title: A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Patients with Multiple Myeloma.
abstract: OBJECTIVE
  Painful peripheral neuropathy is a frequent toxicity associated with bortezomib therapy. This study aimed to identify loci that affect susceptibility to this toxicity.
  
  
  METHODS
  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 patients with multiple myeloma 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 patients with multiple myeloma of the HOVON-65/GMMG-HD4 clinical trial.
  
  
  RESULTS
  An SNP in the PKNOX1 gene was associated with BiPN in the exploratory cohort [rs2839629; OR, 1.89, 95% confidence interval (CI), 1.45-2.44; P = 7.6 × 10(-6)] and in the replication cohort (OR, 2.04; 95% CI, = 1.11-3.33; P = 8.3 × 10(-3)). In addition, rs2839629 is in strong linkage disequilibrium (r(2) = 0.87) with rs915854, located in the intergenic region between PKNOX1 and cystathionine-ß-synthetase (CBS) Expression quantitative trait loci mapping showed that both rs2839629 and rs915854 genotypes have an impact on PKNOX1 expression in nerve tissue, whereas rs2839629 affects CBS expression in skin and blood.
  
  
  CONCLUSIONS
  The use of GWAS in multiple myeloma 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. Clin Cancer Res; 22(17); 4350-5. ©2016 AACR.
authors.affiliation: INSERM UMR 892, CNRS UMR 6299, Université de Nantes, Nantes, France.|Centre Hospitalier Universitaire, Nantes, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Magrangeas
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Rowan
authors.initials: R
authors.lastname: Kuiper
authors.affiliation: Centre Hospitalier Universitaire, Toulouse, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Avet-Loiseau
authors.affiliation: INSERM UMR 892, CNRS UMR 6299, Université de Nantes, Nantes, France.|Institut de Cancérologie de l'Ouest, Nantes-Saint Herblain, France.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Gouraud
authors.affiliation: INSERM UMR 892, CNRS UMR 6299, Université de Nantes, Nantes, France.|Institut de Cancérologie de l'Ouest, Nantes-Saint Herblain, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Guérin-Charbonnel
authors.affiliation: Institut de Cancérologie de l'Ouest, Nantes-Saint Herblain, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Ferrer
authors.affiliation: LIRIS UMR 5205 CNRS Université Claude Bernard Lyon I, Lyon, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Aussem
authors.affiliation: LIRIS UMR 5205 CNRS Université Claude Bernard Lyon I, Lyon, France.
authors.forename: Haytham
authors.initials: H
authors.lastname: Elghazel
authors.affiliation: Institut de Cancérologie de l'Ouest, Nantes-Saint Herblain, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Suhard
authors.affiliation: LUNAM Université, IRCCyN, CNRS UMR 6597, Polytech Nantes, France.
authors.forename: Henri Der
authors.initials: H
authors.lastname: Sakissian
authors.affiliation: Centre Hospitalier Universitaire, Toulouse, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Attal
authors.affiliation: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.|Boston Veterans Administration Healthcare System, West Roxbury, MA, 02132, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: C Munshi
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Sonneveld
authors.affiliation: INSERM UMR 1052, CNRS 5286 Centre Léon Bérard, Lyon, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
authors.affiliation: INSERM UMR 892, CNRS UMR 6299, Université de Nantes, Nantes, France.|Centre Hospitalier Universitaire, Nantes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: van Duin
authors.affiliation: INSERM UMR 892, CNRS UMR 6299, Université de Nantes, Nantes, France.|Institut de Cancérologie de l'Ouest, Nantes-Saint Herblain, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Campion
authors.affiliation: INSERM UMR 892, CNRS UMR 6299, Université de Nantes, Nantes, France.|Centre Hospitalier Universitaire, Nantes, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Minvielle
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000069286:Bortezomib / Q000009:adverse effects* / Q000627:therapeutic use; D002891:Chromosomes, Human, Pair 21; D019295:Computational Biology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D009101:Multiple Myeloma / Q000150:complications* / Q000188:drug therapy; D010523:Peripheral Nervous System Diseases / Q000209:etiology*; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D000970:Antineoplastic Agents; D000069286:Bortezomib