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

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 C Munshi (8, 9) , Pieter Sonneveld (2) , Charles Dumontet (10) , Philippe Moreau (1) , Mark van Duin (2) , Loïc Campion (1, 4) , Stéphane Minvielle (1)

1 CRCNA - Centre de Recherche en Cancérologie Nantes-Angers
2 Erasmus MC - Erasmus University Medical Center [Rotterdam]
3 CRCT - Centre de Recherches en Cancérologie de Toulouse
4 UNICANCER/ICO - Institut de Cancérologie de l'Ouest [Angers/Nantes]
5 DM2L - Data Mining and Machine Learning
6 IRCCyN - Institut de Recherche en Communications et en Cybernétique de Nantes
7 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
8 Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center
9 Boston Veterans Administration Healthcare System
10 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon

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.

Domaines: Cancer

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, 2016, Epub ahead of print. ⟨10.1158/1078-0432.CCR-15-3163⟩. ⟨inserm-01313506⟩