Abstract
Specific somatic mutations in cancer genomes result in amino acid alterations and derivative novel immunogenic peptides called neoantigens. The MHC molecule mediates the immunologic presentation of these cancer mutation-derived peptides. Based on a limited number of polymorphisms, the configuration of the MHC molecule is one of the major factors in determining whether mutated peptides can elicit immune response or not. To provide insight in the full diversity of potential neoantigens across the entire human genome, we identified all possible amino acid substitutions and estimated their potential binding affinities to the 86 MHC genotypes. As a first step, we evaluated every possible nucleotide changes at every single position using exons and related alternative transcripts as defined by the Consensus Coding Sequence (CCDS) resource. We evaluated 159 million (M) possible nucleotide changes among ~31,000 autosomal transcripts from ~ 19,000 genes. Overall, this comprised a genome sequence “space” of 53 M nucleotides. Among this coding regions space, we evaluated 123 M candidate nonsynonmous mutations. Among these mutations, we identified short mutated peptides of nine amino acids in length across this mutation space. We estimated the binding affinity of all mutated peptides across 86 MHG polymorphisms. Based on the predicted binding affinity, 0.6% ~ 1.0 % were found to be potential strong binders to the one of MHC molecules while 1.7% ~ 2.5% of them are weak binder to the one of MHC molecules. HLA-A0201 had the high number of potential candidate neoantigens. The KRAS cancer had candidate epitopes that binds to >50 different MHC molecules include KRAS D12V, which is very hot spot, that make epitopes that binds to 30 MHC molecules. In addition, we mapped the frequencies of missense mutations observed in TCGA and COSMIC to these candidate neoantigens. For releasing the results of our study, we are developing the “Immunogenomic Explorer” available at http://genomeportal.stanford.edu/immune. This portal enables users to explore the potential immunogenic epitopes from genes of their interest such as KRAS. Users can search by HLA genotypes as well. This web interface allows researchers to address important questions regarding their immunotherapy or cancer vaccine.
Citation Format: HoJoon Lee, Stephanie U. Greer, Hanlee P. Ji. Mapping the comprehensive landscape of missense-mutation neoantigens across the human genome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1298.
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