Identification of a TOP3A genetic variant as a novel biomarker for sensitivity to doxorubicin.

Doxorubicin (DOX), though an effective cytostatic drug, is associated with dose limiting toxicities. Consequently, mandated cumulative-dose restriction may result in compromised tumour control. Improved characterisation of interindividual DOX sensitivity could enable more precise, patient-tailored therapy. We therefore assessed DOX sensitivity in human lymphoblastoid cell lines (LCLs) in relation to common genetic variability in candidate genes encoding five human topoisomerases, putative molecular targets of DOX. EC50 values for DOX cytotoxicity were determined in 184 LCLs of European ancestry via fluorescence-activated cell sorting. The cohort was split into a training (n = 120) and an independent test (n = 64) set. Comprehensive genotype data were retrieved from the 1,000 Human Genome and the HapMap Project. Across TOP1, TOP2A, TOP2B, TOP3A, and TOP3B, 1,126 polymorphic sites were identified, with 468 at a minor allele frequency (MAF) ≥ 5%. Associations with EC50 in the training set were ranked by p-value and evaluated in the test set using a Bonferroni-corrected significance threshold. In the training set, 12 genetic markers showed associations at p < 0.05 with DOX EC50 values. One of these, rs113270903 in TOP3A, replicated in the test set after multiple testing correction. Variant T-allele carriers (CT or TT) exhibited approximately 30% lower DOX EC50 than CC homozygotes in both the training and the test sets. Comprehensive analysis of common diversity in genetic loci coding for human topoisomerases identified rs113270903 in TOP3A as a new promising determinant of DOX sensitivity.