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

IF 2.9 3区 医学 Q2 GENETICS & HEREDITY Pharmacogenomics Journal Pub Date : 2023-01-28 DOI:10.1038/s41397-023-00299-7
Nancy Gillis, Amy S. Etheridge, Sushant A. Patil, D. Neil Hayes, Michele C. Hayward, J. Todd Auman, Joel S. Parker, Federico Innocenti
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Abstract

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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肿瘤 DNA 中的药物反应基因测序及其对癌症患者精准医疗的影响
肿瘤 DNA 测序正成为患者治疗决策的标准。我们评估了肿瘤DNA和血液基因组DNA之间的基因型一致性,并对752名实体瘤患者中21个药物反应基因的体细胞突变的功能影响进行了编目。以肿瘤和血液DNA变异等位基因比例(VAF)相差10%为阈值,异源基因型调用的一致性为78% ,以30% VAF 为阈值,一致性提高到97.5%。在所有 21 个药物反应基因中都观察到了体细胞突变,44% 的患者在这些基因中至少有一个体细胞突变。在肿瘤DNA中,有8名患者的CYP2C8发生了框架移位突变,而CYP2C8可代谢紫杉类药物。总体而言,体细胞拷贝数丢失比拷贝数增加更频繁,其中CYP2C19和CYP2D6的拷贝数丢失最为频繁。然而,TPMT的拷贝数增益是拷贝数丢失的四倍多。7%的患者存在抗癌药多药耐药性转运体ABCB1的拷贝数增加。这些结果表明,仅通过肿瘤DNA测序来确定药物反应变异的种系基因型可能并不可靠。
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来源期刊
Pharmacogenomics Journal
Pharmacogenomics Journal 医学-药学
CiteScore
7.20
自引率
0.00%
发文量
35
审稿时长
6-12 weeks
期刊介绍: The Pharmacogenomics Journal is a print and electronic journal, which is dedicated to the rapid publication of original research on pharmacogenomics and its clinical applications. Key areas of coverage include: Personalized medicine Effects of genetic variability on drug toxicity and efficacy Identification and functional characterization of polymorphisms relevant to drug action Pharmacodynamic and pharmacokinetic variations and drug efficacy Integration of new developments in the genome project and proteomics into clinical medicine, pharmacology, and therapeutics Clinical applications of genomic science Identification of novel genomic targets for drug development Potential benefits of pharmacogenomics.
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