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

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 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.

Figure 1

21q22.3 locus showing genome-wide level of evidence of BiPN in MM. Illustration of the locus with the local linkage disequilibrium and recombination rate over 500-kb centred on rs2839629 (blue triangle). Each diamond, triangle, circle or square represents a SNP found in this locus, rs76516641 and rs915854 are indicated (red diamond). The figure was generated using the web-based tool SNiPA (http://www.snipa.org; 22).

Figure 2

Relationship between nerve-tibial PKNOX1 expression and rs2839629 genotype from the GTEX Portal v6 (http://www.gtexportal.org; 23).

Figure 3

UCS Genome Browser views of histone marks H3K27ac and H3K4me1 enrichment and H3K4me3 depletion within the region covering PKNOX1 and CBS in Hela cells. Arrow indicates the variant sequence and location in position-weight matrix for FOXA1.