Using an improved computational tool to identify and quantify small indel frame-shift mutations, Balhausen, Przybilla and Jendrusch et. al. characterized the patterns, immunogenicity and evolution of coding microsatellite (cMS) mutations in endometrial and colorectal cancer. A negative correlation between predicted immunogenicity (balanced for HLA allele frequency) indicated a signature of immuno-editing of highly immunogenic frameshift peptides, supported by only a weak trend in patients with reduced immune selection due to β2m mutations, and an impact of HLA allele. Retention of cMS with high predicted immunogenic scores suggests a selective advantage.
Contributed by Ed Fritsch
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.
Author Info: (1) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Cen
Author Info: (1) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (2) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (3) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (4) Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany. (5) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (6) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (7) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (8) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (9) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (10) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (11) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (12) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (13) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (14) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (15) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (16) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (17) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (18) Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Vaccine Design, German Center for Infection Research (DZIF), partner site Heidelberg, Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. (19) Department of Obstetrics and Gynecology, University Hospital Heidelberg, Heidelberg, Germany. (20) Institute of Pathology, University Hospital Leipzig, Leipzig, Germany. (21) Department of Gastrointestinal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland. (22) Department of Education and Research, Central Finland Central Hospital, Jyvskyl, Finland. Department of Sports and Health Sciences, University of Jyvskyl, Jyvskyl, Finland. (23) Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. (24) Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. (25) Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany. (26) Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany. (27) Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany. (28) Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Vaccine Design, German Center for Infection Research (DZIF), partner site Heidelberg, Heidelberg, Germany. (29) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. (30) Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. matthias.kloor@med.uni-heidelberg.de. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. matthias.kloor@med.uni-heidelberg.de. Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany. matthias.kloor@med.uni-heidelberg.de.
