A comparison between p53 accumulation determined by immunohistochemistry and TP53 mutations as prognostic variables in tumours from breast cancer patients

Background. p53 accumulation and TP53 mutations are known prognostic markers for breast cancer. To clarify their interrelationship and the importance of different TP53 mutation types, these markers were investigated in tumours; from 630 patients with breast cancer. Materials and methods. Tumour sections were stained for p53 and scored based on staining intensity and percentages of invasive tumour cells with nuclear staining. TP53 mutations were identified by sequencing. Patient cohorts were from the DBCG (Danish Breast Cancer Cooperative Group) protocols DBCG82 and DBCG89. Results. TP53 was mutated in 29% of the patients. The disease-specific survival (DSS) at 15 years of follow-up for patients with missense mutations directly involved in DNA or zinc binding was 21 +/- 8%. Patients with the remaining missense mutations within the structural/conserved domains and patients with null mutations had a DSS of 36+/-6% and 31+/-17%, respectively. For patients without TP53 mutations and patients with mutations affecting amino acids outside these domains, the 15 year DSS was 51+/-3% and 71+/-10%, respectively. p53 accumulation was successfully scored in 567 patients and categorized into three groups. Tumours with no p53 expression had a high frequency of null mutations (37% compared to 10% in the whole cohort), and tumours with high p53 expression contained 82% of the missense mutations inside structural/conserved domains including those directly involved in DNA or zinc binding. Conclusion. The clinical outcome for breast cancer patients is significantly different for different TP53 mutation types, but further functional studies are required to clarify the exact role of these mutation types. Most of the mutations that lead to mutant p53 protein accumulation can be detected by immunohistochemistry but the specificity is low. Samples showing lack of detectable p53 protein should be considered as an indication of a possible null mutation.