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Marty R , Kaabinejadian S , Rossell D , Slifker MJ , van de Haar J , Engin HB , de Prisco N , Ideker T , Hildebrand WH , Font-Burgada J , Carter H
MHC-I Genotype Restricts the Oncogenic Mutational Landscape
Cell. 2017 Nov 30;171(6) :1272-1283 e15
PMID: 29107334    PMCID: PMC5711564    URL: https://www.ncbi.nlm.nih.gov/pubmed/29107334
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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 each individual carries defines the sub-peptidome that can be effectively presented. We applied this concept to human cancer, hypothesizing that oncogenic mutations could arise in gaps in personal MHC-I presentation. To validate this hypothesis, we developed and applied a residue-centric patient presentation score to 9,176 cancer patients across 1,018 recurrent oncogenic mutations. We found that patient MHC-I genotype-based scores could predict which mutations were more likely to emerge in their tumor. Accordingly, poor presentation of a mutation across patients was correlated with higher frequency among tumors. 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.
1097-4172 Marty, Rachel Kaabinejadian, Saghar Rossell, David Slifker, Michael J van de Haar, Joris Engin, Hatice Billur de Prisco, Nicola Ideker, Trey Hildebrand, William H Font-Burgada, Joan Carter, Hannah U54 CA209891/CA/NCI NIH HHS/United States DP5 OD017937/OD/NIH HHS/United States R00 CA191152/CA/NCI NIH HHS/United States U24 CA184427/CA/NCI NIH HHS/United States K99 CA191152/CA/NCI NIH HHS/United States Journal Article United States Cell. 2017 Oct 20. pii: S0092-8674(17)31144-3. doi: 10.1016/j.cell.2017.09.050.