Genome-wide association study of aromatase inhibitor discontinuation due to musculoskeletal symptoms.
Genome-wide association study of aromatase inhibitor discontinuation due to musculoskeletal symptoms.
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DOI：
10.1007/s00520-022-07243-8
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发表时间：
2022-10
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影响因子：
--
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芳香化酶抑制剂（AI）通常用于治疗激素受体阳性（HR+）乳腺癌。AI诱导的肌肉骨骼综合征（AIMSS）是导致AI治疗中止的常见毒性。这项全基因组关联研究（GWAS）的目的是确定与AIMSS导致的AI治疗中止相关的遗传变异，并试图复制先前报道的关联。在依西美坦和来曲唑药物遗传学（ELPh）研究中，HR+非转移性乳腺癌绝经后患者随机接受来曲唑或依西美坦治疗。对生殖系DNA进行全基因组基因分型，然后进行插补。使用考克斯比例风险模型，假设加性遗传效应，并调整年龄、基线疼痛评分、既往紫杉烷治疗和AI组，对每个插补变量与AIMSS导致的治疗终止时间的相关性进行了检验。在每个AI组内进行了二次分析，并对先前报告与AIMSS风险相关的候选变量进行了分析。400名ELPh参与者被纳入综合分析。在初步分析中，有两种变异超过了全基因组显著性水平（p值<5×10−8），一种是CCDC 148内的内含子变异（rs79048288）（HR=4.42，95% CI：2.67-7.33），另一种是PPP 1 R14 C上游的基因间变异（rs 912571）（HR=0.30，95% CI：0.20-0.47）。在次要分析中，已知与SUPT 20 H表达相关的rs74418677与因AIMSS而停止来曲唑治疗显著相关（HR=5.91，95% CI：3.16-11.06）。我们能够复制先前在该队列中报告与AIMSS相关的候选变体的关联，但无法复制先前在其他患者队列中报告的任何其他变体的关联。我们的GWAS研究结果确定了几种可能与AI或来曲唑的AIMSS风险相关的候选变体。在将这些发现转化为临床实践以改善HR+乳腺癌患者的治疗结局之前，需要在独立队列中验证这些相关性。
Aromatase inhibitors (AI) are commonly used to treat hormone receptor positive (HR+) breast cancer. AI-induced musculoskeletal syndrome (AIMSS) is a common toxicity that causes AI treatment discontinuation. The objective of this genome-wide association study (GWAS) was to identify genetic variants associated with discontinuation of AI therapy due to AIMSS and attempt to replicate previously reported associations. In the Exemestane and Letrozole Pharmacogenetics (ELPh) study, postmenopausal patients with HR+ non-metastatic breast cancer were randomized to letrozole or exemestane. Genome-wide genotyping of germline DNA was conducted followed by imputation. Each imputed variant was tested for association with time-to-treatment discontinuation due to AIMSS using a Cox proportional hazards model assuming additive genetic effects and adjusting for age, baseline pain score, prior taxane treatment, and AI arm. Secondary analyses were conducted within each AI arm and analyses of candidate variants previously reported to be associated with AIMSS risk. Four hundred ELPh participants were included in the combined analysis. Two variants surpassed the genome-wide significance level in the primary analysis (p-value<5×10−8), an intronic variant (rs79048288) within CCDC148 (HR=4.42, 95% CI: 2.67–7.33) and an intergenic variant (rs912571) upstream of PPP1R14C (HR=0.30, 95% CI: 0.20–0.47). In the secondary analysis, rs74418677, which is known to be associated with expression of SUPT20H, was significantly associated with discontinuation of letrozole therapy due to AIMSS (HR=5.91, 95% CI: 3.16–11.06). We were able to replicate associations for candidate variants previously reported to be associated with AIMSS in this cohort, but were not able to replicate associations for any other variants previously reported in other patient cohorts. Our GWAS findings identify several candidate variants that may be associated with AIMSS risk from AI generally or letrozole specifically. Validation of these associations in independent cohorts is needed before translating these findings into clinical practice to improve treatment outcomes in patients with HR+ breast cancer.
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影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
3.8
作者：
Borrie, Adrienne E.;Rose, Finnley A.;Kim, Richard B.
通讯作者：
Kim, Richard B.
影响因子：
50.5
作者：
Hadji, P.;Jackisch, C.;Harbeck, N.
通讯作者：
Harbeck, N.
影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
影响因子：
45.3
作者：
Henry, N. Lynn;Azzouz, Faouzi;Storniolo, Anna Maria
通讯作者：
Storniolo, Anna Maria