RWDD3 and TECTA variants not linked to paclitaxel induced peripheral neuropathy in North American trial Alliance N08C1

Abstract

Chemotherapy induced peripheral neuropathy (CIPN) is a dose limiting toxicity of paclitaxel, termed here paclitaxel induced peripheral neuropathy (PIPN). PIPN affects a minority of patients and cannot be predicted from clinical patient characteristics. Therefore, a phamacogenomic basis has been proposed for PIPN (1). Genome wide association studies (GWAS) provide an unbiased approach for the identification of novel genetic loci associated with complex traits (2). Schneider et al. performed the first PIPN GWAS in 2011, (3) finding that the risk of PIPN was linked to two single nucleotide variants (SNV) in two genes that had previously not been known to be associated with this condition or with CIPN due to any other drug. The SNV rs2296308 in RWDD3 was reported to be associated with PIPN with a HR=1.5 and a significance level of p=8.5 × 10−8. The rs1829 SNV in TECTA was reported to be associated with PIPN with a HR= 2.1 and a significance level of p=3.2×10−7. Both SNV thereby passed the threshold set by the authors for genome-wide significance thereby representing important novel PIPN gene candidates. Bergmann et al. investigated rs2296308 and rs1829 in a Scandinavian ovarian cancer patient cohort (4). Their study failed to corroborate the report by Schneider et al., thereby calling that GWAS result into question. The original GWAS consisted of a very large cohort, 2204 patients, while the validation attempt by Bergmann et al. was limited to a smaller cohort of 241 patients. Both studies used similar phenotyping and analyses relying on Common Toxicity Criteria Adverse Effects (CTCAE) reporting of toxicity and time-to-grade 2 or worse scores as the primary endpoint. These conflicting results thereby created uncertainty in the field regarding the role of RWWD3 and TECTA. We recently reported a new PIPN cohort, N08C1, for which improved phenotyping was available using serial assessments of PIPN symptoms with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) CIPN-20 (CIPN20) (5). Here, we report testing of the association of rs2296308 in RWWD3 and rs1829 in TECTA with PIPN in N08C1.