Journal Article

DKFZ-2020-01929

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution.

Ballhausen, A. (First author)DKFZ* ; Przybilla, M. J. (First author)DKFZ* ; Jendrusch, M. (First author)DKFZ* ; Haupt, S. ; Pfaffendorf, E.DKFZ* ; Seidler, F.DKFZ* ; Witt, J.DKFZ* ; Hernandez Sanchez, A.DKFZ* ; Urban, K.DKFZ* ; Draxlbauer, M.DKFZ* ; Krausert, S.DKFZ* ; Ahadova, A.DKFZ* ; Kalteis, M. S.DKFZ* ; Pfuderer, P.DKFZ* ; Heid, D.DKFZ* ; Stichel, D.DKFZ* ; Gebert, J.DKFZ* ; Bonsack, M.DKFZ* ; Schott, S. ; Bläker, H. ; Seppälä, T. ; Mecklin, J.-P. ; Ten Broeke, S. ; Nielsen, M. ; Heuveline, V. ; Krzykalla, J.DKFZ* ; Benner, A.DKFZ* ; Riemer, A.DKFZ* ; von Knebel Doeberitz, M.DKFZ* ; Kloor, M. (Last author)DKFZ*

2020
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-020-18514-5

Abstract: 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.

Note: #EA:F210#LA:F210#

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Contributing Institute(s):

1. Angewandte Tumorbiologie (F210)
2. KKE Neuropathologie (B300)
3. F130 Immuntherapie und -prävention (F130)
4. C060 Biostatistik (C060)

Research Program(s):

1. 316 - Infections and cancer (POF3-316) (POF3-316)

Appears in the scientific report 2020

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