Transcriptional profiling reveals a subset of human breast tumors that retain wt TP53 but display mutant p53-associated features

Abstract

TP53 gene mutations are very common in human cancer. While such mutations abrogate the tumor suppressive activities of the wild type (wt) p53 protein, some of them also endow the mutant protein with oncogenic gain-of-function (GOF), facilitating cancer progression. Yet, p53 may acquire altered functionality even without being mutated; in particular, experiments with cultured cells revealed that wt p53 can be rewired to adopt mutant-like features in response to growth factors or cancer-mimicking genetic manipulations. To assess whether such rewiring also occurs in human tumors, we interrogated gene expression profiles and pathway deregulation patterns in the METABRIC breast cancer (BC) dataset as a function of TP53 gene mutation status. Harnessing the power of machine learning, we optimized a gene expression classifier for ER+Her2- patients that distinguishes tumors carrying TP53 mutations from those retaining wt TP53. Interestingly, a small subset of wt TP53 tumors displayed gene expression and pathway deregulation patterns markedly similar to those of TP53-mutated tumors. Moreover, similar to TP53 mutated tumors, these "pseudomutant" cases displayed a signature for enhanced proliferation and had worse prognosis than typical wt p53 tumors. Notably, these tumors revealed upregulation of genes which, in BC cell lines, were reported to be positively regulated by p53 GOF mutants. Thus, such tumors may benefit from mutant p53-associated activities without having to accrue TP53 mutations.