Genomics

Dataset Information

27

A Genome Wide Association Study Reveals Genetic Predisposition for Bortezomib-Induced Peripheral Neuropathy in Multiple Myeloma by Variation in the PREP1-CBS locus.


ABSTRACT: We performed a genome-wide association study using Affymetrix HD-SNP arrays 6.0 to identify risk variants for developing bortezomib-induced peripheral neuropathy (BiPN) in 469 multiple myeloma (MM) patients who received bortezomib-dexamethasone (VD) induction therapy prior to autologous stem-cell transplantation (ASCT) and conducted validation in an independent cohort of 114 MM patients. We identified one previously unreported gene locus associated with BiPN at 21q22.3 (rs2839629, PKNOX1; OR = 1.89, P= 6.47 x 10-7). PKNOX1 is known to regulate expression of MCP-1, a potent mediator of chemotherapy-induced peripheral neuropathy. rs2839629 is in strong linkage disequilibrium (LD, r2 = 0.87) with rs915854, localized 6.5kb centromeric to CBS encoding an endogenous H2S-producing enzyme. CBS-H2S signalling pathway is implicated in the pathogenesis of a variety of neurodegenerative and inflammatory disorders, and specifically in neuropathy models. Our data provide conclusive evidence for genetic susceptibility to BiPN in MM and new potential targets in neuro-protective strategies of treatment. Overall design: Identify risk variants for developing bortezomib-induced peripheral neuropathy (BiPN) within a cohort of 469 MM patients by means of genome wide association study, validation in an independent cohort of 114 MM patients

INSTRUMENT(S): [GenomeWideSNP_6] Affymetrix Genome-Wide Human SNP 6.0 Array

SUBMITTER: Wilfried Gouraud 

PROVIDER: GSE65777 | GEO | 2016-11-23

SECONDARY ACCESSION(S): PRJNA275004

REPOSITORIES: GEO

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Publications

A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Patients with Multiple Myeloma.

Magrangeas Florence F   Kuiper Rowan R   Avet-Loiseau Hervé H   Gouraud Wilfried W   Guérin-Charbonnel Catherine C   Ferrer Ludovic L   Aussem Alexandre A   Elghazel Haytham H   Suhard Jérôme J   Sakissian Henri Der H   Attal Michel M   C Munshi Nikhil N   Sonneveld Pieter P   Dumontet Charles C   Moreau Philippe P   van Duin Mark M   Campion Loïc L   Minvielle Stéphane S  

Clinical cancer research : an official journal of the American Association for Cancer Research 20160408 17


Painful peripheral neuropathy is a frequent toxicity associated with bortezomib therapy. This study aimed to identify loci that affect susceptibility to this toxicity.A genome-wide association study (GWAS) of 370,605 SNPs was performed to identify risk variants for developing severe bortezomib-induced peripheral neuropathy (BiPN) in 469 patients with multiple myeloma who received bortezomib-dexamethasone therapy prior to autologous stem cell in randomized clinical trials of the Intergroupe Franc  ...[more]

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