Abstract SY25-03: Germline MHC-I and -II variation constrains the somatic mutational landscape

Abstract

Abstract Tumors arise when cells accumulate genomic alterations that allow them to sustain rapid growth. Since the immune system is capable of eliminating tumor cells, another prerequisite for tumor formation is evasion of immune recognition. Recently, therapies that reactivate the immune system have been able to eliminate some tumors. However, only a small fraction of patients receives a sustained benefit from these immunotherapies, suggesting that we have yet to understand the complexity of tumor-immune interactions. The immune response to tumors is mediated by the major histocompatibility complex (MHC), one of the most variable molecules encoded by the human genome. The MHC communicates cellular health to the immune system by binding and presenting antigen to circulating T cells. Due to technical limitations, the impact of the inter-patient MHC heterogeneity on tumor development has remained understudied. To address this gap, we utilized a large phenotypically-annotated cohort of cancer patient and recent algorithmic advances to assess the role of MHC variation on tumor progression. Though there are two classes of MHC with different functional mechanisms, we found that germline variation in both classes impacts patient somatic mutation susceptibility and population somatic mutation frequencies. The methods we developed expose the role of the immune system in shaping tumor formation and lay the foundation for improved development of immunotherapies. Citation Format: Rachel Marty. Germline MHC-I and -II variation constrains the somatic mutational landscape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY25-03.