Taxane-induced sensory peripheral neuropathy is associated with an SCN9A single nucleotide polymorphism in Japanese patients

Abstract

Background: Sodium channels located in the dorsal root ganglion, particularly Nav1.7 and Nav1.8, encoded by SCN9A and SCN10A, respectively, act as molecular gatekeepers for pain detection. Our aim was to determine the association between TIPN and SCN9A and SCN10A polymorphisms. Methods: Three single nucleotide polymorphisms (SNPs) in SCN9A and two in SCN10A were investigated using wholegenome genotyping data from 186 Japanese breast or ovarian cancer patients classified into two groups as follows: cases that developed taxane-induced grade 2-3 neuropathy (N = 108) and controls (N = 78) with grade 0-1 neuropathy. Multiple logistic regression analyses were conducted to evaluate associations between TIPN and SNP genotypes. Results: SCN9A-rs13017637 was a significant predictor of grade 2 or higher TIPN (odds ratio (OR) = 3.463; P = 0.0050) after correction for multiple comparisons, and precision was improved when only breast cancer patients were included (OR 5.053, P = 0.0029). Moreover, rs13017637 was a significant predictor of grade 2 or higher TIPN 1 year after treatment (OR 3.906, P = 0.037), indicating its contribution to TIPN duration. Conclusion: SCN9A rs13017637 was associated with the severity and duration of TIPN. These findings are highly exploratory and require replication and validation prior to any consideration of clinical use.

Pharmacogenetics of taxane‐induced neurotoxicity in breast cancer: Systematic review and meta‐analysis

“…Fifteen of them were nested designs coming from randomized controlled trials (5 case controls 7 , 23 , 24 , 25 , 26 and 10 cohorts 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ), 17 were cohort studies, 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 and 10 were case‐control studies. 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 The studies were conducted in the United States (15 studies 24 , 26 , 27 , 31 , 34 , 35 , 36 , 42 , 48 , ...…”

“…Three studies involved more than one country. 30 , 43 , 47 Studied patients were most commonly White (22 studies 7 , 23 , 27 , 28 , 29 , 30 , 32 , 33 , 36 , 38 , 39 , 43 , 44 , 47 , 49 , 53 , 54 , 55 , 56 , 59 , 60 , 62 ), followed by Asians (5 studies 25 , 37 , 40 , 41 , 45 ), Middle Easterners (2 studies 46 , 58 ) and African Americans (1 study 26 ). Ten studies included patients of more than one ethnicity, 24 , 31 , 34 , 35 , 42 , 48 , 51 , 52 , 61 , 63 and two did not report ethnicity.…”

Biomarkers of Chemotherapy-Induced Peripheral Neuropathy: Current Status and Future Directions

“…Disturbance in neuronal function through ion channels may also contribute to CIPN, and alterations in these genes have been associated with CIPN sensitivity ( 1 , 73 , 77 ). In 186 Japanese breast and ovarian cancer patients treated with taxanes a SNP in SCN9A , encoding voltage-gated sodium channels, was associated with developing ≥grade 2 CIPN, and predicted CIPN persistence post-treatment ( 56 ). In 94 Spanish patients with gastrointestinal cancer treated with oxaliplatin another polymorphism in SCN9A was associated with a lower risk of acute CIPN by neurologic evaluation ( 57 ), and in 228 South Indian gastrointestinal cancer patients treated with oxaliplatin it was associated with increased incidence of chronic CIPN ( 58 ).…”

Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces and prevents pain chronification in a mouse model of oxaliplatin-induced neuropathic pain

“…Furthermore, silencing NaV1.7 expression using either a zinc finger protein or a CRISPR construct targeting Scn9a , the gene encoding NaV1.7, resulted in robust reversal of the neuropathic pain phenotype in mice with CIPN ( Moreno et al, 2021 ). Interestingly, another report identified a single nucleotide polymorphism in a Japanese family that predisposed patients to development of CIPN following treatment with drugs in the taxane class ( Tanabe et al, 2020 ). These findings support a crucial role for NaV1.7 in mediating development of sensory neuropathy following treatment with anti-neoplastic agents and suggests targeting NaV1.7 is a viable strategy for ameliorating CIPN associated pain.…”