PURPOSE: To indentify genetic variation that can modulate and predict the risk of developing thalidomide-related peripheral neuropathy (TrPN). PATIENTS AND METHODS: We analyzed DNA from 1,495 patients with multiple myeloma. Using a custom-built single nucleotide polymorphism (SNP) array, we tested the association of TrPN with 3,404 SNPs. The SNPs were selected in predicted functional regions within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response, and adverse effects associated with myeloma and its therapy. Patient cases and controls were derived from two large clinical trials that compared thalidomide with conventional-based treatment in myeloma patients (Medical Research Council Myeloma-IX and HOVON-50/GMMG-HD3). RESULTS: We report TrPN associations with SNPs-ABCA1 (rs363717), ICAM1 (rs1799969), PPARD (rs2076169), SERPINB2 (rs6103), and SLC12A6 (rs7164902)-where we show cross validation of the associations in both trials. To investigate whether TrPN SNP associations were related to exposure to thalidomide only or general drug-related peripheral neuropathy, we performed a second analysis on patients treated with vincristine. We report SNPs associated with vincristine neuropathy, with a seemingly distinct underlying genetic mechanism. CONCLUSION: Our results are consistent with the hypothesis that an individual's risk of developing a peripheral neuropathy after thalidomide treatment can be mediated by polymorphisms in genes governing repair mechanisms and inflammation in the peripheral nervous system. These findings will contribute to the development of future neuroprotective strategies with thalidomide therapy and the better use of this important compound.
PURPOSE: To indentify genetic variation that can modulate and predict the risk of developing thalidomide-related peripheral neuropathy (TrPN). PATIENTS AND METHODS: We analyzed DNA from 1,495 patients with multiple myeloma. Using a custom-built single nucleotide polymorphism (SNP) array, we tested the association of TrPN with 3,404 SNPs. The SNPs were selected in predicted functional regions within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response, and adverse effects associated with myeloma and its therapy. Patient cases and controls were derived from two large clinical trials that compared thalidomide with conventional-based treatment in myelomapatients (Medical Research Council Myeloma-IX and HOVON-50/GMMG-HD3). RESULTS: We report TrPN associations with SNPs-ABCA1 (rs363717), ICAM1 (rs1799969), PPARD (rs2076169), SERPINB2 (rs6103), and SLC12A6 (rs7164902)-where we show cross validation of the associations in both trials. To investigate whether TrPN SNP associations were related to exposure to thalidomide only or general drug-related peripheral neuropathy, we performed a second analysis on patients treated with vincristine. We report SNPs associated with vincristineneuropathy, with a seemingly distinct underlying genetic mechanism. CONCLUSION: Our results are consistent with the hypothesis that an individual's risk of developing a peripheral neuropathy after thalidomide treatment can be mediated by polymorphisms in genes governing repair mechanisms and inflammation in the peripheral nervous system. These findings will contribute to the development of future neuroprotective strategies with thalidomide therapy and the better use of this important compound.
Authors: Alexandre Chan; Daniel L Hertz; Manuel Morales; Elizabeth J Adams; Sharon Gordon; Chia Jie Tan; Nathan P Staff; Jayesh Kamath; Jeong Oh; Shivani Shinde; Doreen Pon; Niharkia Dixit; James D'Olimpio; Cristina Dumitrescu; Margherita Gobbo; Kord Kober; Samantha Mayo; Linda Pang; Ishwaria Subbiah; Andreas S Beutler; Katherine B Peters; Charles Loprinzi; Maryam B Lustberg Journal: Support Care Cancer Date: 2019-07-30 Impact factor: 3.603
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Authors: Florence Magrangeas; Rowan Kuiper; Hervé Avet-Loiseau; Wilfried Gouraud; Catherine Guérin-Charbonnel; Ludovic Ferrer; Alexandre Aussem; Haytham Elghazel; Jérôme Suhard; Henri Der Sakissian; Michel Attal; Nikhil C Munshi; Pieter Sonneveld; Charles Dumontet; Philippe Moreau; Mark van Duin; Loïc Campion; Stéphane Minvielle Journal: Clin Cancer Res Date: 2016-04-08 Impact factor: 12.531