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

Alexej Ballhausen, Moritz Jakob Przybilla, Michael Jendrusch, Saskia Haupt, Elisabeth Pfaffendorf, Florian Seidler, Johannes Witt, Alejandro Hernandez Sanchez, Katharina Urban, Markus Draxlbauer, Sonja Krausert, Aysel Ahadova, Martin Simon Kalteis, Pauline L. Pfuderer, Daniel Heid, Damian Stichel, Johannes Gebert, Maria Bonsack, Sarah Schott, Hendrik Bläker, Toni Seppälä, Jukka-Pekka Mecklin, Sanne Broeke, Maartje Nielsen, Vincent Heuveline, Julia Krzykalla, Axel Benner, Angelika Beate Riemer, Magnus von Knebel Doeberitz and Matthias Kloor ()
Additional contact information
Alexej Ballhausen: University of Heidelberg
Moritz Jakob Przybilla: University of Heidelberg
Michael Jendrusch: University of Heidelberg
Saskia Haupt: Heidelberg University
Elisabeth Pfaffendorf: University of Heidelberg
Florian Seidler: University of Heidelberg
Johannes Witt: University of Heidelberg
Alejandro Hernandez Sanchez: University of Heidelberg
Katharina Urban: University of Heidelberg
Markus Draxlbauer: University of Heidelberg
Sonja Krausert: University of Heidelberg
Aysel Ahadova: University of Heidelberg
Martin Simon Kalteis: University of Heidelberg
Pauline L. Pfuderer: University of Heidelberg
Daniel Heid: University of Heidelberg
Damian Stichel: University of Heidelberg
Johannes Gebert: University of Heidelberg
Maria Bonsack: German Cancer Research Center (DKFZ)
Sarah Schott: University Hospital Heidelberg
Hendrik Bläker: University Hospital Leipzig
Toni Seppälä: Helsinki University Hospital and University of Helsinki
Jukka-Pekka Mecklin: Central Finland Central Hospital
Sanne Broeke: Leiden University Medical Center
Maartje Nielsen: Leiden University Medical Center
Vincent Heuveline: Heidelberg University
Julia Krzykalla: German Cancer Research Center (DKFZ)
Axel Benner: German Cancer Research Center (DKFZ)
Angelika Beate Riemer: German Cancer Research Center (DKFZ)
Magnus von Knebel Doeberitz: University of Heidelberg
Matthias Kloor: University of Heidelberg

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18514-5

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DOI: 10.1038/s41467-020-18514-5

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