title: Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients.
abstract: Bortezomib induced peripheral neuropathy is a dose-limiting side effect and a major concern in the treatment of multiple myeloma. To identify genetic risk factors associated with the development of this side effect in bortezomib treated multiple myeloma patients, a pharmacogenetic association study was performed using a discovery set (IFM 2005-01; n = 238) and a validation set (HOVON65/GMMG-HD4 and a Czech dataset; n = 231). After multiplicity correction, none of the 2,149 single nucleotide polymorphisms tested revealed any significant association with bortezomib induced peripheral neuropathy. However, 56 single nucleotide polymorphisms demonstrated an association with bortezomib induced peripheral neuropathy with pointwise, uncorrected significance. Pathway analysis of these polymorphisms demonstrated involvement of neurological disease (FDR <20%). Also a clear enrichment of major bortezomib metabolizing genes was found. Univariate evaluation of these 56 polymorphisms in the validation set demonstrated one single nucleotide polymorphism with pointwise significance: rs619824 in CYP17A1. (IFM 2005-01 clinicaltrials.gov identifier: NCT00200681; HOVON-65/GMMG-HD4 isrctn.org identifier: ISRCTN64455289).
authors.affiliation: Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Sophie L
authors.initials: SL
authors.lastname: Corthals
authors.forename: Rowan
authors.initials: R
authors.lastname: Kuiper
authors.forename: David C
authors.initials: DC
authors.lastname: Johnson
authors.forename: Pieter
authors.initials: P
authors.lastname: Sonneveld
authors.forename: Roman
authors.initials: R
authors.lastname: Hajek
authors.forename: Bronno
authors.initials: B
authors.lastname: van der Holt
authors.forename: Florence
authors.initials: F
authors.lastname: Magrangeas
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
authors.forename: Hervé
authors.initials: H
authors.lastname: Avet-Loiseau
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects*; D000069286:Bortezomib; D005260:Female; D006801:Humans; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects*; D012307:Risk Factors
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib