Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients

Corthals, Sophie L.; Kuiper, Rowan; Johnson, David C.; Sonneveld, Pieter; Hájek, Roman; Holt, Bronno van der; Magrangeas, Florence; Goldschmidt, Hartmut; Morgan, Gareth J.; Avet-Loiseau, Hervé

doi:10.3324/haematol.2011.041434

Cited by 51 publications

(28 citation statements)

References 25 publications

(27 reference statements)

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“…The present pharmacogenomics GWA study also confirmed the modest association of the rs619824 genotype with BiPN ( P =0.043) previously identified by Corthals and colleagues (8). Although there has been no overlap with a previous study on late-onset of BiPN associated variants reported by Broyl and colleagues (10) as shown in Supplementary Table S4.…”

Section: Resultssupporting

confidence: 92%

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

Magrangeas

Kuiper

Avet-Loiseau

et al. 2016

Clinical Cancer Research

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Purpose Painful peripheral neuropathy is a frequent toxicity associated with bortezomib therapy. This study aimed to identify loci that affect susceptibility to this toxicity. Experimental Design 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 multiple myeloma (MM) patients who received bortezomib-dexamethasone therapy prior to autologous stem-cell in randomized clinical trials of the Intergroupe Francophone du Myelome (IFM) and findings were replicated in 114 MM patients of the HOVON-65/GMMG-HD4 clinical trial. Results A single SNP in the PKNOX1 gene was associated with BiPN in the exploratory cohort (rs2839629; OR, 1.89, 95% CI: [1.45-2.44]; P = 7.6 × 10−6) and in the replication cohort (OR, 2.04; 95% CI = [1.11-3.33]; P= 8.3 × 10−3). In addition, rs2839629 is in strong linkage disequilibrium (r2 = 0.87) with rs915854, located in the intergenic region between PKNOX1 and CBS. Expression quantitative trait loci mapping showed that both rs2839629 and rs915854 genotypes impact PKNOX1 expression in nerve tissue while rs2839629 affects CBS expression in skin and blood. Conclusions The use of GWAS in MM pharmacogenomics has identified a novel candidate genetic locus mapping to PKNOX1 and in the immediate vicinity of CBS at 21q22.3 associated with the severe bortezomib-induced toxicity. The proximity of these two genes involved in neurologic pain whose tissue-specific expression is modified by the two variants provides new targets for neuro-protective strategies.

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Section: Resultssupporting

confidence: 92%

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

Magrangeas

Kuiper

Avet-Loiseau

et al. 2016

Clinical Cancer Research

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“…Bortezomib inhibits the proteasome within PCs, resulting in inability to degrade misfolded proteins, which eventually leads to apoptosis. While Bortezomib has shown promise in reducing disease activity and decreasing autoAbs concentrations while increasing complement levels [71], this drug has been associated with serious neurotoxicity [73]. …”

Section: Therapiesmentioning

confidence: 99%

The pathogenesis, diagnosis and treatment of lupus nephritis

Schwartz

Goilav

Putterman

2014

Current Opinion in Rheumatology

114

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Purpose of review Renal involvement is a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). In this review we provide an update on recent discoveries in the pathogenesis, diagnosis, and treatment of lupus nephritis (LN). Recent findings Localized long-lived plasma cells have been identified as playing an important role in LN. In addition, the roles of aberrant expression of microRNAs and pro-inflammatory cytokines have been explored. Early diagnosis is important for effective treatment and multiple biomarkers have been identified; however, none have been yet validated for clinical use. Biomarker panels may turn out to be more accurate than each individual component. Biologic agents for the treatment of LN are being studied, including Belimumab which was recently approved for non-renal SLE. Rituximab has not proven itself in large, placebo-controlled trials, although it is still being used in refractory cases of LN. Summary LN is a potentially devastating complication of SLE. Immune cells, cytokines, and epigenetic factors have all been recently implicated in LN pathogenesis. These recent discoveries may enable a paradigm shift in the treatment of this complex disease, allowing the tailoring of treatment to target specific pathogenic mediators at specific points in time in the progression of disease.

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“…We initiated this study to determine whether SC administration of bortezomib could decrease the incidence of Pn in Korean patients. Genetic factors, including single-nucleotide polymorphisms (SnPs) in CYP families, CDKn1B, tnFα, IKBKaP, and the CtLa4 gene [11], are known to be associated with BIPn. the frequency of some SnPs, such as rs11466155 and rs228851, varies across ethnic groups.…”

Section: Discussionmentioning

confidence: 99%

Bortezomib-associated peripheral neuropathy requiring medical treatment is decreased by administering the medication by subcutaneous injection in Korean multiple myeloma patients

Koh

Lee

Kim

et al. 2014

Cancer Chemother Pharmacol

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Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients

Abstract: In addition, a dataset based on the patients from the HOVON-65/GMMG-HD4 trial were used as a validation set.11

Cited by 51 publications

References 25 publications

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

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

The pathogenesis, diagnosis and treatment of lupus nephritis

Bortezomib-associated peripheral neuropathy requiring medical treatment is decreased by administering the medication by subcutaneous injection in Korean multiple myeloma patients

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