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, S. 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., . . . Kloor, M. (2020). The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution. Nature Communications, 11, Article 4740. https://doi.org/10.1038/s41467-020-18514-5
Published inNature Communications
© The Author(s) 2020
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, suggesting a possible driver role during MSI tumor evolution. Neoantigens resulting from shared mutations represent promising vaccine candidates for prevention of MSI cancers. ...
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Additional information about fundingThe present study has been funded in part by grants of the Wilhelm Sander Foundation (Grant number 2016.056.1). Open Access funding provided by Projekt DEAL.
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