Computational pharmacogenotype extraction from clinical next-generation sequencing.
Computational pharmacogenotype extraction from clinical next-generation sequencing.
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DOI：
10.3389/fonc.2023.1199741
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发表时间：
2023
影响因子：
4.7
通讯作者：
Skaar, Todd C.
中科院分区：
文献类型：
--
作者：
Shugg, Tyler;Ly, Reynold C.;Osei, Wilberforce;Rowe, Elizabeth J.;Granfield, Caitlin A.;Lynnes, Ty C.;Medeiros, Elizabeth B.;Hodge, Jennelle C.;Breman, Amy M.;Schneider, Bryan P.;Sahinalp, S. Cenk;Numanagic, Ibrahim;Salisbury, Benjamin A.;Bray, Steven M.;Ratcliff, Ryan;Skaar, Todd C.
关键词：
下一代测序（NGS），包括全基因组测序（WGS）和全外显子组测序（WES），正越来越多地用于临床护理。虽然NGS数据有可能被重新用于支持临床药物基因组学（PGx），但目前的计算方法尚未使用临床数据进行广泛验证。在这项研究中，我们评估了准确性的Aldy计算方法提取PGx基因型从WGS和WES数据的14和13个主要药物基因，分别。从我们的机构分子实体肿瘤委员会收集的264名患者的全血样品中分离生殖系DNA。在我们的机构临床实验室改进修正案（CLIA）认证的PGx实验室内，使用DNA进行基于小组的基因分型。DNA也被送到其他CLIA认证的商业实验室进行临床WGS或WES。使用Aldy v3.3和v4.4从这些NGS数据中提取PGx基因型，并将结果与基于样本组的基因分型参比标准品进行比较，该参比标准品包含CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6、CYP3A4、CYP3A5、CYP4F2、DPYD、G6PD、NUDT 15、SLCO 1B1、TPMT和VKORC 1内的45个星星等位基因定义变体。对于除G6PD之外的所有变体区域，平均WGS读取深度> 30倍（平均读取深度为29个读取），并且对于所有变体区域，平均WES读取深度> 30倍。对于94例WGS患者，当排除具有未通过靶向基因分型、模糊定相和CYP 2D6杂合等位基因检测的其他主要星星等位基因的双倍型时，99.5%的病例中Aldy v3.3双倍型调用与基因分型参考标准的结果一致。Aldy v3.3确定了CYP2B6、CYP2C19、DPYD、SLCO 1B1和NUDT 15中基因分型未涵盖的另外15个临床上可操作的星星等位基因。在WGS队列中，Aldy v4.4双倍型调用与99.7%病例的基因分型一致。当排除CYP2D6拷贝数变异的患者时，除1个CYP3A4双体型调用外，所有Aldy v4.4双体型调用均与WES队列中161例患者的基因分型一致。Aldy v3.3和v4.4从临床WES和WGS数据中调用了主要药物基因的双体型，准确率>99%。这些发现支持使用Aldy重新利用临床NGS数据来告知临床PGx。
Next-generation sequencing (NGS), including whole genome sequencing (WGS) and whole exome sequencing (WES), is increasingly being used for clinic care. While NGS data have the potential to be repurposed to support clinical pharmacogenomics (PGx), current computational approaches have not been widely validated using clinical data. In this study, we assessed the accuracy of the Aldy computational method to extract PGx genotypes from WGS and WES data for 14 and 13 major pharmacogenes, respectively. Germline DNA was isolated from whole blood samples collected for 264 patients seen at our institutional molecular solid tumor board. DNA was used for panel-based genotyping within our institutional Clinical Laboratory Improvement Amendments- (CLIA-) certified PGx laboratory. DNA was also sent to other CLIA-certified commercial laboratories for clinical WGS or WES. Aldy v3.3 and v4.4 were used to extract PGx genotypes from these NGS data, and results were compared to the panel-based genotyping reference standard that contained 45 star allele-defining variants within CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP4F2, DPYD, G6PD, NUDT15, SLCO1B1, TPMT, and VKORC1. Mean WGS read depth was >30x for all variant regions except for G6PD (average read depth was 29 reads), and mean WES read depth was >30x for all variant regions. For 94 patients with WGS, Aldy v3.3 diplotype calls were concordant with those from the genotyping reference standard in 99.5% of cases when excluding diplotypes with additional major star alleles not tested by targeted genotyping, ambiguous phasing, and CYP2D6 hybrid alleles. Aldy v3.3 identified 15 additional clinically actionable star alleles not covered by genotyping within CYP2B6, CYP2C19, DPYD, SLCO1B1, and NUDT15. Within the WGS cohort, Aldy v4.4 diplotype calls were concordant with those from genotyping in 99.7% of cases. When excluding patients with CYP2D6 copy number variation, all Aldy v4.4 diplotype calls except for one CYP3A4 diplotype call were concordant with genotyping for 161 patients in the WES cohort. Aldy v3.3 and v4.4 called diplotypes for major pharmacogenes from clinical WES and WGS data with >99% accuracy. These findings support the use of Aldy to repurpose clinical NGS data to inform clinical PGx.
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影响因子：
2.7
作者：
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影响因子：
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DOI：
10.1161/circgenetics.116.001573
发表时间：
2017-02
期刊：
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影响因子：
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影响因子：
4.7
作者：
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通讯作者：
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