NEW YORK (GenomeWeb) – A team of investigators led by researchers at the University of California, San Diego has developed a way to predict individuals' cancer susceptibilities from knowledge of their MHC-I genotypes.
MHC-I molecules expose the intracellular protein content on the cell surface, allowing T cells to detect foreign or mutated peptides. The combination of six MHC-I alleles that each individual carries defines the sub-peptidome that can be effectively presented, the researchers wrote yesterday in Cell.
They hypothesized that oncogenic mutations could arise in gaps in personal MHC-I presentation. They developed a residue-centric patient presentation score for 9,176 cancer patients across 1,018 recurrent oncogenic mutations, and found that the patients' personal MHC-I genotype-based scores could predict their oncogenic mutational landscapes.
"Accordingly, poor presentation of a mutation across patients was correlated with higher frequency among tumors," the authors wrote. "These results support that MHC-I genotype-restricted immunoediting during tumor formation shapes the landscape of oncogenic mutations observed in clinically diagnosed tumors and paves the way for predicting personal cancer susceptibilities from knowledge of MHC-I genotype."
The researchers began by characterizing the interactions between patient MHC-I allele combinations and recurrent cancer mutations for thousands of tumors from The Cancer Genome Atlas, and using existing in silico tools to predict HLA-specific MHC-I peptide binding affinities. This allowed them to devise a score capable of estimating the qualitative likelihood of MHC-I-based presentation of sequences containing specific mutations based on peptide binding affinities while accounting for each individual's six MHC alleles.
This allowed them to then study the interactions between each patient's HLA alleles and the corresponding MHC-I binding affinities for more than 1,000 recurrent mutations in known oncogenes and tumor suppressors, which are likely to be enriched for driver mutations and other early events in cancer development. Further, the team aimed to study the influence of MHC-I genotype in shaping the genomes of tumors, and developed a qualitative residue-centric presentation score to evaluate whether a sequence containing a residue will be presented on the cell surface.
The researchers then studied HLA alleles for patients in the TCGA, in order to determine whether individual variation in MHC-I genotypes resulted in patient-level differences in the presentation of mutations in a large human cancer cohort.
They found that their score model is predictive of which recurrent oncogenic mutations are likely to drive an individual's tumor during the early stages of tumor development across all cancer types. However, they also determined that the score could be more predictive in some tumor types than others.
"The strongest effects were observed in thyroid cancer, while no association was observed in acute myeloid leukemia, lung squamous cell carcinoma, sarcoma, or clear cell renal carcinoma," the team wrote.
Importantly, the researchers found that MHC-I-based restriction of oncogenic mutations is likely to be active predominantly during the early stages of tumorigenesis. "This suggests a model whereby mutation-related phenotypes could differ according to the effectiveness of immune surveillance throughout tumorigenesis," the authors wrote. "According to this model, mutations should accumulate more quickly when tumor cell populations are expanding rapidly under conditions of tumor-driven immune suppression, and the majority of these mutations should be passenger mutations that provide no fitness advantage to tumor cells."
These findings suggest MHC-I is a "gatekeeper" of early immunoediting, they added, and MHC-I genotype-specific binding affinity is a determinant of the oncogenic mutations that are subject to immune surveillance by T cells.