Abstract：
Tamoxifen is part of the standard of care of endocrine therapy for adjuvant treatment of breast cancer. However, survival outcomes with tamoxifen are highly variable. The concentration of endoxifen, the 30-100 times more potent metabolite of tamoxifen and bioactivated by the CYP2D6 enzyme, has been described as the most relevant metabolite of tamoxifen metabolism. A genome-wide association study (GWAS) was performed with the objective to identify genetic polymorphisms associated with endoxifen serum concentration levels and clinical outcome in early-stage breast cancer patients receiving tamoxifen. A GWAS was conducted in 608 women of the CYPTAM study (NTR1509/PMID: 30120701). Germline DNA and clinical and survival characteristics were readily available. Genotyping was performed on Infinium Global Screening Array (686,082 markers) and single nucleotide polymorphism (SNP) imputation by using 1000 Genomes. Relapse-free survival during tamoxifen (RFSt) was defined the primary clinical outcome. Endoxifen serum concentration was analyzed as a continuous variable. Several genetic variants reached genome-wide significance (P value: ≤5 × 10-8). Endoxifen concentrations analysis identified 430 variants, located in TCF20 and WBP2NL genes (chromosome 22), which are in strong linkage disequilibrium with CYP2D6 variants. In the RFSt analysis, several SNP were identified (LPP gene: rs77693286, HR 18.3, 95% CI: 15.2-21.1; rs6790761, OR 18.2, 95% CI: 15.5-21.1). Endoxifen concentrations have a strong association with the chromosome 22, which contains the CYP2D6 gene.
摘要：
他莫昔芬是乳腺癌辅助治疗内分泌治疗标准护理的一部分。然而,他莫昔芬的生存结局差异很大.内西芬的浓度，三苯氧胺的30-100倍更有效的代谢产物，并被CYP2D6酶生物活化，已被描述为他莫昔芬代谢最相关的代谢产物。进行了一项全基因组关联研究（GWAS），目的是确定接受他莫昔芬治疗的早期乳腺癌患者中与内西芬血清浓度水平和临床结局相关的遗传多态性。在CYPTAM研究的608名女性中进行了GWAS(NTR1509/PMID:30120701)。种系DNA和临床和存活特征是容易获得的。通过使用1000个基因组在Infinium全局筛选阵列(686,082个标记)和单核苷酸多态性(SNP)填补上进行基因分型。他莫昔芬（RFSt）期间的无复发生存被定义为主要临床结局。将Endoxifen血清浓度作为连续变量进行分析。几种遗传变异达到全基因组意义（P值：≤5×10-8）。Endoxifen浓度分析确定了430种变体，位于TCF20和WBP2NL基因（染色体22），与CYP2D6变体处于强连锁不平衡状态。在RFSt分析中，确定了几个SNP（LPP基因：rs77693286，HR18.3，95％CI：15.2-21.1；rs6790761，OR18.2，95％CI：15.5-21.1）。Endoxifen浓度与包含CYP2D6基因的22号染色体具有很强的相关性。
