Abstract A097: Complement system mutations in cancer: Uncovering new relationships between tumor hypoxia and complement

The complement system has been proposed to facilitate cancer hallmarks such as increased metastatic potential, proliferation and apoptosis evasion. Despite the association between complement and tumor progression, a detailed characterization of cancer genetic alterations in the complement system has not been performed to date. Here, we report a number of previously unappreciated mutations in complement system genes. Taken together as a pathway, mutations in complement genes occur at a relatively high frequency and across a number of cancer types. Notably, when grouping complement mutations into functionally relevant subgroups according to gene function, mutations and copy number alterations in genes within these subgroups are associated with changes in overall survival outcomes in a range of cancers. We use specific complement component mutations in colorectal cancer to uncover and experimentally validate crosstalk between complement and hypoxia, providing new associations between this innate immunity pathway and a prevalent component of the tumor microenvironment. Our data highlight the complex mechanism employed by cancers to manipulate the innate immune system and point to the potential use of complement system mutations in successful patient stratification into clinically and biologically relevant groups. Citation Format: Monica M. Olcina, Nikolas G. Balanis, Ryan K. Kim, Michael J. Thompson, Thomas G. Graeber, Amato J. Giaccia. Complement system mutations in cancer: Uncovering new relationships between tumor hypoxia and complement [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A097.