A meta-analysis GWAS of taxane-induced peripheral neuropathy in patients with breast cancer.

Abstract

12089 Background: Taxane-induced peripheral neuropathy (TIPN) is a common dose-limiting toxicity in the medical management of breast cancer patients. Despite the clinical efficacy of taxane treatment, there is significant heterogeneity in the development of neuropathy and its severity, and no clear genetic etiologies have yet been identified. We sought to discover genetic risk variants in two large electronic health record linked DNA biobanks. Methods: A meta-analysis genome wide association study (GWAS) was performed with participants in the All of Us Research Program and BioVU biobanks. All participants of the study population were of female sex at birth and had a breast cancer diagnosis. Cases were defined as taxane-exposed participants who received their first neuropathy diagnosis code within one year after first taxane exposure. Controls were defined as taxane-exposed participants without a neuropathy diagnosis code and without gabapentin initiation after taxane exposure. GWAS was performed with PLINK version 2.0 using age at taxane initiation, number of taxane cycles received, and the first 10 principal components as covariates. Expression quantitative trait loci (eQTL) analysis was performed with the GTEx 8.0 and EyeGEx databases. Results: The All of Us cohort had 196 cases and 254 controls. The BioVU cohort had 244 cases and 528 controls. In our meta-analysis GWAS, rs3065465 (chr11:69138693; closest gene by distance is LOC338694) was associated with TIPN (OR=2.14, P= 8.27E-09) and was similar across different genetic ancestries (Table). The eQTL analysis of rs3065465 shows significant association with mRNA expression of TPCN2(P= 6.44E-06), a cation channel involved in neuronal differentiation and intracellular calcium homeostasis. Conclusions: rs3065465 represents a potential novel genetic marker for TIPN risk in breast cancer patients.[Table: see text]