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A bipartite graph-based expected networks approach identifies DDR genes not associated with TMB yet predictive of immune checkpoint blockade response

Immune checkpoint blockade (ICB) has had remarkable success for treatment of solid tumors. However, as only a subset of patients exhibit responses, there is a continued need for biomarker development. Numerous reports have shown a link between tumor mutational burden (TMB) and ICB response, while ot...

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Detalles Bibliográficos
Autores principales: Weir, William H., Mucha, Peter J., Kim, William Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133403/
https://www.ncbi.nlm.nih.gov/pubmed/35584624
http://dx.doi.org/10.1016/j.xcrm.2022.100602
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author Weir, William H.
Mucha, Peter J.
Kim, William Y.
author_facet Weir, William H.
Mucha, Peter J.
Kim, William Y.
author_sort Weir, William H.
collection PubMed
description Immune checkpoint blockade (ICB) has had remarkable success for treatment of solid tumors. However, as only a subset of patients exhibit responses, there is a continued need for biomarker development. Numerous reports have shown a link between tumor mutational burden (TMB) and ICB response, while others have identified a link between ICB response and mutation in DNA damage repair (DDR) genes. However, it remains unclear to what extent mutations in DDR genes hold predictive value above and beyond their association with TMB. Herein, we present a networks-based test and bipartite graph-based expected TMB score (BiG-BETS) with higher specificity for discriminating DDR genes and pathways that are associated with elevated TMB. Moreover, we find that mutations in certain DDR genes that are not associated with elevated TMB (low BiG-BETS) are nevertheless predictive of ICB benefit in high TMB patients, demonstrating that their inactivation contributes to ICB response in a TMB-independent manner.
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spelling pubmed-91334032022-05-27 A bipartite graph-based expected networks approach identifies DDR genes not associated with TMB yet predictive of immune checkpoint blockade response Weir, William H. Mucha, Peter J. Kim, William Y. Cell Rep Med Report Immune checkpoint blockade (ICB) has had remarkable success for treatment of solid tumors. However, as only a subset of patients exhibit responses, there is a continued need for biomarker development. Numerous reports have shown a link between tumor mutational burden (TMB) and ICB response, while others have identified a link between ICB response and mutation in DNA damage repair (DDR) genes. However, it remains unclear to what extent mutations in DDR genes hold predictive value above and beyond their association with TMB. Herein, we present a networks-based test and bipartite graph-based expected TMB score (BiG-BETS) with higher specificity for discriminating DDR genes and pathways that are associated with elevated TMB. Moreover, we find that mutations in certain DDR genes that are not associated with elevated TMB (low BiG-BETS) are nevertheless predictive of ICB benefit in high TMB patients, demonstrating that their inactivation contributes to ICB response in a TMB-independent manner. Elsevier 2022-04-18 /pmc/articles/PMC9133403/ /pubmed/35584624 http://dx.doi.org/10.1016/j.xcrm.2022.100602 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Report
Weir, William H.
Mucha, Peter J.
Kim, William Y.
A bipartite graph-based expected networks approach identifies DDR genes not associated with TMB yet predictive of immune checkpoint blockade response
title A bipartite graph-based expected networks approach identifies DDR genes not associated with TMB yet predictive of immune checkpoint blockade response
title_full A bipartite graph-based expected networks approach identifies DDR genes not associated with TMB yet predictive of immune checkpoint blockade response
title_fullStr A bipartite graph-based expected networks approach identifies DDR genes not associated with TMB yet predictive of immune checkpoint blockade response
title_full_unstemmed A bipartite graph-based expected networks approach identifies DDR genes not associated with TMB yet predictive of immune checkpoint blockade response
title_short A bipartite graph-based expected networks approach identifies DDR genes not associated with TMB yet predictive of immune checkpoint blockade response
title_sort bipartite graph-based expected networks approach identifies ddr genes not associated with tmb yet predictive of immune checkpoint blockade response
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133403/
https://www.ncbi.nlm.nih.gov/pubmed/35584624
http://dx.doi.org/10.1016/j.xcrm.2022.100602
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