p53 mutation-associated prognosis across cancer types underlines hematological malignancy as an applicable cancer type to p53-rescue therapy.

Tumor suppressor p53 is mutated and thereafter loses tumor-suppressive function in about 50% of cancer cases, across nearly all cancer types. Efforts to rescue mutant p53 pharmacologically have been ongoing for decades, leading to reports of approximately 71 mutant p53-rescue small-molecule compounds and > 20 clinical trials. However, no statistically significant patient benefit has been achieved, possibly due to the lack of rationalization of cancer type selection in the trials. Here, we analyzed p53 mutation-associated prognosis of overall survival, together with tumor mutation burden and concurrent cancer driver mutation with p53 mutation, across 33 cancer types in The Cancer Genome Atlas (TCGA), through which hematology malignancy was predicted as a cancer type potentially responding to p53-rescue therapy. In validation experiments, p53-null hematological malignant cell lines exhibited high sensitivity to the introduction of exogenous wild-type p53 as compared to solid-tumor cell lines. Furthermore, hematological malignant cell lines harboring structural mutant p53 are also more sensitive to the established mutant p53 rescue compound arsenic trioxide (ATO). In p53-mutant hematological malignant cells, the majority of the beneficial p53-regulating genes are upregulated while the majority of the deleterious p53-regulating genes are downregulated by ATO treatment, predicting a beneficial outcome of ATO in treating hematological malignancies in the clinic. Together, we propose a guideline for the rational selection of cancer types in the rapidly expanding p53-rescue clinical trials.