Cumulative genetic risk predicts platinum/taxane-induced neurotoxicity

McWhinney-Glass, S., Winham, S.J., Hertz, D.L., Yen Revollo, J., Paul, J. , He, Y., Brown, R., Motsinger-Reif, A.A. and McLeod, H.L. (2013) Cumulative genetic risk predicts platinum/taxane-induced neurotoxicity. Clinical Cancer Research, 19(20), pp. 5769-5776. (doi: 10.1158/1078-0432.CCR-13-0774)

Abstract

Purpose: The combination of a platinum and taxane are standard of care for many cancers, but the utility is often limited due to debilitating neurotoxicity. We examined whether single-nucleotide polymorphisms (SNP) from annotated candidate genes will identify genetic risk for chemotherapy-induced neurotoxicity.<p></p> Patients and Methods: A candidate–gene association study was conducted to validate the relevance of 1,261 SNPs within 60 candidate genes in 404 ovarian cancer patients receiving platinum/taxane chemotherapy on the SCOTROC1 trial. Statistically significant variants were then assessed for replication in a separate 404 patient replication cohort from SCOTROC1.<p></p> Results: Significant associations with chemotherapy-induced neurotoxicity were identified and replicated for four SNPs in SOX10, BCL2, OPRM1, and TRPV1. The population attributable risk for each of the four SNPs ranged from 5% to 35%, with a cumulative risk of 62%. According to the multiplicative model, the odds of developing neurotoxicity increase by a factor of 1.64 for every risk genotype. Patients possessing three risk variants have an estimated OR of 4.49 (2.36–8.54) compared to individuals with 0 risk variants. Neither the four SNPs nor the risk score were associated with progression-free survival or overall survival.<p></p> Conclusions: This study shows that SNPs in four genes have a significant cumulative association with increased risk for the development of chemotherapy-induced neurotoxicity, independent of patient survival. <p></p>

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Paul, Mr James
• Authors: McWhinney-Glass, S., Winham, S.J., Hertz, D.L., Yen Revollo, J., Paul, J., He, Y., Brown, R., Motsinger-Reif, A.A., and McLeod, H.L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Clinical Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 1078-0432