Sodium channels located in the dorsal root ganglion (DRG), particularly Nav1.7, act as molecular gatekeepers for pain detection. Nav1.7, predominantly expressed in the DRG pain-sensing neurons and sympathetic ganglia neurons, is encoded by SCN9A. Several SCN9A sodium channelopathies have been recognized as the cause of paroxysmal extreme pain disorder and primary erythromelalgia. Hence, the aim of this study was to determine a possible association between paclitaxel-induced peripheral neuropathy (PIPN) and SCN9A polymorphisms.
Three SNPs in SCN9A were prospectively investigated by using the whole-genome genotyping data of 186 Japanese patients with breast and ovarian cancer. PIPN was assessed according to the National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) ver 4.0. The peripheral venous blood of these patients was sampled for genotyping with the iScan System and the BeadChip HumanOmniExpressExome-8 v1.1 (Illumina K.K.). Multiple linear regression analyses were conducted. The dependent variable was the maximum NCI-CTC grade (grades 0-1 or 2-3), and the independent variables were the status of breast cancer, age, latency to PIPN, and genotype data of each SNP; or the dependent variable was the NCI-CTC grade one year after treatment, and the independent variables were the maximum NCI-CTC grade, duration of PIPN, and genotype data of each SNP.
Of the 3 SNPs evaluated, SCN9A rs13017637 was found to be a significant predictor of grade 2 or higher PIPN (Odds ratio (OR) 3.463, p = 0.0050) after correction of multiple comparisons, and the precision was greater when only breast cancer patients were included in the analysis (OR 5.053, p = 0.0029). Moreover, rs13017637 was found to be a significant predictor of grade 2 or higher PIPN one year after treatment (OR 3.906, p = 0.037), indicating the contribution of this SNP to duration of PIPN.
Our results suggest that a SCN9A variant, SCN9A rs13017637, may be associated with the severity and duration of PIPN. These findings may help clinicians determine which patients should avoid paclitaxel.
Clinical trial identification
Legal entity responsible for the study
Scientific Research Grant of the Ministry of Health, Labor and Welfare (H21- 021), and the National Cancer Center Research and Development Fund (23-A-30, 26-A-20)
Y. Fujiwara: Grants from Taiho Pharmaceutical Co. Ltd, Takeda Pharmaceutical Company Ltd, Takeda Bio Development Center Ltd, Chugai Pharmaceutical Co Ltd and EliLilly Japan KK. C. Shimizu: Grants from EliLilly Japan KK and Pfizer. All other authors have declared no conflicts of interest.