A Genome Wide Association Study Reveals Genetic Predisposition for Bortezomib-Induced Peripheral Neuropathy in Multiple Myeloma by Variation in the PREP1-CBS locus.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE65777 | GEO | 2016/11/23
SECONDARY ACCESSION(S): PRJNA275004
REPOSITORIES: GEO
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.
2016-06-01 | GSE66903 | GEO
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 manufacturerâs 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].
2016-06-01 | E-GEOD-66903 | biostudies-arrayexpress
Project description:CIMP (CpG island methylator phenotype) is an epigenetic molecular subtype, observed in multiple malignancies and associated with the epigenetic silencing of tumour suppressors. Currently, for most cancers including gastric cancer [GC], mechanisms underlying CIMP remain poorly understood. We sought to discover molecular contributors to CIMP in GC, by performing global DNA methylation, gene expression, and proteomics profiling across 14 gastric cell lines, followed by similar integrative analysis in 50 GC cell lines and 467 primary GCs. We identify the cystathionine beta-synthase enzyme (CBS) as a highly recurrent target of epigenetic silencing in CIMP GC. Likewise, we show that CBS epimutations are significantly associated with CIMP in various other cancers, occurring even in premalignant gastroesophageal conditions and longitudinally linked to clinical persistence. Of note, CRISPR deletion of CBS in normal gastric epithelial cells induces widespread DNA methylation changes that overlap with primary GC CIMP patterns. Reflecting its metabolic role as a gatekeeper interlinking the methionine and homocysteine cycles, CBS loss in vitro also causes reductions in the anti-inflammatory gasotransmitter hydrogen sulphide (H2S), with concomitant increase in NF-κB activity. In a murine genetic model of CBS-deficiency, preliminary data indicate upregulated immune-mediated transcriptional signatures in the stomach. Our results implicate CBS as a bi-faceted modifier of aberrant DNA methylation and inflammation in GC and highlights H2S donors as a potential new therapy for CBS-silenced lesions.
2021-04-19 | GSE149411 | GEO
Project description:A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade M-bM-^IM-%2 PN. Gene expression profiles (GEP) of CD138+ plasma cells were analyzed from 122 VTD-treated patients. The incidence of grade M-bM-^IM-%2 PN was 35% in the VTD arm and 10% in the TD arm (p<0.001). PN resolved in 88% and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade M-bM-^IM-%2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTD-induced PN. 120 samples have been analyzed; the homogeneity of samples has been ensured by the immunomagnetic enrichment procedure: only >90% pure CD138+ cells have been employed.
2014-12-23 | E-GEOD-58133 | biostudies-arrayexpress
Project description:A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade ≥2 PN. Gene expression profiles (GEP) of CD138+ plasma cells were analyzed from 122 VTD-treated patients. The incidence of grade ≥2 PN was 35% in the VTD arm and 10% in the TD arm (p<0.001). PN resolved in 88% and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade ≥2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTD-induced PN.
2014-12-23 | GSE58133 | GEO
Project description:Hydrogen sulfide (H2S) is an endogenous gasotransmitter and is capable of regulating various endogenous signaling pathways, inculding inflamation and immune response. In mammals, H2S is mainly generated by two pyridoxal-5'-phosphate-dependent enzymes, termed cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). CBS-deficient mice showed autoimmune disorders. H2S play important roles in T cell development and differentiation, especially Treg cells development and differentiation. We used microarrays to detail the global gene expression of WT and CBS-deficient CD4+ T cells.
2015-07-22 | GSE59241 | GEO
Project description:Recents studies in mice and humans demonstrated the relevance of H2S-synthesising enzymes (such as CTH, CBS and MPST) in adipose tissue physiology and preadipocyte differentiation into adipocytes. Here, we aimed to investigate the combined role of CTH, CBS and MPST in the preservation of adipocyte protein persulfidation and adipogenesis. Joint CTH, CBS and MPST gene knockdown was achieved treating fully human adipocytes with siRNAs against these transcripts (siRNA_MIX). Adipocyte protein persulfidation was analyzed by a mass spectrometry label-free quantitative approach coupled with a dimedone-switch method for protein labeling and purification. The proteomic analysis quantified 216 proteins with statistically different persulfidation levels in KD cells compared to control adipocytes. In fully differentiated adipocytes, CBS and MPST mRNA and protein levels were abundant, whereas CTH expression was very low. Of note, siRNA_MIX administration resulted in a significant decrease in CBS and MPST expression, without impacting on CTH. Dual CBS and MPST gene knockdown resulted in decreased expression of relevant genes for adipocyte biology, including adipogenesis, mitochondrial biogenesis and lipogenesis, but increased proinflammatory- and senescence-related genes, in parallel to a significant disruption in adipocyte protein persulfidation pattern. While among less persulfidated proteins, we identified several relevant proteins for adipocyte adipogenesis and function, among the most persulfidated, key mediators of adipocyte inflammation and dysfunction, but also some proteins that might have a positive role of adipogenesis were found. In conclusion, current study indicates that joint knockdown of CBS and MPST (but not CTH) in adipocytes impairs adipogenesis and promotes inflammation, possibly by disrupting the pattern of protein persulfidation in these cells, and suggesting that these enzymes were required for the functional maintenance of adipocytes.
2022-08-12 | PXD032370 | Pride
Project description:Proteomics were used in this research to reveal the mechanisms by which cbs-derived H2S increased the fitness of V. cholerae in host against oxidative stress
2021-02-03 | PXD023949 | iProX
Project description:Bortezomib and thalidomide-based therapies have significantly contributed to improved survival of multiple myeloma (MM) patients. However, treatment-induced peripheral neuropathy (TiPN) is a common adverse event associated with them. Risk factors for TiPN in MM patients include advanced age, prior neuropathy, and other drugs, but there are conflicting results about the role of genetics in predicting the risk of TiPN. Thus, we carried out a genome-wide association study (GWAS) based on more than 300,000 exome single nucleotide polymorphisms (SNPs) in 172 MM patients receiving therapy involving bortezomib and thalidomide. We compared patients developing and not developing TiPN under similar treatment conditions (GEM05>65, NCT00443235). The highest-ranking SNP was rs45443101, located in the PLCG2 gene, but no significant differences were found after multiple comparison correction (adjusted p=0.1708). Prediction analyses, cytoband enrichment and pathway analyses were also performed, but none yielded any significant findings. A copy number approach was also explored, but this gave no significant results either. In summary, our study did not find a consistent genetic component associated with TiPN under bortezomib and thalidomide therapy that could be used for prediction, which makes clinical judgment essential in the practical management of MM treatment
2018-04-30 | GSE80278 | GEO
Project description:Hydrogen sulfide (H2S) is an endogenous gasotransmitter and is capable of regulating various endogenous signaling pathways, inculding inflamation and immune response. In mammals, H2S is mainly generated by two pyridoxal-5’-phosphate-dependent enzymes, termed cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE). CBS-deficient mice showed autoimmune disorders. H2S play important roles in T cell development and differentiation, especially Treg cells development and differentiation. We used microarrays to detail the global gene expression of WT and CBS-deficient CD4+ T cells. CD4+ T cells from WT and CBS-deficient mice were isolated for RNA extraction and hybridization on Affymetrix microarrays. We sought to obtain the homogeneous populations of mice at 6 weeks in order to increase the temporal resolution of expression profiles.
2015-07-22 | E-GEOD-59241 | biostudies-arrayexpress