TY - JOUR
T1 - The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution
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 L.
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 Beate
AU - von Knebel Doeberitz, Magnus
AU - Kloor, Matthias
N1 - Funding Information:
The present study has been funded in part by grants of the Wilhelm Sander Foundation (Grant number 2016.056.1). The excellent technical assistance of Nina Nelius, Petra Hoefler, and Beate Kuchenbuch is gratefully acknowledged.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
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.
U2 - 10.1038/s41467-020-18514-5
DO - 10.1038/s41467-020-18514-5
M3 - Article
C2 - 32958755
AN - SCOPUS:85091310227
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4740
ER -
