Dataset Information

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]

PMID: 27060151

Similar Datasets

Project description:Performing GWAS on multiple myeloma in relation to the development of the toxicity neuropathy. This set was used as validation set. 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 therapy prior to autologous stem-cell transplantation and conducted validation in an independent cohort of 116 MM patients. We identified one previously unreported BiPN risk locus at 21q22.3 (rs2839629, PKNOX1; OR = 0.53, 95% CI: [0.40-0.69]). PKNOX1 is known to regulate MCP-1, a potent mediator of chemotherapy-induced peripheral neuropathy. rs2839629 is in strong linkage disequilibrium ( r2 = 0.87) with rs915854, localized 6.5kb centromeric to CBS encoding 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. Each patient of both IFM and HOVON cohorts was genotyped using the Affymetrix SNP6.0 Human DNA chip (Affymetrix, Santa Clara, CA) according to manufacturer’s instructions (Affymetrix, Santa Clara, CA). The HOVON65 samples were genotyped using CRLMM v2 resulting in a call rate higher than 95%. Unannotated SNPs according to the hg19 na32 SNP6 Affymetrix annotations (n= 130) along with SNPs from MT and sexual chromosomes (n= 37,326) were not considered in the study. To perform GWAS in the IFM cohort, we used stringent criteria to select a total of 370,605 SNPs from the 872,166 SNPs available onto the array. A SNP was analysed if an AA or BB genotype was present in more than 5% of patients, if its genotype was determined in at least 95% of the patients and if the Hardy-Weinberg rule was not rejected. Statistical analyses were performed using SNPTEST v2.5.11. Firstly, we compared 370,605 genotypes from 155 IFM patients with neuropathy (grade >= 2) after bortezomib exposure to 314 control patients treated with bortezomib who did not develop neuropathy (grade 0-1). Secondly, we performed a validation in the HOVON 65/GMMG-HD4cohort for the highest associated SNPs as identified in the discovery cohort. We compared 41 bortezomib-treated patients with neuropathy (grade >= 2) with 75 bortezomib-treated controls who did not develop neuropathy. We applied a one-sided logistic regression with 10,000 label swapping permutations to correct for multiple testing in order to confirm BiPN association in this independent cohort. This set was used as a validation set. An independent dataset was used for discovery [GSE65777].

Project description:Nineteen patients with steroid-refractory cGVHD (chronic graft versus host disease) received weekly bortezomib from 2 – 12 months (1.6 mg/m2 q wk x 4 followed by one week of rest). Treatment was well tolerated with no > grade 3 adverse events. Six patients achieved CR or good PR (gPR). Average Rodnan scores decreased from 22.6 ± 12.8 to 5.9 ± 6.2 (p<0.005) for 8 patients with sclerosis who completed > 2 treatments, including one patient with marked healing of suppurating lesions and significantly reduced chronic diarrhea in another. Thus, weekly bortezomib was safe and produced early improvements in some patients with longstanding refractory disease. CR or gPR correlated with a younger age and lower number of involved organs with a severity score of > 2. Based on gene expression array and pathway analyses, High Responders displayed an immune response profile that resembled that of hematopoietic stem cell-transplanted patients without cGVHD. By comparison, Low Responders showed markedly altered gene expressions in both cell-mediated immune response and proinflammatory pathways. Our preliminary findings suggest that bortezomib responsiveness may be predicated by distinct immunopathological manifestations among cGVHD patients. This trial was registered at www.clinicaltrials.gov as NCT01158105. Overall design: 54 total samples, 0 replicates, 8 healthy controls, 6 disease controls. Sample details follow. Eligible patients were 18 years or older with a confirmed clinical diagnosis of steroid-refractory cGVHD, defined as either failure to improve after 2 months or progression after 1 month of standard steroid-based therapy, and had no prior bortezomib treatment for cGVHD. Enrolled patients were required to be in remission from his/her primary malignancy for which HSCT was indicated, ECOG performance status < 3, life expectancy > 3 months, have not had myocardial infarction within 6 months prior to enrollment and not having received radiation therapy within 3 weeks, platelet count ≥ 50 x 10^9/L, absolute neutrophil count ≥ 1.0 x 10^9/L, total bilirubin ≤ 1.5x upper normal limit, creatinine clearance ≥ 30 mL/min and no peripheral neuropathy episodes (≥ Grade 2) within 14 days before enrollment. Patients with prior hypersensitivity to bortezomib, boron or mannitol were excluded from trial. Bortezomib was supplied in vials as open-label stock. Patients received Kytril premedication per institutional standards (1 mg intravenous/IV push) before start of VELCADE® (bortezomib; Millennium Pharmaceuticals) infusion (1.6 mg/m2). Bortezomib was administered on days 1, 8, 15, 22 of a 35-day cycle. Steroid dose that was in effect on Day 1 was maintained. All other agents given for GVHD treatment were withdrawn as tolerated. Patients with stable disease or better after two cycles continued for up to six cycles of bortezomib. Patients who continued to do well were eligible for up to six months of maintenance. Those patients continued on the same dose of bortezomib but on days 1 and 15 of a 28-day cycle. Followup after the final dose was for 6 months. Subjects were assessed for signs and symptoms of cGVHD on day 1 of each cycle by standardized criteria for cGVHD diagnosis, new clinical scoring system, and new guidelines for global assessment of cGVHD severity (NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD). Safety was assessed according to adverse event incidents for 30 days following the last dose for up to 6 months. Adverse events were recorded throughout the trial and followed by investigator until resolution. Enrolled patients also completed a neurotoxicity-directed questionnaire on presence and intensity of neuropathic pain and/or peripheral neuropathy from the patient's perspective. Responses were reviewed to assist with evaluation of onset and intensity of peripheral neuropathy and other neurotoxicities that may require intervention or dose modification. No change from baseline was considered as stable disease (SD). >50% improvement in any specific organ score or overall performance was considered partial response (PR). Disappearance of symptoms of cGVHD was considered complete response (CR). Worsening of symptoms in specific organ or overall observed in two consecutive assessment time points was considered as progressive disease (PD). All human subject-related study protocols were reviewed and approved by the institutional Review Board for Human Protection, Baylor University Medical Center. All patients signed informed consent before being enrolled into study. This trial was registered at www.clinicaltrials.gov as NCT01158105.

Project description:A rare complication of multiple myeloma is a secondary extramedullary involvement, and the skin is one of the possible sites, due to the physiological homing of plasma cells (PCs) into the skin. The article reports a case of a relapsed refractory MM patient, who developed a cutaneous localization after 16 months from the diagnosis under Bortezomib treatment without a leukemic phase. Patient was refractory to Bortezomib. We analyzed the gene expression profiles, the immunophenotypic and immunohistochemistry profiles of MM cells across the course of the disease at the bone marrow and skin localization. Data obtained were further expanded by an immunohistochemistry analysis on selected molecules in a large cohort of MM patients with cutaneous localization. In particular we focused on the expression of chemokines and chemokine receptors involved in the PC skin homing. The mechanisms behind the extramedullary spread and the formation of localizations outside the BM are not completely understood. Several studies investigated the expression profile of myeloma cells in the extramedullary localization by immunohistochemistry without a prospective molecular and immunohistochemistry study across the progression of the disease and consequently the development of extramedullary localization. This case indicates that the skin homing of MM cells could be related to the high CCR10 expression of at the diagnosis and relapse and the loss of CXCR4 surface expression across the progression of the disease in the contest of Bortezomib resistance. This data was further confirmed in a larger series of patients. Moreover, high expression of CD44, together with the down-regulation of CD54 and the lack of expression of CD56 by MM cells in the BM relapse with the re-acquisition of both antigens during the cutaneous relapse may be the mechanism that drives the escape from BM of PCs and their localization into the skin. Our data have identified a possible mechanism that drives the escape from BM of myeloma cells and their localization into the skin. Overall design: To investigate the genes differentially expressed in malignant plasma cells of a patient with relapsed refractory MM patient, who developed a cutaneous localization, we performed gene expression profiling using Affymetrix GeneChip analysis of plasma cells purified from the bone marrow aspirates at diagnosis and relapse.