BACKGROUND: Brain metastasis from breast cancer is usually associated with a poor prognosis and early death. Alteration of p53 may
contribute to malignant progression by abrogation of apoptosis induced by oncogene activation and by acquisition of gain-of-function
properties, which promote tumour aggression. Mutation in TP53 occurs at high frequency in carcinomas of the lung and gastrointestinal tract, but is much less frequent, at 25%, in primary breast cancer. The frequency of TP53 alteration in the central nervous
system (CNS) metastatic breast cancer is not known.
METHODS: In all, 23 cases of histologically confirmed CNS metastatic breast cancer were identified and the coding sequence of TP53
determined. TP53 was also sequenced in two control series of primary breast carcinomas from independent clinical centres.
RESULTS: We demonstrate a strikingly high frequency of TP53 mutation in the CNS metastatic lesions with an over-representation of
complex mutations (non-sense/deletions/insertions). Complex mutations occur in metastatic lesions in both triple-negative breast
cancer and hormone receptor/HER2-positive cases. Analysis of paired primary carcinomas and brain metastatic lesions revealed
evidence for both clonal selection and generation of new mutations (missense and complex) in progression from a primary breast
carcinoma to brain metastasis.
CONCLUSION: Mutation in TP53 is the most common genetic alteration reported during metastasis to the brain in breast cance