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

Campo, Chiara; da Silva Filho, Miguel Inacio LU ; Weinhold, Niels; Mahmoudpour, Seyed Hamidreza LU ; Goldschmidt, Hartmut; Hemminki, Kari LU ; Merz, Maximilian and Försti, Asta LU (2017) In Hematological Oncology
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
Bortezomib, Genetic variants, GWAS, Multiple myeloma, Neuropathy, SNPs
in
Hematological Oncology
publisher
John Wiley and Sons Ltd
external identifiers
  • scopus:85016395676
ISSN
0278-0232
DOI
10.1002/hon.2391
language
English
LU publication?
yes
id
e3a6a058-272e-43bb-925d-bf5b3d890551
date added to LUP
2017-04-19 11:08:05
date last changed
2017-04-20 03:00:08
@article{e3a6a058-272e-43bb-925d-bf5b3d890551,
  abstract     = {<p>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.</p>},
  author       = {Campo, Chiara and da Silva Filho, Miguel Inacio and Weinhold, Niels and Mahmoudpour, Seyed Hamidreza and Goldschmidt, Hartmut and Hemminki, Kari and Merz, Maximilian and Försti, Asta},
  issn         = {0278-0232},
  keyword      = {Bortezomib,Genetic variants,GWAS,Multiple myeloma,Neuropathy,SNPs},
  language     = {eng},
  month        = {03},
  publisher    = {John Wiley and Sons Ltd},
  series       = {Hematological Oncology},
  title        = {Bortezomib-induced peripheral neuropathy : A genome-wide association study on multiple myeloma patients},
  url          = {http://dx.doi.org/10.1002/hon.2391},
  year         = {2017},
}