Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients

Autores
Bruzzoni Giovanelli, Heriberto; Zouali, Habib; Sahbatou, Mourad; Maneglier, Benjamin; Cayuela, Jean Michel; Rebollo, Angelita; Marin, Gustavo Horacio; Geromin, Daniela; Tomczak, Carole; Alberdi, Antonio; Deleuze, Jean Francois; Rousselot, Philippe
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The tyrosine kinase Inhibitor (TKI) imatinib is approved for the treatment of the chronicphase of chronic myeloid leukemia (CP-CML). Pharmacokinetic studies have highlighted the im-portance of inter-patient variability on imatinib plasma trough concentrations (ima[C]min). In theOPTIM-imatinib trial, we demonstrated that therapeutic drug monitoring (TDM) is able to improvethe molecular response of CP-CML patients treated with imatinib. Here, we analyzed the constitu-tional exomes and RNAseq data of these patients. We performed an association analysis betweenthe constitutional genetic variants of the patients and their ima[C]min, measured after 12 weeks oftreatment with 400 mg once daily. Using linear regression, we identified 50 SNPs that showed excess heterozygosity depending on the ima[C]min. Ten SNPs were from non-coding sequences, and among the 40 remaining, 30 (from 25 genes) could be split into two categories. The first group of 16 SNPs concerns genes encoding extracellular matrix, cell junction, and membrane proteins. Coincidentally, cell adhesion proteins were also identified by RNA-seq as being overexpressed in patients with high ima[C]min. The other group of 14 SNPs were from genes encoding proteins involved in transcription/translation. Although most of the SNPs are intronic variants (28), we also identified missense (3), synonymous (4), 5′/3′ (2), splicing (1), and upstream (4) variants. A haplotype analysis of four genes showed a significant association with high ima[C]min. None of the SNPs were significantly associated with the response. In conclusion, we identified a number of ima[C]min-associated SNPs, most of which correspond to genes encoding proteins that could play a role in the diffusion and transit of imatinib through membranes or epithelial barriers.
Fil: Bruzzoni Giovanelli, Heriberto. Université Paris Diderot - Paris 7; Francia
Fil: Zouali, Habib. Centre Détude Du Polymorphisme Humain; Francia
Fil: Sahbatou, Mourad. Université Paris Diderot - Paris 7; Francia
Fil: Maneglier, Benjamin. Centre Hospitalier de Versailles; Francia
Fil: Cayuela, Jean Michel. Hôpital Saint-Louis; Francia
Fil: Rebollo, Angelita. Inserm; Francia
Fil: Marin, Gustavo Horacio. Universidad Nacional de La Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Geromin, Daniela. Hôpital Saint-Louis; Francia
Fil: Tomczak, Carole. Hôpital Saint-Louis; Francia
Fil: Alberdi, Antonio. Centre National de la Recherche Scientifique; Francia
Fil: Deleuze, Jean Francois. Universite Paris-Saclay ;
Fil: Rousselot, Philippe. Centre Hospitalier de Versailles; Francia
Materia
chronic myeloid leukemia
imatinib
Pharmacokinetics
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/238775
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/238775
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia PatientsBruzzoni Giovanelli, HeribertoZouali, HabibSahbatou, MouradManeglier, BenjaminCayuela, Jean MichelRebollo, AngelitaMarin, Gustavo HoracioGeromin, DanielaTomczak, CaroleAlberdi, AntonioDeleuze, Jean FrancoisRousselot, Philippechronic myeloid leukemiaimatinibPharmacokineticshttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The tyrosine kinase Inhibitor (TKI) imatinib is approved for the treatment of the chronicphase of chronic myeloid leukemia (CP-CML). Pharmacokinetic studies have highlighted the im-portance of inter-patient variability on imatinib plasma trough concentrations (ima[C]min). In theOPTIM-imatinib trial, we demonstrated that therapeutic drug monitoring (TDM) is able to improvethe molecular response of CP-CML patients treated with imatinib. Here, we analyzed the constitu-tional exomes and RNAseq data of these patients. We performed an association analysis betweenthe constitutional genetic variants of the patients and their ima[C]min, measured after 12 weeks oftreatment with 400 mg once daily. Using linear regression, we identified 50 SNPs that showed excess heterozygosity depending on the ima[C]min. Ten SNPs were from non-coding sequences, and among the 40 remaining, 30 (from 25 genes) could be split into two categories. The first group of 16 SNPs concerns genes encoding extracellular matrix, cell junction, and membrane proteins. Coincidentally, cell adhesion proteins were also identified by RNA-seq as being overexpressed in patients with high ima[C]min. The other group of 14 SNPs were from genes encoding proteins involved in transcription/translation. Although most of the SNPs are intronic variants (28), we also identified missense (3), synonymous (4), 5′/3′ (2), splicing (1), and upstream (4) variants. A haplotype analysis of four genes showed a significant association with high ima[C]min. None of the SNPs were significantly associated with the response. In conclusion, we identified a number of ima[C]min-associated SNPs, most of which correspond to genes encoding proteins that could play a role in the diffusion and transit of imatinib through membranes or epithelial barriers.Fil: Bruzzoni Giovanelli, Heriberto. Université Paris Diderot - Paris 7; FranciaFil: Zouali, Habib. Centre Détude Du Polymorphisme Humain; FranciaFil: Sahbatou, Mourad. Université Paris Diderot - Paris 7; FranciaFil: Maneglier, Benjamin. Centre Hospitalier de Versailles; FranciaFil: Cayuela, Jean Michel. Hôpital Saint-Louis; FranciaFil: Rebollo, Angelita. Inserm; FranciaFil: Marin, Gustavo Horacio. Universidad Nacional de La Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Geromin, Daniela. Hôpital Saint-Louis; FranciaFil: Tomczak, Carole. Hôpital Saint-Louis; FranciaFil: Alberdi, Antonio. Centre National de la Recherche Scientifique; FranciaFil: Deleuze, Jean Francois. Universite Paris-Saclay ;Fil: Rousselot, Philippe. Centre Hospitalier de Versailles; FranciaMDPI2024-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/238775Bruzzoni Giovanelli, Heriberto; Zouali, Habib; Sahbatou, Mourad; Maneglier, Benjamin; Cayuela, Jean Michel; et al.; Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients; MDPI; Pharmaceutics; 16; 6; 6-2024; 1-141999-4923CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.3390/pharmaceutics16060834info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:58:05Zoai:ri.conicet.gov.ar:11336/238775instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:58:06.225CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients
title Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients
spellingShingle Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients
Bruzzoni Giovanelli, Heriberto
chronic myeloid leukemia
imatinib
Pharmacokinetics
title_short Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients
title_full Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients
title_fullStr Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients
title_full_unstemmed Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients
title_sort Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients
dc.creator.none.fl_str_mv Bruzzoni Giovanelli, Heriberto
Zouali, Habib
Sahbatou, Mourad
Maneglier, Benjamin
Cayuela, Jean Michel
Rebollo, Angelita
Marin, Gustavo Horacio
Geromin, Daniela
Tomczak, Carole
Alberdi, Antonio
Deleuze, Jean Francois
Rousselot, Philippe
author Bruzzoni Giovanelli, Heriberto
author_facet Bruzzoni Giovanelli, Heriberto
Zouali, Habib
Sahbatou, Mourad
Maneglier, Benjamin
Cayuela, Jean Michel
Rebollo, Angelita
Marin, Gustavo Horacio
Geromin, Daniela
Tomczak, Carole
Alberdi, Antonio
Deleuze, Jean Francois
Rousselot, Philippe
author_role author
author2 Zouali, Habib
Sahbatou, Mourad
Maneglier, Benjamin
Cayuela, Jean Michel
Rebollo, Angelita
Marin, Gustavo Horacio
Geromin, Daniela
Tomczak, Carole
Alberdi, Antonio
Deleuze, Jean Francois
Rousselot, Philippe
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv chronic myeloid leukemia
imatinib
Pharmacokinetics
topic chronic myeloid leukemia
imatinib
Pharmacokinetics
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The tyrosine kinase Inhibitor (TKI) imatinib is approved for the treatment of the chronicphase of chronic myeloid leukemia (CP-CML). Pharmacokinetic studies have highlighted the im-portance of inter-patient variability on imatinib plasma trough concentrations (ima[C]min). In theOPTIM-imatinib trial, we demonstrated that therapeutic drug monitoring (TDM) is able to improvethe molecular response of CP-CML patients treated with imatinib. Here, we analyzed the constitu-tional exomes and RNAseq data of these patients. We performed an association analysis betweenthe constitutional genetic variants of the patients and their ima[C]min, measured after 12 weeks oftreatment with 400 mg once daily. Using linear regression, we identified 50 SNPs that showed excess heterozygosity depending on the ima[C]min. Ten SNPs were from non-coding sequences, and among the 40 remaining, 30 (from 25 genes) could be split into two categories. The first group of 16 SNPs concerns genes encoding extracellular matrix, cell junction, and membrane proteins. Coincidentally, cell adhesion proteins were also identified by RNA-seq as being overexpressed in patients with high ima[C]min. The other group of 14 SNPs were from genes encoding proteins involved in transcription/translation. Although most of the SNPs are intronic variants (28), we also identified missense (3), synonymous (4), 5′/3′ (2), splicing (1), and upstream (4) variants. A haplotype analysis of four genes showed a significant association with high ima[C]min. None of the SNPs were significantly associated with the response. In conclusion, we identified a number of ima[C]min-associated SNPs, most of which correspond to genes encoding proteins that could play a role in the diffusion and transit of imatinib through membranes or epithelial barriers.
Fil: Bruzzoni Giovanelli, Heriberto. Université Paris Diderot - Paris 7; Francia
Fil: Zouali, Habib. Centre Détude Du Polymorphisme Humain; Francia
Fil: Sahbatou, Mourad. Université Paris Diderot - Paris 7; Francia
Fil: Maneglier, Benjamin. Centre Hospitalier de Versailles; Francia
Fil: Cayuela, Jean Michel. Hôpital Saint-Louis; Francia
Fil: Rebollo, Angelita. Inserm; Francia
Fil: Marin, Gustavo Horacio. Universidad Nacional de La Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Geromin, Daniela. Hôpital Saint-Louis; Francia
Fil: Tomczak, Carole. Hôpital Saint-Louis; Francia
Fil: Alberdi, Antonio. Centre National de la Recherche Scientifique; Francia
Fil: Deleuze, Jean Francois. Universite Paris-Saclay ;
Fil: Rousselot, Philippe. Centre Hospitalier de Versailles; Francia
description The tyrosine kinase Inhibitor (TKI) imatinib is approved for the treatment of the chronicphase of chronic myeloid leukemia (CP-CML). Pharmacokinetic studies have highlighted the im-portance of inter-patient variability on imatinib plasma trough concentrations (ima[C]min). In theOPTIM-imatinib trial, we demonstrated that therapeutic drug monitoring (TDM) is able to improvethe molecular response of CP-CML patients treated with imatinib. Here, we analyzed the constitu-tional exomes and RNAseq data of these patients. We performed an association analysis betweenthe constitutional genetic variants of the patients and their ima[C]min, measured after 12 weeks oftreatment with 400 mg once daily. Using linear regression, we identified 50 SNPs that showed excess heterozygosity depending on the ima[C]min. Ten SNPs were from non-coding sequences, and among the 40 remaining, 30 (from 25 genes) could be split into two categories. The first group of 16 SNPs concerns genes encoding extracellular matrix, cell junction, and membrane proteins. Coincidentally, cell adhesion proteins were also identified by RNA-seq as being overexpressed in patients with high ima[C]min. The other group of 14 SNPs were from genes encoding proteins involved in transcription/translation. Although most of the SNPs are intronic variants (28), we also identified missense (3), synonymous (4), 5′/3′ (2), splicing (1), and upstream (4) variants. A haplotype analysis of four genes showed a significant association with high ima[C]min. None of the SNPs were significantly associated with the response. In conclusion, we identified a number of ima[C]min-associated SNPs, most of which correspond to genes encoding proteins that could play a role in the diffusion and transit of imatinib through membranes or epithelial barriers.
publishDate 2024
dc.date.none.fl_str_mv 2024-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/238775
Bruzzoni Giovanelli, Heriberto; Zouali, Habib; Sahbatou, Mourad; Maneglier, Benjamin; Cayuela, Jean Michel; et al.; Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients; MDPI; Pharmaceutics; 16; 6; 6-2024; 1-14
1999-4923
CONICET Digital
CONICET
url http://hdl.handle.net/11336/238775
identifier_str_mv Bruzzoni Giovanelli, Heriberto; Zouali, Habib; Sahbatou, Mourad; Maneglier, Benjamin; Cayuela, Jean Michel; et al.; Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients; MDPI; Pharmaceutics; 16; 6; 6-2024; 1-14
1999-4923
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.3390/pharmaceutics16060834
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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