Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome

Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders characterised by a highly increased risk of cancer development. This is due to germline aberrations in the mismatch repair (MMR) genes, which results in a high mutational load in tumours of these patie...

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Veröffentlicht in:Cancers 2021-05, Vol.13 (10), p.2345
Hauptverfasser: Abidi, Asima, Gorris, Mark A. J., Brennan, Evan, Jongmans, Marjolijn C. J., Weijers, Dilys D., Kuiper, Roland P., de Voer, Richarda M., Hoogerbrugge, Nicoline, Schreibelt, Gerty, de Vries, I. Jolanda M.
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container_issue 10
container_start_page 2345
container_title Cancers
container_volume 13
creator Abidi, Asima
Gorris, Mark A. J.
Brennan, Evan
Jongmans, Marjolijn C. J.
Weijers, Dilys D.
Kuiper, Roland P.
de Voer, Richarda M.
Hoogerbrugge, Nicoline
Schreibelt, Gerty
de Vries, I. Jolanda M.
description Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders characterised by a highly increased risk of cancer development. This is due to germline aberrations in the mismatch repair (MMR) genes, which results in a high mutational load in tumours of these patients, including insertions and deletions in genes bearing microsatellites. This generates microsatellite instability and cause reading frameshifts in coding regions that could lead to the generation of neoantigens and opens up avenues for neoantigen targeting immune therapies prophylactically and therapeutically. However, major obstacles need to be overcome, such as the heterogeneity in tumour formation within and between LS and CMMRD patients, which results in considerable variability in the genes targeted by mutations, hence challenging the choice of suitable neoantigens. The machine-learning methods such as NetMHC and MHCflurry that predict neoantigen- human leukocyte antigen (HLA) binding affinity provide little information on other aspects of neoantigen presentation. Immune escape mechanisms that allow MMR-deficient cells to evade surveillance combined with the resistance to immune checkpoint therapy make the neoantigen targeting regimen challenging. Studies to delineate shared neoantigen profiles across patient cohorts, precise HLA binding algorithms, additional therapies to counter immune evasion and evaluation of biomarkers that predict the response of these patients to immune checkpoint therapy are warranted.
doi_str_mv 10.3390/cancers13102345
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J. ; Brennan, Evan ; Jongmans, Marjolijn C. J. ; Weijers, Dilys D. ; Kuiper, Roland P. ; de Voer, Richarda M. ; Hoogerbrugge, Nicoline ; Schreibelt, Gerty ; de Vries, I. Jolanda M.</creator><creatorcontrib>Abidi, Asima ; Gorris, Mark A. J. ; Brennan, Evan ; Jongmans, Marjolijn C. J. ; Weijers, Dilys D. ; Kuiper, Roland P. ; de Voer, Richarda M. ; Hoogerbrugge, Nicoline ; Schreibelt, Gerty ; de Vries, I. Jolanda M.</creatorcontrib><description>Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders characterised by a highly increased risk of cancer development. This is due to germline aberrations in the mismatch repair (MMR) genes, which results in a high mutational load in tumours of these patients, including insertions and deletions in genes bearing microsatellites. 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source PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; EZB-FREE-00999 freely available EZB journals; PubMed Central
subjects Antibodies
Brain cancer
Cancer therapies
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA repair
Endometrium
FDA approval
Genes
Hematology
Histocompatibility antigen HLA
Immune checkpoint inhibitors
Immunotherapy
Learning algorithms
Medical prognosis
Metabolism
Metastasis
Microsatellite instability
Microsatellites
Mismatch repair
Mutation
Neoantigens
Patients
Proteins
Review
Tumors
title Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome
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