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

TP53gene 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 (mut) 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 wtp53 can be rewired to adopt mut-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 ofTP53gene mutation status. Harnessing the power of machine learning, we optimized a gene expression classifier for ER+Her2- patients that distinguishes tumors carryingTP53mutations from those retaining wtTP53. Interestingly, a small subset of wtTP53tumors displayed gene expression and pathway deregulation patterns markedly similar to those ofTP53-mutated tumors. Moreover, similar toTP53-mutated tumors, these 'pseudomutant' cases displayed a signature for enhanced proliferation and had worse prognosis than typical wtp53 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 mut p53-associated activities without having to accrueTP53mutations.