Bortezomib-induced peripheral neuropathy: A genome-wide association study on multiple myeloma patients.
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.
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Chiara
http://orcid.org/0000-0002-2461-765X
C
Campo
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Miguel Inacio
MI
da Silva Filho
Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.|Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Niels
N
Weinhold
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Seyed Hamidreza
SH
Mahmoudpour
Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.|National Centre of Tumor Diseases, Heidelberg, Germany.
Hartmut
H
Goldschmidt
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Malmö, Sweden.
Kari
K
Hemminki
Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.|Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Maximilian
M
Merz
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Malmö, Sweden.
Asta
A
Försti
D000069286:Bortezomib / Q000009:adverse effects*; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D000069286:Bortezomib
GWAS; SNPs; bortezomib; genetic variants; multiple myeloma; neuropathy