A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Multiple Myeloma Patients

Florence Magrangeas; Rowan Kuiper; Hervé Avet-Loiseau; Wilfried Gouraud; Catherine Guérin-Charbonnel; Ludovic Ferrer; Alexandre Aussem; Haytham Elghazel; Jérôme Suhard; Henri Der Sakissian; Michel Attal; Nikhil Munshi; Pieter Sonneveld; Charles Dumontet; Philippe Moreau; Mark van Duin; Loïc Campion; Stéphane Minvielle

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 ⁶ Henri Der Sakissian ⁷ Michel Attal ⁸ Nikhil Munshi ^{9, 10} Pieter Sonneveld ² Charles Dumontet ¹¹ Philippe Moreau ¹ Mark van Duin ^{2, *} Loïc Campion ^{1, 4, *} Stéphane Minvielle ^{1, *}

* Corresponding author

1 CRCNA - Centre de Recherche en Cancérologie / Nantes - Angers

2 Erasmus MC - Erasmus University Medical Center [Rotterdam]

3 CRCT - Centre de Recherche en Cancérologie de Toulouse

4 ICO Nantes - Institut de cancérologie de l'Ouest - Nantes

5 DM2L - Data Mining and Machine Learning

LIRIS - Laboratoire d'InfoRmatique en Image et Systèmes d'information

6 Institut de Cancérologie de l'Ouest

7 IRCCyN - Institut de Recherche en Communications et en Cybernétique de Nantes

8 CHU Toulouse [Toulouse]

9 Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center

10 Boston Veterans Administration Healthcare System

11 CRCL - Centre de Recherche en Cancérologie de Lyon

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.

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Journal articles

Domain :

Life Sciences [q-bio] / Cancer

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A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Multiple Myeloma Patients : GWAS in multiple myeloma pharmacogenomics

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