Genetic variation associated with bortezomib-induced peripheral neuropathy

Autor: Jean-Luc Harousseau, George Mulligan, Helgi van de Velde, Yu Sun, Reyna Favis, Paul G. Richardson, Deborah Ricci, Erin Broderick, Laura Levey, Michael Meyers
Rok vydání: 2011
Předmět:
Oncology
Male
Candidate gene
Bortezomib
Transcription Factor 4
immune system diseases
hemic and lymphatic diseases
Multicenter Studies as Topic
CTLA-4 Antigen
General Pharmacology
Toxicology and Pharmaceutics
Genetics (clinical)
Multiple myeloma
Randomized Controlled Trials as Topic
Genetics
Aged
80 and over
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Peripheral Nervous System Diseases
Middle Aged
Boronic Acids
Pyrazines
Molecular Medicine
Female
Multiple Myeloma
medicine.drug
Adult
medicine.medical_specialty
Single-nucleotide polymorphism
Antineoplastic Agents
Polymorphism
Single Nucleotide
Antigens
CD
Internal medicine
Genetic variation
medicine
Humans
cardiovascular diseases
Genetic variability
neoplasms
Molecular Biology
Genetic Association Studies
Aged
business.industry
medicine.disease
Cathepsins
Peripheral neuropathy
Clinical Trials
Phase III as Topic
Schwann Cells
business
Pharmacogenetics
Transcription Factors
Zdroj: Pharmacogenetics and genomics. 21(3)
ISSN: 1744-6880
Popis: To develop a predictive genetic signature for the development of bortezomib-induced peripheral neuropathy (PN).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.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).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.
Databáze: OpenAIRE
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