Complement system mutational landscape reveals C4BPA mutations enhance apoptosis in an immune-independent manner

The complement system is an important pathway in immunity. When dysregulated in the tumor microenvironment, complement is associated with suppression of antitumor immunity and tumorigenesis promotion. While complement has been reported to have important intracellular functions in immune cells, the role of intracellular complement in cancer has remained poorly understood to date. In this study we investigated the prevalence and significance of pathway-wide complement mutations as well as their role with respect to intracellular complement in cancer. We describe mutations in both individual genes as well as within functional groups that are significantly associated with altered survival outcomes. Analyzing mutations occurring across multiple TCGA cancer types highlighted the potential clinical significance of certain mutations that would otherwise not have surfaced at a single cancer level. As an example, we test the significance of mutations in complement regulator C4BPA in vitro and in vivo in a single cancer type. This approach allowed us to uncover a new immune-independent biologic function of the complement system with potential clinical implications for colorectal cancer patients. Specifically, we find that colorectal cancer cells with specific C4BPA mutations display increased oxaliplatin-induced intracellular C4BPA stabilization. By studying the mechanistic basis of this association we report novel crosstalk between intracellular complement and apoptosis signaling, occurring in an NFκB/RelA-dependent manner. Based on both experimental and patient outcome data, we therefore propose that assessing complement mutation status might facilitate patient stratification. In the case of C4BPA mutations, this would be particularly relevant to improve accuracy of prognosis assessment in stage II colorectal patients where TNM staging alone does not accurately predict outcome in patients who might benefit from adjuvant chemotherapy. Citation Format: Monica M. Olcina, Nikolas G. Balanis, Ryan K. Kim, Michael J. Thompson, Thomas G. Graeber, Amato J. Giaccia. Complement system mutational landscape reveals C4BPA mutations enhance apoptosis in an immune-independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4382.