QCB Colloquium | Dr. Hannah Carter

Dr. Hannah Carter
Assistant Professor, UCSD, Health Sciences
Lab Website

MHC genotype shapes the oncogenic landscape

Thursday, September 5
2 PM
RRI 101

Abstract: Significant insights into tumorigenesis have been gained by characterizing the extensive somatic alterations that arise during cancer and uncovering rare inherited mutations that lead to early onset cancer syndromes. However, little is understood about the role of genetic background in ‘sporadic’ adulthood cancers. Mounting evidence suggests that the somatic evolution of a tumor is influenced by inherited polymorphisms. We investigated this phenomenon in the context of the immune system, which is a major source of selective pressure during tumor development. The genomic region encoding the Major Histocompatibility Complex Class (MHC) is one of the most variable regions in the human population. MHC molecules expose peptide fragments on the cell surface, allowing T-Cell elimination of cells contaminated by foreign peptide. Although this system has evolved as a defense against microbial and viral agents, MHC can also trigger elimination of cells harboring mutant peptides (neoantigens) in cancer. Each individual carries multiple MHC alleles that define the set of peptides that can be effectively presented for immune surveillance. We hypothesized that individual variation in MHC could create personal gaps in immune surveillance, generating individual-specific susceptibility for cells to acquire specific oncogenic mutations. To test this hypothesis, we developed residue-centric patient presentation scores for MHC class I and II molecules and applied them to 1,018 recurrent oncogenic mutations in 9,176 cancer patients. This analysis uncovered a clear signature of immune selection acting on tumors with implications for age at diagnosis, driver occurrence in tumors and frequency of driver mutations in cancer cohorts. Thus, the landscape of oncogenic mutations observed in clinically diagnosed tumors is shaped by MHC genotype-restricted immunoediting during tumor formation, and individual MHC genotype provides information about the mutations likely to emerge in tumors that develop later in life.

Host: Dr. Michael Waterman