6533b837fe1ef96bd12a27ef
RESEARCH PRODUCT
The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution
Elisabeth PfaffendorfElisabeth PfaffendorfElisabeth PfaffendorfSaskia HauptHendrik BläkerVincent HeuvelineDamian StichelDamian StichelMartin Simon KalteisMartin Simon KalteisMartin Simon KalteisToni T. SeppäläAxel BennerKatharina UrbanKatharina UrbanKatharina UrbanSanne W. Ten BroekePauline L. PfudererPauline L. PfudererPauline L. PfudererMaartje NielsenMarkus DraxlbauerMarkus DraxlbauerMarkus DraxlbauerSarah SchottFlorian SeidlerFlorian SeidlerFlorian SeidlerJulia KrzykallaAlexej BallhausenAlexej BallhausenAlexej BallhausenMagnus Von Knebel DoeberitzMagnus Von Knebel DoeberitzMagnus Von Knebel DoeberitzJohannes GebertJohannes GebertJohannes GebertJukka-pekka MecklinMatthias KloorMatthias KloorMatthias KloorAysel AhadovaAysel AhadovaAysel AhadovaMichael JendruschMichael JendruschMichael JendruschAlejandro Hernandez SanchezAlejandro Hernandez SanchezAlejandro Hernandez SanchezSonja KrausertSonja KrausertSonja KrausertMoritz Jakob PrzybillaMoritz Jakob PrzybillaMoritz Jakob PrzybillaDaniel HeidDaniel HeidDaniel HeidJohannes WittJohannes WittJohannes WittMaria BonsackMaria BonsackAngelika B. Riemersubject
0301 basic medicineMutation rateGeneral Physics and Astronomymedicine.disease_causeCOLORECTAL-CANCER0302 clinical medicineINDEL MutationMutation RateimmunologiaHLA AntigensNeoplasmsFrameshift Mutationlcsh:ScienceImmunologic SurveillanceGeneticsMutationMultidisciplinaryMISMATCH REPAIR DEFICIENCYQPEPTIDES3. Good healthkohdunrungon syöpäsyöpäsolutimmuunivaste030220 oncology & carcinogenesisTumour immunologyMicrosatellite InstabilityDNA mismatch repairINDEL MutationEXPRESSIONcongenital hereditary and neonatal diseases and abnormalitieskasvaimetDATABASESciencegastrointestinal cancerINSTABILITY3122 CancerssuolistosyövätBiologycomplex mixturesArticleGeneral Biochemistry Genetics and Molecular BiologyFrameshift mutationGastrointestinal cancer03 medical and health sciencesAntigens NeoplasmCOLONmedicineHumansCELLSelection GeneticIndelSIGNATUREStumour immunologyMicrosatellite instabilityGeneral ChemistryDNAmedicine.disease3126 Surgery anesthesiology intensive care radiologydigestive system diseases030104 developmental biologyImmunoeditinglcsh:Qmutaatiotbeta 2-MicroglobulinMicrosatellite Repeatsdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-09-21 |