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Journal articles
A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Multiple Myeloma Patients: GWAS in multiple myeloma pharmacogenomics
Florence Magrangeas
1
Rowan Kuiper
2
Hervé Avet-Loiseau
3
Wilfried Gouraud
1, 4
Catherine Guérin-Charbonnel
1, 4
Ludovic Ferrer
4
Alexandre Aussem
5
Haytham Elghazel
5
Jérôme Suhard
4
Henri Der Sakissian
6
Michel Attal
7
Nikhil Munshi
8, 9
Pieter Sonneveld
2
Charles Dumontet
10
Philippe Moreau
1
Mark van Duin
2, *
Loïc Campion
1, 4, *
Stéphane Minvielle
1, *
*
Corresponding author
5
DM2L - Data Mining and Machine Learning
LIRIS - Laboratoire d'InfoRmatique en Image et Systèmes d'information
Florence Magrangeas 1
Author
Rowan Kuiper 2
Author
Hervé Avet-Loiseau 3
Author
Wilfried Gouraud 1, 4
Author
Catherine Guérin-Charbonnel 1, 4
Author
Ludovic Ferrer 4
Author
Alexandre Aussem 5
Mail :
Author IdHAL : alexandre-aussem
Haytham Elghazel 5
Mail :
Author IdHAL : haytham-elghazel
Jérôme Suhard 4
Author
Henri Der Sakissian 6
Author
Michel Attal 7
Author
Nikhil C Munshi 8, 9
Author
Pieter Sonneveld 2
Author
Charles Dumontet 10
Author
Philippe Moreau 1
Author
Mark van Duin 2
Mail :
Correspondent author
Loïc Campion 1, 4
Mail :
Correspondent author
Stéphane Minvielle 1
Mail :
Correspondent author
1
CRCNA - Centre de Recherche en Cancérologie Nantes-Angers (France)
- CHU Angers - Centre Hospitalier Universitaire d'Angers (4 rue Larrey - 49933 Angers cedex 9 - France)
- Hôtel-Dieu de Nantes (France)
- INSERM - Institut National de la Santé et de la Recherche Médicale (101, rue de Tolbiac, 75013 Paris - France)
- Hôpital Laennec (France)
- CNRS - Centre National de la Recherche Scientifique (France)
- Faculté de Médecine d'Angers (Rue Haute de Reculée 49045 Angers - France)
- CHU Nantes - Centre hospitalier universitaire de Nantes (1 Place Alexis-Ricordeau, 44000 Nantes - France)
2
Erasmus MC - Erasmus University Medical Center [Rotterdam] (Rotterdam - Netherlands)
3
CRCT - Centre de Recherches en Cancérologie de Toulouse (Centre de Recherches en Cancérologie de Toulouse
2 Avenue Hubert Curien
31037 Toulouse Cedex 1
FRANCE - France)
- UT3 - Université Toulouse III - Paul Sabatier (118 route de Narbonne - 31062 Toulouse - France)
- Université Fédérale Toulouse Midi-Pyrénées (41 Allée Jules Guesde, 31000 Toulouse - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1037 (101, rue de Tolbiac, 75013 Paris - France)
- CNRS - Centre National de la Recherche Scientifique : ERL5294 (France)
4
UNICANCER/ICO - Institut de Cancérologie de l'Ouest [Angers/Nantes] (15, rue André Boquel - 49055 Angers cedex 02 - France)
- UNICANCER (101, rue de Tolbiac, 75654 Paris Cedex 13 - France)
5
DM2L - Data Mining and Machine Learning (France)
- LIRIS - Laboratoire d'InfoRmatique en Image et Systèmes d'information (Bâtiment Blaise Pascal - 20, avenue Albert Einstein - 69621 Villeurbanne cedex - France)
- UL2 - Université Lumière - Lyon 2 (86, rue Pasteur - 69007 Lyon - France)
- ECL - École Centrale de Lyon (36 avenue Guy de Collongue - 69134 Ecully cedex - France)
- Université de Lyon (92 rue Pasteur - CS 30122, 69361 Lyon Cedex 07 - France)
- UCBL - Université Claude Bernard Lyon 1 (43, boulevard du 11 novembre 1918, 69622 Villeurbanne cedex - France)
- Université de Lyon (92 rue Pasteur - CS 30122, 69361 Lyon Cedex 07 - France)
- CNRS - Centre National de la Recherche Scientifique : UMR5205 (France)
- INSA Lyon - Institut National des Sciences Appliquées de Lyon (20 Avenue Albert Einstein,
69621 Villeurbanne cedex - France)
- Université de Lyon (92 rue Pasteur - CS 30122, 69361 Lyon Cedex 07 - France)
- INSA - Institut National des Sciences Appliquées (France)
6
IRCCyN - Institut de Recherche en Communications et en Cybernétique de Nantes (1, rue de la Noë BP92101 44321 Nantes Cedex 03 - France)
- Mines Nantes - Mines Nantes (La Chantrerie - 4, rue Alfred Kastler - BP 20722 - 44307 Nantes cedex 3 - France)
- ECN - École Centrale de Nantes (1 rue de la Noë - BP 92101 - 44321 Nantes cedex 3 - France)
- Polytech Nantes - Ecole Polytechnique de l'Université de Nantes (Campus Chantrerie : Rue Christian Pauc - CS 50609 - 44306 Nantes Cedex 3
Campus Gavy : Gavy Océanis - CS 70152 - 44603 Saint-Nazaire Cedex
Campus Courtaisière : 18 Boulevard Gaston Defferre - 85035 La Roche-sur-Yon Cedex - France)
- UN - Université de Nantes : 93263 (1, quai de Tourville - BP 13522 - 44035 Nantes cedex 1 - France)
- UNAM - PRES Université Nantes Angers Le Mans (France)
- CNRS - Centre National de la Recherche Scientifique : UMR6597 (France)
7
CHU Toulouse [Toulouse] (Hôtel-Dieu Saint Jacques
2, rue Viguerie
TSA 80035
31059 Toulouse cedex 9 - France)
8
Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center (United States)
- HMS - Harvard Medical School [Boston] (25 Shattuck Street Boston, MA 02115 - United States)
10
UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon (28, rue Laennec - 69373 Lyon - France)
- Centre Léon Bérard [Lyon] (28, rue Laennec 69373 LYON Cedex 08 - France)
- UCBL - Université Claude Bernard Lyon 1 (43, boulevard du 11 novembre 1918, 69622 Villeurbanne cedex - France)
- Université de Lyon (92 rue Pasteur - CS 30122, 69361 Lyon Cedex 07 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1052 (101, rue de Tolbiac, 75013 Paris - France)
- CNRS - Centre National de la Recherche Scientifique : UMR5286 (France)
Abstract : Purpose: Painful peripheral neuropathy is a frequent toxicity associated with bortezomib therapy.
This study aimed to identify loci that affect susceptibility to this toxicity.
Experimental Design: A genome-wide association study (GWAS) of 370,605 SNPs was
performed to identify risk variants for developing severe bortezomib-induced peripheral neuropathy
(BiPN) in 469 multiple myeloma (MM) patients who received bortezomib-dexamethasone therapy
prior to autologous stem-cell in randomized clinical trials of the Intergroupe Francophone du
Myelome (IFM) and findings were replicated in 114 MM patients of the HOVON-65/GMMG-HD4
clinical trial.
Results: A single SNP in the PKNOX1 gene was associated with BiPN in the exploratory cohort
(rs2839629; OR, 1.89, 95% CI: [1.45-2.44]; P = 7.6 x 10-6) and in the replication cohort (OR, 2.04;
95% CI = [1.11-3.33]; P= 8.3 x 10-3). In addition, rs2839629 is in strong linkage disequilibrium (r2
= 0.87) with rs915854, located in the intergenic region between PKNOX1 and CBS . Expression
quantitative trait loci mapping showed that both rs2839629 and rs915854 genotypes impact
PKNOX1 expression in nerve tissue while rs2839629 affects CBS expression in skin and blood.
Conclusions: The use of GWAS in MM pharmacogenomics has identified a novel candidate genetic
locus mapping to PKNOX1 and in the immediate vicinity of CBS at 21q22.3 associated with the
severe bortezomib-induced toxicity. The proximity of these two genes involved in neurologic pain
whose tissue-specific expression is modified by the two variants provides new targets for neuroprotective
strategies.
Document type :
Journal articles
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Complete list of metadatas
https://www.hal.inserm.fr/inserm-01313506
Contributor : Elizabeth Bernardo <>
Submitted on : Tuesday, May 10, 2016 - 9:36:56 AM
Last modification on : Wednesday, July 8, 2020 - 12:43:50 PM
Document(s) archivé(s) le : Tuesday, November 15, 2016 - 11:11:12 PM
Contributor : Elizabeth Bernardo <>
Submitted on : Tuesday, May 10, 2016 - 9:36:56 AM
Last modification on : Wednesday, July 8, 2020 - 12:43:50 PM
Document(s) archivé(s) le : Tuesday, November 15, 2016 - 11:11:12 PM
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Identifiers
- HAL Id : inserm-01313506, version 1
- DOI : 10.1158/1078-0432.CCR-15-3163
- PUBMED : 27060151
Collections
CNRS | EC-NANTES | EC-LYON | IRCCYN | UNAM | UNIV-NANTES | UNIV-LYON2 | LIRIS | AGROCAMPUS-OUEST-UMR-STLO | INSA-LYON | UNIV-LYON1 | CRCL | INSA-GROUPE | LABEXIMU | UNIV-TLSE3 | UDL
Citation
Florence Magrangeas, Rowan Kuiper, Hervé Avet-Loiseau, Wilfried Gouraud, Catherine Guérin-Charbonnel, et al.. A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Multiple Myeloma Patients: GWAS in multiple myeloma pharmacogenomics. Clinical Cancer Research, American Association for Cancer Research, 2016, Epub ahead of print. ⟨10.1158/1078-0432.CCR-15-3163⟩. ⟨inserm-01313506⟩
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