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.

肿瘤 DNA 测序正在成为患者治疗决策的护理标准。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 名实体瘤患者的 21 个药物反应基因的体细胞突变的功能影响进行了分类。使用肿瘤和血液 DNA 变异等位基因分数 (VAF) 之间 10% 差异的阈值，异质基因型调用的一致性为 78%，使用 30% VAF 阈值则增加到 97.5%。在所有 21 个药物反应基因中均观察到体细胞突变，44% 的患者在这些基因中至少有一种体细胞突变。在肿瘤 DNA 中，8 名患者的CYP2C8存在移码突变，该突变负责代谢紫杉烷类药物。总体而言，体细胞拷贝数丢失比增加更频繁，包括拷贝数丢失最频繁的CYP2C19和CYP2D6 。然而， TPMT中的拷贝数增加是丢失的四倍多。7% 的患者的ABCB1拷贝数增加，ABCB1 是一种抗癌药物的多药耐药性转运蛋白。这些结果表明，仅针对肿瘤的 DNA 测序可能无法可靠地识别药物反应变异的种系基因型。