The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution

Ballhausen, A.; Przybilla, M.J.; Jendrusch, M.; Haupt, S.; Pfaffendorf, E.; Seidler, F.; Witt, J.; Hernandez Sanchez, A.; Urban, K.; Draxlbauer, M.; Krausert, S.; Ahadova, A.; Kalteis, M.S.; Pfuderer, P.L.; Heid, D.; Stichel, D.; Gebert, J.; Bonsack, M.; Schott, S.; Blaker, H.; Seppala, T.; Mecklin, J.P.; Broeke, S. ten; Nielsen, M.; Heuveline, V.; Krzykalla, J.; Benner, A.; Riemer, A.B.; Knebel Doeberitz, M. von; Kloor, M.

doi:doi:10.1038/s41467-020-18514-5

The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptides. This correlation is absent in tumors with Beta-2-microglobulin mutations, and HLA-A*02:01 status is related to cMS mutation patterns. Importantly, certain outlier mutations are common in MSI cancers despite being related to frameshift peptides with functionally confirmed immunogenicity,...Show moreThe immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptides. This correlation is absent in tumors with Beta-2-microglobulin mutations, and HLA-A*02:01 status is related to cMS mutation patterns. Importantly, certain outlier mutations are common in MSI cancers despite being related to frameshift peptides with functionally confirmed immunogenicity, suggesting a possible driver role during MSI tumor evolution. Neoantigens resulting from shared mutations represent promising vaccine candidates for prevention of MSI cancers. DNA mismatch repair (MMR)-deficient cancers with microsatellite-instability are characterized by a high load of frameshift mutation-derived neoantigens. Here, by mapping the frameshift mutation landscape and predicting the immunogenicity of the resulting peptides, the authors show evidence of immunoediting in MMR-deficient colorectal and endometrial cancers.Show less

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The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution