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Sequencing of genes of drug response in tumor DNA and implications for precision medicine in cancer patients


Tumor DNA sequencing is becoming standard-of-care for patient treatment decisions. We evaluated genotype concordance between tumor DNA and genomic DNA from blood and catalogued functional effects of somatic mutations in 21 drug response genes in 752 solid tumor patients. Using a threshold of 10% difference between tumor and blood DNA variant allele fraction (VAF), concordance for heterogenous genotype calls was 78% and increased to 97.5% using a 30% VAF threshold. Somatic mutations were observed in all 21 drug response genes, and 44% of patients had at least one somatic mutation in these genes. In tumor DNA, eight patients had a frameshift mutation in CYP2C8, which metabolizes taxanes. Overall, somatic copy number losses were more frequent than gains, including for CYP2C19 and CYP2D6 which had the most frequent copy number losses. However, copy number gains in TPMT were more than four times as common as losses. Seven % of patients had copy number gains in ABCB1, a multidrug resistance transporter of anti-cancer agents. These results demonstrate tumor-only DNA sequencing might not be reliable to call germline genotypes of drug response variants.

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Fig. 1: Concordance in genotype calling between tumor and blood DNA for variants in genes of drug response.
Fig. 2: Somatic mutations and CNAs within genes of drug response in cancer patients.
Fig. 3: Somatic mutations (N = 65) occurring in more than one tumor.

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Data availability

Sequencing data is available in dbGaP (accession number: phs001713.v1.p.1).

Code availability

Available upon request.


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Research in this publication was supported by the University of North Carolina (UNC) University Cancer Research Fund (UCRF) and the UNC Integrative Translational Science Center grant (NCI UG1 CA233333).

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Authors and Affiliations



NG, JSP, and FI were responsible for designing the study, analyzing the data, and writing, reviewing, and editing the manuscript. ASE and SAP were responsible for analyzing the data, and writing, reviewing, and editing the manuscript. DNH and MCH were responsible for the study design, collecting the data, and reviewing and editing the manuscript.

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Correspondence to Amy S. Etheridge.

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Dr. Innocenti is an AbbVie employee and receives stocks from the company. The other authors disclose no conflicts of interest relevant to this manuscript.

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Gillis, N., Etheridge, A.S., Patil, S.A. et al. Sequencing of genes of drug response in tumor DNA and implications for precision medicine in cancer patients. Pharmacogenomics J 23, 73–81 (2023).

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