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

Abstract Colorectal cancer (CRC) is the third most common cancer worldwide. The TP53 gene is mutated in approximately 60% of all CRC cases. Sporadic CRC is characterized by high prevalence of TP53 hotspot missense mutations. In particular, over 20 percent of all TP53-mutated CRC tumors carry either the p53R175H structural mutant or the p53R273H DNA contact mutant. Importantly, clinical data analysis suggests that CRC tumors harboring p53 R273 mutations are more prone to progress to metastatic disease than those with R175 mutations, in association with decreased survival. By combining in vitro CRC cell line models and human CRC data mining, we identified a unique transcriptional signature orchestrated by p53R273H, implicating activation of oncogenic signaling pathways and predicting worse patient outcome. Concordantly, p53R273H selectively promotes rapid CRC cell spreading, migration and invasion in vitro and metastasis in vivo. Mechanistically, the transcriptional output of p53R273H is associated with, and presumably driven by, its preferential binding to regulatory elements of R273 signature genes. Together, this demonstrates that different TP53 missense mutations contribute differently to cancer progression, and that p53R273H possesses distinct gain-of-function activities in CRC that bear on disease course and possibly on patient management strategy. Given that practically all current analytical cancer gene panels include TP53, elucidation of the differential impact of distinct TP53 mutations on disease features is expected to make information on TP53 mutations more actionable and holds potential for better precision-based medicine.