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 (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 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 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 accrue TP53 mutations.
Highlights
One out of eight women is likely to develop breast cancer during her lifetime (DeSantis et al, 2017)
The selected model for ER+Her2- tumors is presented in Table 2; it uses the p53-related gene list as Gene-probe Lists (GL)*, gene probes ranked by correlation to p53 status as gene-probe ranking (GR)*, and Linear Support Vector Machine (LSVM) as the machine learning (ML)* method of choice
Separately for each breast cancer subtype, which differentiate well between tumors that retain wt p53 expression and those that have undergone TP53 mutations
Summary
One out of eight women is likely to develop breast cancer during her lifetime (DeSantis et al, 2017). Some TP53 mutations may facilitate cancer progression by endowing the mutant p53 protein with oncogenic GOF (Brosh and Rotter, 2009) Such GOF, manifested by an increase in proliferation, cell motility, therapy resistance and more, is driven mainly by interactions of the mutant p53 with a variety of other proteins, eventually altering gene expression Wt p53 may undergo aberrant post-translational modifications or be excluded from the cell nucleus, depriving it of its ability to act as a transcription factor. All these mechanisms may result in p53 loss of function (LOF), equivalent to genetic loss of both wt TP53 alleles
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