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 |
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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. |
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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. 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.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers13102345</identifier><identifier>PMID: 34067951</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>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</subject><ispartof>Cancers, 2021-05, Vol.13 (10), p.2345</ispartof><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). 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J.</creatorcontrib><creatorcontrib>Brennan, Evan</creatorcontrib><creatorcontrib>Jongmans, Marjolijn C. J.</creatorcontrib><creatorcontrib>Weijers, Dilys D.</creatorcontrib><creatorcontrib>Kuiper, Roland P.</creatorcontrib><creatorcontrib>de Voer, Richarda M.</creatorcontrib><creatorcontrib>Hoogerbrugge, Nicoline</creatorcontrib><creatorcontrib>Schreibelt, Gerty</creatorcontrib><creatorcontrib>de Vries, I. Jolanda M.</creatorcontrib><title>Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome</title><title>Cancers</title><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.</description><subject>Antibodies</subject><subject>Brain cancer</subject><subject>Cancer therapies</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA biosynthesis</subject><subject>DNA repair</subject><subject>Endometrium</subject><subject>FDA approval</subject><subject>Genes</subject><subject>Hematology</subject><subject>Histocompatibility antigen HLA</subject><subject>Immune checkpoint inhibitors</subject><subject>Immunotherapy</subject><subject>Learning algorithms</subject><subject>Medical prognosis</subject><subject>Metabolism</subject><subject>Metastasis</subject><subject>Microsatellite instability</subject><subject>Microsatellites</subject><subject>Mismatch repair</subject><subject>Mutation</subject><subject>Neoantigens</subject><subject>Patients</subject><subject>Proteins</subject><subject>Review</subject><subject>Tumors</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkctr3DAQxkVpacI2514FueSyXb0sWZdA2KYP2LbQpmchyyOvElvaSnJh__u6TQhp5vINzG8-5oHQW0reca7JxtnoIBfKKWFcNC_QKSOKraXU4uWT_ASdlXJLluCcKqleoxMuiFS6oafobru34whxgIKTx18h2VjDABHf2DxADXHAIeLdMbo9_nGMfU4TYBt7vE2x1FDnGlK0I_4SymTrAn2Hgw0ZvwcfXIDojo9tb9Arb8cCZw-6Qj8_XN9sP6133z5-3l7t1o7rtq6h1Z42veodo6yjVDrSK89IK6mi0C8bCNZ733TStp1gjfWdU5q2gmpOtGJ8hS7vfQ9zN0HvINZsR3PIYbL5aJIN5v9KDHszpN-mpQ1jnC8GFw8GOf2aoVQzheJgHG2ENBfDGi5Fy_WiK3T-DL1Nc14O8o9iQlDZ6IXa3FMup1Iy-MdhKDF_f2me_ZL_ATobkt0</recordid><startdate>20210513</startdate><enddate>20210513</enddate><creator>Abidi, Asima</creator><creator>Gorris, Mark A. 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J.</au><au>Brennan, Evan</au><au>Jongmans, Marjolijn C. J.</au><au>Weijers, Dilys D.</au><au>Kuiper, Roland P.</au><au>de Voer, Richarda M.</au><au>Hoogerbrugge, Nicoline</au><au>Schreibelt, Gerty</au><au>de Vries, I. Jolanda M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome</atitle><jtitle>Cancers</jtitle><date>2021-05-13</date><risdate>2021</risdate><volume>13</volume><issue>10</issue><spage>2345</spage><pages>2345-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>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.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>34067951</pmid><doi>10.3390/cancers13102345</doi><orcidid>https://orcid.org/0000-0002-8653-4040</orcidid><orcidid>https://orcid.org/0000-0002-8222-0343</orcidid><orcidid>https://orcid.org/0000-0003-4928-3809</orcidid><orcidid>https://orcid.org/0000-0003-3621-226X</orcidid><orcidid>https://orcid.org/0000-0003-2393-8141</orcidid><orcidid>https://orcid.org/0000-0002-0156-8365</orcidid><oa>free_for_read</oa></addata></record> |
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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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