Are Tumors Predictable? Inherited Immune Variation Constrains Tumor Evolution

Recent studies have characterized the extensive somatic alterations that arise during cancer, and various studies have probed rare inherited mutations that lead to early-onset cancer syndromes. However, little is understood about the role of genetic background in “sporadic” adulthood cancers. The somatic evolution of a tumor may be significantly affected by inherited polymorphisms carried in the germline. The region encoding the Major Histocompatibility Complex Class I (MHC-I) is one of the most variable regions in the human population. MHC-I is a molecule that exposes the intracellular protein content of a cell on the cell surface, allowing T cells to detect mutated or foreign peptides. Each individual carries six MHC-I alleles that define the set of peptides that can be effectively presented for immune surveillance. We hypothesized that individual variation in MHC-I could create personal gaps in immune surveillance, generating individual-specific susceptibility for cells to acquire specific oncogenic mutations. We tested this hypothesis through the development and application of a residue-centric patient presentation score to 1,018 recurrent oncogenic mutations in 9,176 cancer patients. This analysis found that cancer-causing mutations were more likely to be observed when a patient’s genotype-based scores suggested poor MHC-I based presentation of those mutations. Mutations that were poorly presented by most patients were also more likely to reach high frequency among tumors. Thus the landscape of oncogenic mutations observed in clinically diagnosed tumors is shaped by MHC-I genotype-restricted immunoediting during tumor formation, and individual MHC-I genotype provides information about the mutations likely to emerge in tumors that develop later in life. Citation Format: Rachel Marty, Saghar Kaabinejadian, David Rossel, Michael J. Slifker, Joris Van de Haar, Hattice Billur Engin, Nicola de Prisco, Trey Ideker, William H. Hildebrand, Joan Font-Burgada, Hannah Carter. Are tumors predictable? Inherited immune variation constrains tumor evolution [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA24.