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Updated: May 31, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Identification of a TOP3A genetic variant as a novel biomarker for sensitivity to doxorubicin
Tana Takacova1,2, Markus Anton Schirmer2,3
1Asklepios Tumorzentrum Hamburg, Hamburg, Germany.
Introduction:
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.
Methods:
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.
Results:
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.
Conclusion:
Comprehensive analysis of common diversity in genetic loci coding for human topoisomerases identified rs113270903 in TOP3A as a new promising determinant of DOX sensitivity.
Insights
Genetic variations in topoisomerase genes influence Doxorubicin (DOX) sensitivity. A specific marker in TOP3A (rs113270903) was identified, predicting patient response to this chemotherapy drug.
Area of Science:
- Pharmacogenomics
- Cancer Therapeutics
- Molecular Biology
Background:
- Doxorubicin (DOX) is an effective chemotherapy drug but has dose-limiting toxicities, potentially compromising tumor control.
- Understanding interindividual DOX sensitivity is crucial for developing precise, patient-tailored therapies.
- Topoisomerases are key molecular targets of DOX, making their genetic variability a focus for sensitivity studies.
Purpose of the Study:
- To assess Doxorubicin (DOX) sensitivity in human lymphoblastoid cell lines (LCLs).
- To investigate the relationship between DOX sensitivity and common genetic variations in genes encoding human topoisomerases (TOP1, TOP2A, TOP2B, TOP3A, TOP3B).
- To identify genetic markers that predict patient response to DOX therapy.
Main Methods:
- Determined DOX EC50 values for cytotoxicity in 184 LCLs using fluorescence-activated cell sorting.
- Utilized genotype data from the 1,000 Genomes and HapMap Projects for 1,126 polymorphic sites across five topoisomerase genes.
- Split the cohort into training (n=120) and independent test (n=64) sets to validate findings, applying Bonferroni correction for multiple testing.
Main Results:
- Identified 12 genetic markers associated with DOX EC50 in the training set (p < 0.05).
- rs113270903 in the TOP3A gene replicated significantly in the independent test set.
- Individuals carrying the T-allele of rs113270903 showed approximately 30% lower DOX EC50, indicating increased sensitivity.
Conclusions:
- Common genetic diversity in topoisomerase loci can significantly influence DOX sensitivity.
- rs113270903 in TOP3A is a novel genetic determinant of DOX sensitivity.
- This finding supports the potential for genotype-guided Doxorubicin therapy to optimize treatment outcomes.
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