PDF(Pubmed)
Abstract：
BACKGROUND: Endocrine therapy is the most important treatment modality of breast cancer patients whose tumors express the estrogen receptor α (ERα). The androgen receptor (AR) is also expressed in the vast majority (80-90%) of ERα-positive tumors. AR-targeting drugs are not used in clinical practice, but have been evaluated in multiple trials and preclinical studies.
METHODS: We performed a genome-wide study to identify hormone/drug-induced single nucleotide polymorphism (SNP) genotype - dependent gene-expression, known as PGx-eQTL, mediated by either an AR agonist (dihydrotestosterone) or a partial antagonist (enzalutamide), utilizing a previously well characterized lymphoblastic cell line panel. The association of the identified SNPs-gene pairs with breast cancer phenotypes were then examined using three genome-wide association (GWAS) studies that we have published and other studies from the GWAS catalog.
RESULTS: We identified 13 DHT-mediated PGx-eQTL loci and 23 Enz-mediated PGx-eQTL loci that were associated with breast cancer outcomes post ER antagonist or aromatase inhibitors (AI) treatment, or with pharmacodynamic (PD) effects of AIs. An additional 30 loci were found to be associated with cancer risk and sex-hormone binding globulin levels. The top loci involved the genes IDH2 and TMEM9, the expression of which were suppressed by DHT in a PGx-eQTL SNP genotype-dependent manner. Both of these genes were overexpressed in breast cancer and were associated with a poorer prognosis. Therefore, suppression of these genes by AR agonists may benefit patients with minor allele genotypes for these SNPs.
CONCLUSIONS: We identified AR-related PGx-eQTL SNP-gene pairs that were associated with risks, outcomes and PD effects of endocrine therapy that may provide potential biomarkers for individualized treatment of breast cancer.
METHODS: We performed a genome-wide study to identify hormone/drug-induced single nucleotide polymorphism (SNP) genotype - dependent gene-expression, known as PGx-eQTL, mediated by either an AR agonist (dihydrotestosterone) or a partial antagonist (enzalutamide), utilizing a previously well characterized lymphoblastic cell line panel. The association of the identified SNPs-gene pairs with breast cancer phenotypes were then examined using three genome-wide association (GWAS) studies that we have published and other studies from the GWAS catalog.
RESULTS: We identified 13 DHT-mediated PGx-eQTL loci and 23 Enz-mediated PGx-eQTL loci that were associated with breast cancer outcomes post ER antagonist or aromatase inhibitors (AI) treatment, or with pharmacodynamic (PD) effects of AIs. An additional 30 loci were found to be associated with cancer risk and sex-hormone binding globulin levels. The top loci involved the genes IDH2 and TMEM9, the expression of which were suppressed by DHT in a PGx-eQTL SNP genotype-dependent manner. Both of these genes were overexpressed in breast cancer and were associated with a poorer prognosis. Therefore, suppression of these genes by AR agonists may benefit patients with minor allele genotypes for these SNPs.
CONCLUSIONS: We identified AR-related PGx-eQTL SNP-gene pairs that were associated with risks, outcomes and PD effects of endocrine therapy that may provide potential biomarkers for individualized treatment of breast cancer.
摘要：
背景：内分泌治疗是肿瘤表达雌激素受体α（ERα）的乳腺癌患者最重要的治疗方式。雄激素受体(AR)也在绝大多数(80-90%)ERα阳性肿瘤中表达。AR靶向药物在临床实践中没有使用，但已在多项试验和临床前研究中进行了评估。
方法：我们进行了一项全基因组研究，以鉴定激素/药物诱导的单核苷酸多态性（SNP）基因型依赖性基因表达，被称为PGx-eQTL，由AR激动剂（双氢睾酮）或部分拮抗剂（恩杂鲁胺）介导，利用先前充分表征的淋巴母细胞细胞系面板。然后使用我们已经发表的三个全基因组关联(GWAS)研究和来自GWAS目录的其他研究来检查鉴定的SNP-基因对与乳腺癌表型的关联。
结果：我们确定了13个DHT介导的PGx-eQTL基因座和23个Enz介导的PGx-eQTL基因座，它们与ER拮抗剂或芳香化酶抑制剂（AI）治疗后的乳腺癌预后相关，或具有AI的药效学（PD）作用。发现另外30个基因座与癌症风险和性激素结合球蛋白水平有关。顶部基因座涉及IDH2和TMEM9基因，DHT以PGx-eQTLSNP基因型依赖性方式抑制了它们的表达。这两种基因在乳腺癌中都过表达，并与预后较差有关。因此,AR激动剂对这些基因的抑制可能使具有这些SNP的次要等位基因基因型的患者受益.
结论：我们确定了与风险相关的AR相关PGx-eQTLSNP基因对，可能为乳腺癌个体化治疗提供潜在生物标志物的内分泌治疗的结局和PD效应。
方法：我们进行了一项全基因组研究，以鉴定激素/药物诱导的单核苷酸多态性（SNP）基因型依赖性基因表达，被称为PGx-eQTL，由AR激动剂（双氢睾酮）或部分拮抗剂（恩杂鲁胺）介导，利用先前充分表征的淋巴母细胞细胞系面板。然后使用我们已经发表的三个全基因组关联(GWAS)研究和来自GWAS目录的其他研究来检查鉴定的SNP-基因对与乳腺癌表型的关联。
结果：我们确定了13个DHT介导的PGx-eQTL基因座和23个Enz介导的PGx-eQTL基因座，它们与ER拮抗剂或芳香化酶抑制剂（AI）治疗后的乳腺癌预后相关，或具有AI的药效学（PD）作用。发现另外30个基因座与癌症风险和性激素结合球蛋白水平有关。顶部基因座涉及IDH2和TMEM9基因，DHT以PGx-eQTLSNP基因型依赖性方式抑制了它们的表达。这两种基因在乳腺癌中都过表达，并与预后较差有关。因此,AR激动剂对这些基因的抑制可能使具有这些SNP的次要等位基因基因型的患者受益.
结论：我们确定了与风险相关的AR相关PGx-eQTLSNP基因对，可能为乳腺癌个体化治疗提供潜在生物标志物的内分泌治疗的结局和PD效应。
