Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients

The TP53 gene is mutated in approximately 60% of all colorectal cancer (CRC) cases. Over 20% of all TP53-mutated CRC tumors carry missense mutations at position R175 or R273. Here we report that CRC tumors harboring R273 mutations are more prone to progress to metastatic disease, with decreased survival, than those with R175 mutations. We identify a distinct transcriptional signature orchestrated by p53R273H, implicating activation of oncogenic signaling pathways and predicting worse outcome. These features are shared also with the hotspot mutants p53R248Q and p53R248W. p53R273H selectively promotes rapid CRC cell spreading, migration, invasion and metastasis. The transcriptional output of p53R273H is associated with preferential binding to regulatory elements of R273 signature genes. Thus, different TP53 missense mutations contribute differently to cancer progression. Elucidation of the differential impact of distinct TP53 mutations on disease features may make TP53 mutational information more actionable, holding potential for better precision-based medicine. The differential effects of TP53 missense mutations in colorectal cancer (CRC) remain to be explored. Here the authors compare the gain of function impact of two frequent TP53 mutations in CRC and show that p53R273 mutants control a transcriptional program, which drives oncogenic signaling pathways, leading to a more aggressive phenotype and worse patient outcome.