A Pan-Cancer Assessment of RB1/TP53 Co-Mutations

SIMPLE SUMMARY: Cancers are caused by genetic alterations called mutations. In some cases, specific mutation combinations act synergistically to provide unique advantages for cancer development. These mutation combinations are observed more frequently than by random chance. In this study, we investigated a large public tumor mutation database and found the most diverse and frequent concurrent mutations occur in TP53 and RB1. We enumerated the cancer types with TP53/RB1 co-mutations and investigated the patient outcome and the specific characteristics of cancer cells with TP53/RB1 co-mutations, especially the drugs that can and cannot be used to kill these cells. Our work provides a tool for cancer researchers to investigate co-mutations and provides insights into the treatment of TP53/RB1 co-mutated cancers. ABSTRACT: Nearly all tumors have multiple mutations in cancer-causing genes. Which of these mutations act in tandem with other mutations to drive malignancy and also provide therapeutic vulnerability? To address this fundamental question, we conducted a pan-cancer screen of co-mutation enrichment (looking for two genes mutated together in the same tumor at a statistically significant rate) using the AACR-GENIE 11.0 data (AACR, Philadelphia, PA, USA). We developed a web tool for users to review results and perform ad hoc analyses. From our screen, we identified a number of such co-mutations and their associated lineages. Here, we focus on the RB1/TP53 co-mutation, which we discovered was the most frequently observed co-mutation across diverse cancer types, with particular enrichment in small cell carcinomas, neuroendocrine carcinomas, and sarcomas. Furthermore, in many cancers with a substantial fraction of co-mutant tumors, the presence of concurrent RB1/TP53 mutations is associated with poor clinical outcomes. From pan-cancer cell line multi-omics and functional screening datasets, we identified many targetable co-mutant-specific molecular alterations. Overall, our analyses revealed the prevalence, cancer type-specificity, clinical significance, and therapeutic vulnerabilities of the RB1/TP53 co-mutation in the pan-cancer landscape and provide a roadmap forward for future clinical translational research.