Large-Scale Pharmacogenomics Analysis of Patients With Cancer Within the 100,000 Genomes Project Combining Whole-Genome Sequencing and Medical Records to Inform Clinical Practice.

IF 42.1 1区医学 Q1 ONCOLOGY Journal of Clinical Oncology Pub Date : 2024-10-31 DOI:10.1200/JCO.23.02761

Ivone U S Leong, Claudia P Cabrera, Valentina Cipriani, Paul J Ross, Richard M Turner, Alex Stuckey, Sonali Sanghvi, Dorota Pasko, Loukas Moutsianas, Christopher A Odhams, Greg S Elgar, Georgia Chan, Adam Giess, Susan Walker, Rebecca E Foulger, Eleanor M Williams, Louise C Daugherty, Antonio Rueda-Martin, Daniel J Rhodes, Olivia Niblock, Alexandra Pickard, Lauren Marks, Sarah E A Leigh, Matthew J Welland, Marta Bleda, Catherine Snow, Zandra Deans, Nirupa Murugaesu, Richard H Scott, Michael R Barnes, Matthew A Brown, Augusto Rendon, Sue Hill, Alona Sosinsky, Mark J Caulfield, Ellen M McDonagh

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Abstract

Purpose: As part of the 100,000 Genomes Project, we set out to assess the potential viability and clinical impact of reporting genetic variants associated with drug-induced toxicity for patients with cancer recruited for whole-genome sequencing (WGS) as part of a genomic medicine service.

Methods: Germline WGS from 76,805 participants was analyzed for pharmacogenetic (PGx) variants in four genes (DPYD, NUDT15, TPMT, UGT1A1) associated with toxicity induced by five drugs used in cancer treatment (capecitabine, fluorouracil, mercaptopurine, thioguanine, irinotecan). Linking genomic data with prescribing and hospital incidence records, a phenome-wide association study (PheWAS) was performed to identify whether phenotypes indicative of adverse drug reactions (ADRs) were enriched in drug-exposed individuals with the relevant PGx variants. In a subset of 7,081 patients with cancer, DPYD variants were reported back to clinicians and outcomes were collected.

Results: We identified clinically relevant PGx variants across the four genes in 62.7% of participants in our cohort. Extending this to annual prescription numbers in England for the drugs affected by these PGx variants, approximately 14,540 patients per year could potentially benefit from a reduced dose or alternative drug to reduce the risk of ADRs. Validating PGx associations in a real-world data set, we found a significant association between PGx variants in DPYD and toxicity-related phenotypes in patients treated with capecitabine or fluorouracil. Reported DPYD variants were deemed informative for clinical decision making in a majority of cases.

Conclusion: Reporting PGx variants from germline WGS relevant to patients with cancer alongside primary findings related to their cancer can be clinically informative, informing prescribing to reduce the risk of ADRs. Extending the range of actionable variants to those found in patients of non-European ancestry is important and will extend the potential clinical impact.

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结合全基因组测序和医疗记录为临床实践提供信息的 "十万基因组计划 "癌症患者大规模药物基因组学分析。

目的：作为 "十万基因组计划"（100,000 Genomes Project）的一部分，我们着手评估作为基因组医学服务的一部分，报告癌症患者全基因组测序（WGS）中与药物诱导毒性相关的基因变异的潜在可行性和临床影响：对 76 805 名参与者的种系 WGS 进行了分析，以确定与五种癌症治疗药物（卡培他滨、氟尿嘧啶、巯基嘌呤、硫鸟嘌呤、伊立替康）诱导毒性相关的四个基因（DPYD、NUDT15、TPMT、UGT1A1）的药物遗传学（PGx）变异。将基因组数据与处方和医院发病记录联系起来，进行了一项全表型关联研究（PheWAS），以确定药物不良反应（ADR）的表型是否会在具有相关 PGx 变异的药物暴露个体中富集。在 7081 名癌症患者的子集中，向临床医生报告了 DPYD 变异并收集了结果：我们在队列中 62.7% 的参与者中发现了与临床相关的四个基因的 PGx 变异。根据英格兰每年受这些 PGx 变异影响的药物处方数量，每年约有 14,540 名患者有可能从减少剂量或替代药物中获益，以降低 ADRs 风险。我们在真实世界的数据集中验证了 PGx 关联性，发现在接受卡培他滨或氟尿嘧啶治疗的患者中，DPYD 中的 PGx 变异与毒性相关表型之间存在显著关联。在大多数病例中，报告的DPYD变异被认为对临床决策具有参考价值：结论：报告与癌症患者相关的种系 WGS PGx 变异以及与癌症相关的主要研究结果可为临床提供信息，为处方提供参考，以降低 ADR 风险。将可操作变异的范围扩大到非欧洲血统患者中发现的变异非常重要，这将扩大潜在的临床影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Clinical Oncology 医学-肿瘤学

CiteScore

41.20

自引率

2.20%

发文量

8215

审稿时长

2 months

期刊介绍： The Journal of Clinical Oncology serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. In print and in electronic format, JCO strives to publish the highest quality articles dedicated to clinical research. Original Reports remain the focus of JCO, but this scientific communication is enhanced by appropriately selected Editorials, Commentaries, Reviews, and other work that relate to the care of patients with cancer.