GENOMIC INSTABILITY AND POOR-PROGNOSIS ASSOCIATED WITH ABNORMAL TP53 IN BREAST CARCINOMAS - MOLECULAR AND IMMUNOHISTOCHEMICAL ANALYSIS

Alterations of the TP53 gene were analyzed in samples from 87 primary breast cancer patients, using molecular and immunohistochemical approa ches. Mutations were detected in 17% of the samples, using polymerase chain reaction (PCR) and constant denaturant gel electrophoresis (CDGE ) on exons 5-8 of the TP53 gene, and were confirmed by sequencing. Abn ormal TP53 protein staining was found in 55% of the primary samples, u sing the monoclonal TP53 antibody DO7. A statistically significant ass ociation was found between TP53 mutations and abnormal protein stainin g (p=0.002). Our results suggest that dysfunction of the TP53 protein is associated with tumor progression, as we found an association betwe en TP53 abnormalities and accumulation of genetic lesions, measured as overall allelic imbalance (AI), homogeneously staining regions (HSR) and strong ERBB2 overexpression. Furthermore, patients with TP53 mutat ion had a highly elevated risk of dying from breast cancer during the study period (p<0.001, RR=10.68) at a median follow-up time of 42 mont hs. Abnormal TP53 staining was much more frequent than the mutations, but it was not of prognostic significance, whereas strong staining was an independent prognostic factor. We therefore conclude that loss of functional TP53 leads to genetic instability, resulting in poorer shor t-term prognosis, and that only strong staining of TP53, and not abnor mal protein staining in general, is of prognostic significance.