Genetic Susceptibility and Inflammatory Mechanisms in Bortezomib-Induced Peripheral Neuropathy: Insights From Whole...

Inter-individual variability in patient susceptibility to bortezomib (BTZ)-induced peripheral neuropathy (BIPN) suggests a potential role of genetic predisposition. However, the comprehensive mutational landscape and its functional relevance remain poorly defined. We aimed to characterize the genetic architecture and inflammatory mechanisms underlying BIPN in multiple myeloma (MM) patients. Whole exome sequencing (WES) was performed on peripheral blood mononuclear cells (PBMCs) from 20 newly diagnosed MM patients treated with BTZ, including eight patients who developed grade ≥ 2 BIPN and 12 controls without neuropathy. To functionally interpret genetic alterations, WES data were integrated with transcriptomic datasets from chemotherapy-induced peripheral neuropathy models obtained from GEO databases. Enrichment analyses and molecular docking were conducted to identify key driver genes and potential BTZ-protein interactions. WES identified 90,465 BIPN-associated single nucleotide polymorphisms, with a distinct co-mutation signature involving 33 zinc-finger (ZNF) family genes. Integrative multi-omics analysis yielded 100 candidate genes enriched in inflammatory response, neuronal development, synaptic organization, and MAPK/NF-κB signaling pathways. Three key genes-CACNA1H, CIC, and ABLIM2-were identified as potential driver genes and demonstrated direct binding affinity with BTZ in docking analyses. Notably, enrichment analyses also suggested shared molecular mechanisms between neurotoxicity and cardiotoxicity. Our findings revealed that inflammation-driven neuronal dysfunction mediated by genetic susceptibility represented a central mechanism of BIPN. Integrative genomic profiling might provide a framework for personalized risk assessment and precision management of BTZ-related neurotoxicity and associated organ toxicity.