reaction-single-strand conformation analysis (PCR-SSCA) followed by sequencing. TP53 gene mutations were observed in 66 tumours (31%), including three tumours that contain two mutations. Fifty-four (78%) of these mutations were missense point mutations, one was a nonsense mutation and four were deletions and/or insertions causing disruption of the protein reading frame, whereas four mutations were either silent or a polymorphism (at codon 213; n = 6). Interestingly, the majority of missense mutations were observed at codon 248. The outcome has been related with patient and tumour characteristics, and with prognosis in 177 patients who were eligible for analysis of both relapse-free and overall survival (median survival for patients alive was 115 months). There was no significant association between the frequency of TP53 mutations and menopausal or nodal status, or tumour size. In a Cox univariate analysis, TP53 gene mutation was significantly associated with poor relapse-free survival (RFS: P = 0.02) but not with overall survival (OS: P = 0.07). In a Cox multivariate analysis, including classical prognostic factors, TP53 gene mutation independently predicted poor RFS and OS (RHR = 1.8 and 1.6 respectively). Unexpectedly, the median relapse-free survival of patients with a polymorphism at codon 213 or with a silent mutation was shorter (median 11 months) than the median relapse-free survival of patients with or without a TP53 gene mutation (median 34 or 48 months respectively). In an exploratory subset analysis, mutations in codons that directly contact DNA were related with the poorest relapse-free (P < 0.05) and overall survival (P < 0.02). These data imply that in the analysis of the prognostic value of TP53, the type of mutation and its biological function should be considered.

journal_name

Br J Cancer

journal_title

British journal of cancer

authors

Berns EM,van Staveren IL,Look MP,Smid M,Klijn JG,Foekens JA

doi

10.1038/bjc.1998.187

subject

Has Abstract

pub_date

1998-04-01 00:00:00

pages

1130-6

issue

eissn

0007-0920

issn

1532-1827

journal_volume

pub_type

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Mutations in residues of TP53 that directly contact DNA predict poor outcome in human primary breast cancer.