A Genome Wide Association Study Reveals Genetic Predisposition for Bortezomib-Induced Peripheral Neuropathy in Multiple Myeloma By Variation in the PREP1-Cbs Locus

Introduction: Bortezomib has become an important part of myeloma therapy, despite the occurrence of toxicities such as bortezomib induced peripheral neuropathy (BiPN). Since effective prophylactic treatment is lacking, onset of BiPN can only be remedied by dose reduction or stop of treatment. Here, using a genome-wide genotyping method, we investigated the potential genetic predisposition to BiPN in MM patients who received bortezomib-dexamethasone (VD) induction therapy prior to autologous stem-cell transplantation (ASCT).

Methods: We performed a genome-wide association study using the Affymetrix SNP 6.0 platform. In total 469 cases from the IFM 2005-01, IFM2007-02 clinical trials or routine diagnostic were included as discovery cohort. Another 114 samples from the HOVON-65/GMMG-HD4 trial were used as validation. Patients with BiPN grade 2 or higher after initiation of bortezomib treatment were assigned as cases (n=155 in discovery, n=40 in validation) and the remaining patients that did not developed BiPN were considered controls (n=314 in discovery, n=74 in validation). Additional exclusion criteria were a minor allele frequency ≤ 5%, genotype frequency < 95% or Hardy Weinberg equilibrium p-value <1 x 10^-5; 371,075 tagging SNPs were thus included for analysis. Association of SNPs to BiPN was tested using a Cochran-Armitage trend test. Six SNPs were found with parametric p-value < 1 x 10^-5. These SNPs were validated using the validation cohort.

Results: Of three loci identified by six SNPs in the discovery cohort, one previously unreported gene locus (rs2839629) remained associated to BiPN in the validation data set. This locus at 21q22.3 had odd ratios of 1.89 (p<1x10^-6) and 2.02 (p = 0.02) in the discovery and validation cohorts, respectively. It is localized in the 3’ UTR of PBX/knotted 1 homeobox 1 (PKNOX1; alias PREP1), which encodes for a homeodomain transcription factor. Amongst others, PKNOX1 may modulate levels of chemokine monocyte chemoattractant protein-1 (MCP-1). MCP-1 is universally increased in different models of peripheral neuropathic pain and may be considered as a biomarker of chronic pain (Zhang and de Koninck, J. Neurochem. 97:772-783 (2006)). Haplotype analysis revealed a strong linkage disequilibrium (LD, r² = 0.87) to the neighbouring gene CBS which encodes an endogenous H₂S-producing enzyme. The CBS-H₂S signalling pathway is implicated in the pathogenesis of a variety of neurodegenerative and inflammatory disorders, and specifically in neuropathy models (Takahashi et al., Pain, 150, 183-191, 2010).

Conclusions: Our data provides evidence for susceptibility to BiPN in MM by variation in the PREP1-CBS locus, and suggests a new potential target in neuro-protective strategies of treatment. Validation of this finding may allow for the identification of patients at increased risk of BiPN which may benefit alternative treatments such as carfilzomib and better clinical management of this toxicity.