Bortezomib‐induced peripheral neuropathy: A genome‐wide association study on multiple myeloma patients

Abstract

The proteasome-inhibitor bortezomib was introduced into the treatment of multiple myeloma more than a decade ago. It is clinically beneficial, but peripheral neuropathy (PNP) is a side effect that may limit its use in some patients. To examine the possible genetic predisposing factors to PNP, we performed a genome-wide association study on 646 bortezomib-treated German multiple myeloma patients. Our aim was to identify genetic risk variants associated with the development of PNP as a serious side effect of the treatment. We identified 4 new promising loci for bortezomib-induced PNP at 4q34.3 (rs6552496), 5q14.1 (rs12521798), 16q23.3 (rs8060632), and 18q21.2 (rs17748074). Even though the results did not reach genome-wide significance level, they support the idea of previous studies, suggesting a genetic basis for neurotoxicity. The identified single nucleotide polymorphisms map to genes or next to genes involved in the development and function of the nervous system (CDH13, DCC, and TENM3). As possible functional clues, 2 of the variants, rs12521798 and rs17748074, affect enhancer histone marks in the brain. The rs12521798 may also impact expression of THBS4, which affects specific signal trasduction pathways in the nervous system. Further research is needed to clarify the mechanism of action of the identified single nucleotide polymorphisms in the development of drug-induced PNP and to functionally validate our in silico predictions.

Biological predictors of chemotherapy-induced peripheral neuropathy (CIPN): MASCC neurological complications working group overview

“…The CYP3A5*1/*1 genotype is associated with a lower incidence of neuropathy compared with the CYP3A5*3/*3 genotype [38]. However, others have also reported no effect of CYP3A5 genotype on the development of neuropathy [33,39]. Early evidence suggests that vincristine PK may be associated with neuropathy [18]; however, validation has been challenging [35,40].…”

“…SNPs in CTLA4 rs4553808 and PSMB1 rs1474642 have been reported to be associated with bortezomib-induced neuropathy [41]. A GWAS study identified 4 new loci that were associated with bortezomib-induced peripheral neuropathy, found in genes involved in the development and function of the nervous system including CDH13, DCC, and TENM3 [39]. Another GWAS study identified a gene locus mapping to PKNOX1 and in close proximity to CBS at 21q22.3 that was correlated with the severe bortezomib-induced toxicity [42].…”

Role of Germline Genetics in Identifying Survivors at Risk for Adverse Effects of Cancer Treatment

“…There have been a number of GWAS of chemotherapy-induced peripheral neuropathy associated with vincristine, 25 paclitaxel, 21–23 docetaxel, 24 bortezomib, 27,28 oxaliplatin, 80 and cisplatin. 29 GWAS of paclitaxel-induced peripheral neuropathy in a large cooperative trial identified a signal in EPHA5 (rs7349683) 22 that was replicated by others, 21,81 but interestingly also met replication significance (p < .05) in a study of cisplatin-induced neuropathy.…”

Microneurosurgical treatment options in peripheral nerve compression syndromes after chemotherapy and radiation treatment

“…These electrodiagnostic tests may demonstrate decreased sensory nerve action potential amplitudes without any reduction in motor nerve conduction velocities . Taxanes and platinum drugs are the agents most commonly associated with peripheral neuropathy but vinca alkaloids and bortezomib have also been implicated as well . CIPN is largely a sensory deficit with pain, numbness, paresthesias, and temperature sensitivity along the distal aspects of the upper and/or lower extremities that tends to be symmetrical in a stocking‐and‐glove distribution.…”