Abstract 2607: Homogenous TP53mut-associated tumor biology across mutation and cancer types revealed by comprehensive mRNA expression analysis

Abstract TP53 mutations are the most common single gene alteration in human cancer with diagnostic and prognostic implications in some cancer types. While no TP53-targeting therapeutics have been approved in the USA or Europe yet, drugs tailored to specific TP53 mutations, restoring the functionality of mutated TP53 (TP53mut), and protecting TP53 from negative regulation are being explored in preclinical studies and clinical trials. We performed a comprehensive mRNA expression analysis in 24 cancer types of the TCGA to extract (i) a consensus expression signature shared across TP53 mutation types and cancer types, (ii) differential gene expression patterns between different TP53 mutation types such as LOF, GOF, as well as dominant-negative mutations, and (iii) cancer types specific gene expression patterns. Mutational hotspots showed a similar pattern across cancer types, but at the same time prevalence was significantly different between cancer types for about half of the most prevalent hotspots. Both can be explained in part by the mutational processes operational for example the clock-like process behind SBS1 that is operational across cancer types and aflatoxin exposure assocated with SBS24 that ist operational in liver hepatocellular carcinoma. Virtually no genes were differential between tumors harboring different types of TP53 mutations in none of the cancer types, while hundreds of genes were over- and underexpressed in TP53mut compared to TP53wt tumors. A consensus gene list of 178 common over- and 32 common underexpressed genes was shared between at least two-thirds of the 24 cancer types. Analysis of the immune tumor microenvironment revealed exclusively decreased immune cell populations in the TP53mut tumors in six, a mixed pattern in four, exclusively increased immune cell populations in two, and no significant alterations in 20 cancer subtypes. The analysis of a large cohort of human tumors complements results from experimental studies and support the development of novel strategies for therapeutic targeting of TP53mut. Citation Format: Jan Budczies, Eva Romanovsky, Klaus Kluck, Iordanis Ourailidis, Michael Menzel, Susanne Beck, Markus Ball, Daniel Kazdal, Petros Christopoulos, Peter Schirmacher, Thorsten Stiewe, Albrecht Stenzinger. Homogenous TP53mut-associated tumor biology across mutation and cancer types revealed by comprehensive mRNA expression analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2607.