Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity

POLE driver mutations in the exonuclease domain (ExoD driver) are prevalent in several cancers, including colorectal cancer and endometrial cancer, leading to dramatically ultra-high tumor mutation burden (TMB). To understand whether POLE mutations that are not classified as drivers (POLE Variant) c...

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Authors: Shah, Shreya M., Demidova, Elena V., Ringenbach, Salena, Faezov, Bulat, Andrake, Mark, Gandhi, Arjun, Mur, Pilar, Viana Errasti, Julen, Xiu, Joanne, Swensen, Jeffrey, Valle, Laura, Dunbrack, Roland L., Hall, Michael J., Arora, Sanjeevani
Format: article
Status:Published version
Publication Date:2024
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/214567
Online Access:https://hdl.handle.net/2445/214567
Access Level:Open access
Keyword:Mutació (Biologia)
Genètica molecular
Mutation (Biology)
Molecular genetics
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repository_id_str
spelling Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor MutagenicityShah, Shreya M.Demidova, Elena V.Ringenbach, SalenaFaezov, BulatAndrake, MarkGandhi, ArjunMur, PilarViana Errasti, JulenXiu, JoanneSwensen, JeffreyValle, LauraDunbrack, Roland L.Hall, Michael J.Arora, SanjeevaniMutació (Biologia)Genètica molecularMutation (Biology)Molecular geneticsPOLE driver mutations in the exonuclease domain (ExoD driver) are prevalent in several cancers, including colorectal cancer and endometrial cancer, leading to dramatically ultra-high tumor mutation burden (TMB). To understand whether POLE mutations that are not classified as drivers (POLE Variant) contribute to mutagenesis, we assessed TMB in 447 POLE-mutated colorectal cancers, endometrial cancers, and ovarian cancers classified as TMB-high >= 10 mutations/Mb (mut/Mb) or TMB-low <10 mut/Mb. TMB was significantly highest in tumors with POLE ExoD driver plus POLE Variant (colorectal cancer and endometrial cancer, P < 0.001; ovarian cancer, P < 0.05). TMB increased with additional POLE variants (P < 0.001), but plateaued at 2, suggesting an association between the presence of these variants and TMB. Integrated analysis of AlphaFold2 POLE models and quantitative stability estimates predicted the impact of multiple POLE variants on POLE functionality. The prevalence of immunogenic neoepitopes was notably higher in the POLE ExoD driver plus POLE Variant tumors. Overall, this study reveals a novel correlation between POLE variants in POLE ExoD-driven tumors, and ultra-high TMB. Currently, only select pathogenic ExoD mutations with a reliable association with ultra-high TMB inform clinical practice. Thus, these findings are hypothesis-generating, require functional validation, and could potentially inform tumor classification, treatment responses, and clinical outcomes. Significance: Somatic POLE ExoD driver mutations cause proofreading deficiency that induces high TMB. This study suggests a novel modifier role for POLE variants in POLE ExoD-driven tumors, associated with ultra-high TMB. These data, in addition to future functional studies, may inform tumor classification, therapeutic response, and patient outcomes.American Association for Cancer Research (AACR)2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/214567Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1158/2767-9764.CRC-23-0312Cancer Research Communications, 2024, vol. 4, num. 1, p. 213-225https://doi.org/10.1158/2767-9764.CRC-23-0312cc by (c) Shah, Shreya M. et al., 2024http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2145672026-05-27T06:46:51Z
dc.title.none.fl_str_mv Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity
title Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity
spellingShingle Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity
Shah, Shreya M.
Mutació (Biologia)
Genètica molecular
Mutation (Biology)
Molecular genetics
title_short Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity
title_full Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity
title_fullStr Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity
title_full_unstemmed Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity
title_sort Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity
dc.creator.none.fl_str_mv Shah, Shreya M.
Demidova, Elena V.
Ringenbach, Salena
Faezov, Bulat
Andrake, Mark
Gandhi, Arjun
Mur, Pilar
Viana Errasti, Julen
Xiu, Joanne
Swensen, Jeffrey
Valle, Laura
Dunbrack, Roland L.
Hall, Michael J.
Arora, Sanjeevani
author Shah, Shreya M.
author_facet Shah, Shreya M.
Demidova, Elena V.
Ringenbach, Salena
Faezov, Bulat
Andrake, Mark
Gandhi, Arjun
Mur, Pilar
Viana Errasti, Julen
Xiu, Joanne
Swensen, Jeffrey
Valle, Laura
Dunbrack, Roland L.
Hall, Michael J.
Arora, Sanjeevani
author_role author
author2 Demidova, Elena V.
Ringenbach, Salena
Faezov, Bulat
Andrake, Mark
Gandhi, Arjun
Mur, Pilar
Viana Errasti, Julen
Xiu, Joanne
Swensen, Jeffrey
Valle, Laura
Dunbrack, Roland L.
Hall, Michael J.
Arora, Sanjeevani
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Mutació (Biologia)
Genètica molecular
Mutation (Biology)
Molecular genetics
topic Mutació (Biologia)
Genètica molecular
Mutation (Biology)
Molecular genetics
description POLE driver mutations in the exonuclease domain (ExoD driver) are prevalent in several cancers, including colorectal cancer and endometrial cancer, leading to dramatically ultra-high tumor mutation burden (TMB). To understand whether POLE mutations that are not classified as drivers (POLE Variant) contribute to mutagenesis, we assessed TMB in 447 POLE-mutated colorectal cancers, endometrial cancers, and ovarian cancers classified as TMB-high >= 10 mutations/Mb (mut/Mb) or TMB-low <10 mut/Mb. TMB was significantly highest in tumors with POLE ExoD driver plus POLE Variant (colorectal cancer and endometrial cancer, P < 0.001; ovarian cancer, P < 0.05). TMB increased with additional POLE variants (P < 0.001), but plateaued at 2, suggesting an association between the presence of these variants and TMB. Integrated analysis of AlphaFold2 POLE models and quantitative stability estimates predicted the impact of multiple POLE variants on POLE functionality. The prevalence of immunogenic neoepitopes was notably higher in the POLE ExoD driver plus POLE Variant tumors. Overall, this study reveals a novel correlation between POLE variants in POLE ExoD-driven tumors, and ultra-high TMB. Currently, only select pathogenic ExoD mutations with a reliable association with ultra-high TMB inform clinical practice. Thus, these findings are hypothesis-generating, require functional validation, and could potentially inform tumor classification, treatment responses, and clinical outcomes. Significance: Somatic POLE ExoD driver mutations cause proofreading deficiency that induces high TMB. This study suggests a novel modifier role for POLE variants in POLE ExoD-driven tumors, associated with ultra-high TMB. These data, in addition to future functional studies, may inform tumor classification, therapeutic response, and patient outcomes.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/214567
url https://hdl.handle.net/2445/214567
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1158/2767-9764.CRC-23-0312
Cancer Research Communications, 2024, vol. 4, num. 1, p. 213-225
https://doi.org/10.1158/2767-9764.CRC-23-0312
dc.rights.none.fl_str_mv cc by (c) Shah, Shreya M. et al., 2024
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Shah, Shreya M. et al., 2024
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research (AACR)
publisher.none.fl_str_mv American Association for Cancer Research (AACR)
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869407568284090368
score 15,812429

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