PO.PS01.07 · 人群科学
雌激素受体介导的药物基因组学 eQTL 作为乳腺癌内分泌治疗反应的预测因子
Estrogen receptor-mediated pharmacogenomic eQTLs as predictors of endocrine therapy response in breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：约 70% 的乳腺癌为雌激素受体阳性（ER+），包括选择性雌激素受体调节剂（SERMs）和芳香化酶抑制剂（AIs）在内的内分泌治疗是标准治疗方案。然而，患者间治疗反应及复发的差异仍然显著，提示存在改变 ER 信号传导的潜在种系药物基因组学因素。在此，我们绘制了 ER 药物基因组学 eQTL 图谱，以鉴定调控雌二醇（E2）和他莫昔芬（Tam）转录反应的种系变异。
方法：我们用溶媒对照、E2、Tam 或 E2+Tam 处理 30 个已基因分型的淋巴母细胞样细胞系（LCLs），并进行 RNA-seq 以定量配体诱导的表达倍数变化。使用 MatrixEQTL，我们鉴定了 SNP-基因 PGx-eQTL（顺式，±200 kb），并要求通过以下证据证明 ER 转录特异性：(i) 双药联合处理时发生逆转，以及 (ii) 与 ER ChIP-seq 结合注释重叠。通过与乳腺癌 GWAS 数据集（包括 NSABP、MA.27 和 M3）关联评估临床相关性。对染色质调控状态进行注释（ChromHMM），并从以 SNP 为中心的 ±200 bp 区域进行转录因子基序富集分析。
结果：为 E2 和 Tam 鉴定出不同的 PGx-eQTL 架构，其配体反应性位点存在部分重叠。ER PGx-eQTL 变异主要富集于增强子染色质，并与经典 ER 结合基序共定位。与乳腺癌结局 GWAS 的整合分析突出了多个药物反应相关位点，包括 rs311392-MRPL15 和 rs7953325-SYCP3。高 MRPL15 表达与较短的无复发生存期相关，而高 SYCP3 表达与更好的结局相关。来自癌症和激素表型 GWAS 目录的其他位点包括 rs2850247-SIK2 和 rs11673604-LSM4，其中较高的 SIK2 表达与更好的无复发生存期相关，而较高的 LSM4 表达与较差的结局相关。
结论：我们鉴定了配体依赖性 ER PGx-eQTL，从机制上将种系调控变异与转录反应异质性及临床内分泌治疗结局联系起来。这些 SNP-基因关系代表了精准内分泌治疗选择的潜在生物标志物，并可能揭示内分泌依赖性的治疗易感性。
查看英文原文 English abstract
Background: Approximately 70% of breast cancers are estrogen receptor-positive (ER+), and endocrine therapies, including selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs), are standard-of-care. However, interpatient variability in treatment response and relapse remains substantial, suggesting underlying germline pharmacogenomic factors that modify ER signaling. Here, we mapped ER pharmacogenomic eQTLs to identify germline variants that modulate transcriptional responses to estradiol (E2) and tamoxifen (Tam).
Methods: We treated 30 genotyped lymphoblastoid cell lines (LCLs) with vehicle, E2, Tam, or E2+Tam and performed RNA-seq to quantify ligand-induced expression fold changes. Using MatrixEQTL, we identified SNP-gene PGx-eQTLs (cis, ±200 kb), requiring evidence of ER transcriptional specificity via (i) reversal by dual treatment, and (ii) overlap with ER ChIP-seq binding annotations. Clinical relevance was assessed by linkage to breast cancer GWAS datasets, including NSABP, MA.27, and M3. Chromatin regulatory states were annotated (ChromHMM), and transcription factor motif enrichment was performed from SNP-centered ±200 bp regions.
Results: Distinct PGx-eQTL architectures were identified for E2 and Tam, with partial overlap in ligand-responsive loci. ER PGx-eQTL variants were predominantly enriched in enhancer chromatin and co-localized with canonical ER-binding motifs. Integrative analysis with GWAS of breast cancer outcomes highlighted multiple drug-response-associated loci, including rs311392-MRPL15 and rs7953325-SYCP3. High MRPL15 expression was linked to shorter relapse-free survival, whereas high SYCP3 expression correlated with improved outcomes. Additional loci derived from a GWAS catalog for cancer and hormone phenotypes included rs2850247-SIK2 and rs11673604-LSM4, where higher SIK2 expression was associated with improved relapse-free survival and higher LSM4 expression with poorer outcomes.
Conclusions: We identified ligand-dependent ER PGx-eQTLs that mechanistically connect germline regulatory variants to transcriptional response heterogeneity and clinical endocrine therapy outcomes. These SNP-gene relationships represent potential biomarkers for precision endocrine therapy selection and may reveal endocrine-dependent therapeutic vulnerabilities.
利益披露 Disclosure
M. Meng, None..
H. Gao, None..
A. John, None..
A. Ghosh, None..
S. Indulkar, None.