TY  - JOUR
AU  - Ballhausen, Alexej
AU  - Przybilla, Moritz Jakob
AU  - Jendrusch, Michael
AU  - Haupt, Saskia
AU  - Pfaffendorf, Elisabeth
AU  - Seidler, Florian
AU  - Witt, Johannes
AU  - Hernandez Sanchez, Alejandro
AU  - Urban, Katharina
AU  - Draxlbauer, Markus
AU  - Krausert, Sonja
AU  - Ahadova, Aysel
AU  - Kalteis, Martin Simon
AU  - Pfuderer, Pauline
AU  - Heid, Daniel
AU  - Stichel, Damian
AU  - Gebert, Johannes
AU  - Bonsack, Maria
AU  - Schott, Sarah
AU  - Bläker, Hendrik
AU  - Seppälä, Toni
AU  - Mecklin, Jukka-Pekka
AU  - Ten Broeke, Sanne
AU  - Nielsen, Maartje
AU  - Heuveline, Vincent
AU  - Krzykalla, Julia
AU  - Benner, Axel
AU  - Riemer, Angelika
AU  - von Knebel Doeberitz, Magnus
AU  - Kloor, Matthias
TI  - The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution.
JO  - Nature Communications
VL  - 11
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2020-01929
SP  - 4740
PY  - 2020
N1  - #EA:F210#LA:F210#
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:32958755
DO  - DOI:10.1038/s41467-020-18514-5
UR  - https://inrepo02.dkfz.de/record/163651
ER  -