Polygenic risk of paclitaxel-induced peripheral neuropathy: a genome-wide association study

Abstract

Background Genetic risk factors for chemotherapy-induced peripheral neuropathy (CIPN), a major dose-limiting side-effect of paclitaxel, are not well understood. Methods We performed a genome-wide association study (GWAS) in 183 paclitaxel-treated patients to identify genetic loci associated with CIPN assessed via comprehensive neuropathy phenotyping tools (patient-reported, clinical and neurological grading scales). Bioinformatic analyses including pathway enrichment and polygenic risk score analysis were used to identify mechanistic pathways of interest. Results In total, 77% of the cohort were classified with CIPN (n = 139), with moderate/severe neuropathy in 36%. GWAS was undertaken separately for the three measures of CIPN. GWAS of patient-reported CIPN identified 4 chromosomal regions that exceeded genome-wide significance (rs9846958, chromosome 3; rs117158921, chromosome 18; rs4560447, chromosome 4; rs200091415, chromosome 10). rs4560447 is located within a protein-coding gene, LIMCH1, associated with actin and neural development and expressed in the dorsal root ganglia (DRG). There were additional risk loci that exceeded the statistical threshold for suggestive genome-wide association (P < 1 × 10–5) for all measures. A polygenic risk score calculated from the top 46 ranked SNPs was highly correlated with patient-reported CIPN (r2 = 0.53; P = 1.54 × 10–35). Overlap analysis was performed to identify 3338 genes which were in common between the patient-reported CIPN, neurological grading scale and clinical grading scale GWAS. The common gene set was subsequently analysed for enrichment of gene ontology (GO) and Reactome pathways, identifying a number of pathways, including the axon development pathway (GO:0061564; P = 1.78 × 10–6) and neuronal system (R-HSA-112316; adjusted P = 3.33 × 10–7). Conclusions Our findings highlight the potential role of axon development and regeneration pathways in paclitaxel-induced CIPN.

Taxane-Induced Peripheral Neuropathy among Early-Stage Breast Cancer Survivors : Prevalence, Risk Factors, Quality of Life and Genetic Prediction Models

“…We found two previously published polygenic prediction models, one based on a 267 SNVs cluster (274) and the other on GWAS with neuropathy and pathway analysis for mechanistic pathways (275). None of these were validated in a test cohort and the one based on SNVs cluster predicted 96.1% accuracy suggesting overfitting.…”

Peripheral Neuropathy in Cancer Patients- Multifactorial Contributors to Dose Limiting and Chronic Toxicity

“…Importantly, polygenic risk factors are likely important in determining CIPN risk, although precise pharmacogenetic pathways have yet to elucidated (51). Genetic contribution to CIPN risk may be agent-specific, due to the different pathophysiological mechanisms associated with neurotoxicity development (52). Multiple single-nucleotide polymorphisms (SNPs) have been associated with CIPN, although meta-analysis failed to find consistent associations, likely related to use of different outcome measures (53).…”

Plasma Lipidomic Profiling Identifies Elevated Triglycerides as Potential Risk Factor in Chemotherapy-Induced Peripheral Neuropathy

“…5 While CIPN severity is broadly influenced by the chemotherapy agent, treatment duration, and dosage, these aspects alone do not explain the various susceptibilities of patients in developing severe and persistent CIPN. 6 Genetic, lifestyle, and metabolic factors have been implicated with CIPN risk with varying levels of evidence, 7 including older age, 8 genetic polymorphisms, 9 obesity, 10,11 and diabetes. 12 Importantly, diabetes and obesity are major metabolic drivers of peripheral neuropathy (PN).…”