{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T17:08:23Z","timestamp":1776877703797,"version":"3.51.2"},"reference-count":109,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T00:00:00Z","timestamp":1620864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Radboudumc","award":["n.a."],"award-info":[{"award-number":["n.a."]}]},{"name":"KiKa Foundation","award":["359"],"award-info":[{"award-number":["359"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers13102345","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T03:08:12Z","timestamp":1620875292000},"page":"2345","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome"],"prefix":"10.3390","volume":"13","author":[{"given":"Asima","family":"Abidi","sequence":"first","affiliation":[{"name":"Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3621-226X","authenticated-orcid":false,"given":"Mark A. J.","family":"Gorris","sequence":"additional","affiliation":[{"name":"Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evan","family":"Brennan","sequence":"additional","affiliation":[{"name":"Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marjolijn C. J.","family":"Jongmans","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands"},{"name":"Department of Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dilys D.","family":"Weijers","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4928-3809","authenticated-orcid":false,"given":"Roland P.","family":"Kuiper","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands"},{"name":"Department of Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8222-0343","authenticated-orcid":false,"given":"Richarda M.","family":"de Voer","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2393-8141","authenticated-orcid":false,"given":"Nicoline","family":"Hoogerbrugge","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0156-8365","authenticated-orcid":false,"given":"Gerty","family":"Schreibelt","sequence":"additional","affiliation":[{"name":"Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8653-4040","authenticated-orcid":false,"given":"I. Jolanda M.","family":"de Vries","sequence":"additional","affiliation":[{"name":"Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"name":"Department of Medical Oncology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,13]]},"reference":[{"key":"ref_1","first-page":"7","article-title":"Lynch Syndrome and Immunotherapy","volume":"8","author":"Hampel","year":"2017","journal-title":"J. Adv. Pract. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s10689-017-0053-3","article-title":"Phenotypic and genotypic heterogeneity of Lynch syndrome: A complex diagnostic challenge","volume":"17","author":"Lynch","year":"2018","journal-title":"Fam. 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