title: Genetic variation associated with bortezomib-induced peripheral neuropathy.
abstract: OBJECTIVE
  To develop a predictive genetic signature for the development of bortezomib-induced peripheral neuropathy (PN).
  
  
  METHODS
  Two thousand and sixteen single-nucleotide polymorphisms (SNPs) were genotyped in 139 samples from myeloma patients treated with bortezomib-melphalan-prednisone in the VISTA phase 3 trial. Single-marker association analysis for PN onset and time/cumulative dose to PN onset using the Cox proportional hazards model and multiple covariates was performed under additive, dominant, and recessive genotypic models, followed by correction for multiplicity. Associations were also pursued in a cohort of 212 samples from patients treated with bortezomib-dexamethasone in the IFM 2005-01 phase 3 trial.
  
  
  RESULTS
  In the VISTA cohort, after Bonferroni correction, two SNPs significantly associated with time to onset of PN [CTLA4 rs4553808, false discovery rate (FDR)=0.002] and time to onset of grade of at least 2 PN (PSMB1 rs1474642, FDR=0.014). Using FDR less than 0.05 as the threshold, two additional SNPs significantly associated with time to onset of grade of at least 2 (CTSS rs12568757, FDR=0.027) or grade of at least 3 PN (GJE1 rs11974610, FDR=0.041). DYNC1I1 rs916758 significantly associated (FDR=0.012) with cumulative dose to onset of grade of at least 2 PN. These associations were generally not detected in the IFM 2005-01 cohort, although CTLA4 rs4553808 showed the same trend in association with time to onset (P=0.138). In addition, in the IFM 2005-01 cohort, TCF4 rs1261134 significantly associated with onset of any neurologic event (FDR=0.048).
  
  
  CONCLUSIONS
  Genes associated with immune function (CTLA4, CTSS), reflexive coupling within Schwann cells (GJE1), drug binding (PSMB1), and neuron function (TCF4, DYNC1I1) associated with bortezomib-induced PN in this study.
authors.affiliation: Johnson and Johnson Pharmaceutical Research and Development, Raritan, New Jersey 08869, USA.
authors.forename: Reyna
authors.initials: R
authors.lastname: Favis
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Helgi
authors.initials: H
authors.lastname: van de Velde
authors.forename: Erin
authors.initials: E
authors.lastname: Broderick
authors.forename: Laura
authors.initials: L
authors.lastname: Levey
authors.forename: Michael
authors.initials: M
authors.lastname: Meyers
authors.forename: George
authors.initials: G
authors.lastname: Mulligan
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Harousseau
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Ricci
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D001897:Boronic Acids / Q000009:adverse effects* / Q000627:therapeutic use; D000069286:Bortezomib; D060908:CTLA-4 Antigen; D002403:Cathepsins / Q000235:genetics; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009101:Multiple Myeloma / Q000188:drug therapy*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011719:Pyrazines / Q000009:adverse effects* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012583:Schwann Cells; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001897:Boronic Acids; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D011719:Pyrazines; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D000069286:Bortezomib; D002403:Cathepsins; C028217:cathepsin S