文章：

转移性乳腺癌中与雌激素受体通路活性相关的基因组改变对下游ER信号传导具有差异性影响

Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling

原文发布日期：4 September 2023

DOI: 10.3390/cancers15174416

类型: Article

开放获取: 是

英文摘要：

Mutations in the estrogen receptor gene (ESR1), its transcriptional regulators, and the mitogen-activated protein kinase (MAPK) pathway are enriched in patients with endocrine-resistant metastatic breast cancer (MBC). Here, we integrated whole genome sequencing with RNA sequencing data from the same samples of 101 ER-positive/HER2-negative MBC patients who underwent a tumor biopsy prior to the start of a new line of treatment for MBC (CPCT-02 study, NCT01855477) to analyze the downstream effects of DNA alterations previously linked to endocrine resistance, thereby gaining a better understanding of the associated mechanisms. Hierarchical clustering was performed using expression ofESR1target genes. Genomic alterations at the DNA level, gene expression levels, and last administered therapy were compared between the identified clusters. Hierarchical clustering revealed two distinct clusters, one of which was characterized by increased expression ofESR1and its target genes. Samples in this cluster were significantly enriched for mutations inESR1and amplifications inFGFR1andTSPYL.Patients in the other cluster showed relatively lower expression levels ofESR1and its target genes, comparable to ER-negative samples, and more often received endocrine therapy as their last treatment before biopsy. Genes in the MAPK-pathway, includingNF1, andESR1transcriptional regulators were evenly distributed. In conclusion, RNA sequencing identified a subgroup of patients with clear expression ofESR1and its downstream targets, probably still benefiting from ER-targeting agents. The lower ER expression in the other subgroup might be partially explained by ER activity still being blocked by recently administered endocrine treatment, indicating that biopsy timing relative to endocrine treatment needs to be considered when interpreting transcriptomic data.

摘要翻译： 

在内分泌抵抗性转移性乳腺癌（MBC）患者中，雌激素受体基因（ESR1）及其转录调控因子和丝裂原活化蛋白激酶（MAPK）信号通路的突变频率显著增高。本研究整合了101例ER阳性/HER2阴性MBC患者（CPCT-02研究，NCT01855477）在接受新治疗方案前肿瘤活检样本的全基因组测序与RNA测序数据，旨在分析既往与内分泌抵抗相关的DNA变异的下游效应，从而深入理解其作用机制。通过ESR1靶基因表达谱进行层次聚类分析，并对不同聚类组间的DNA水平基因组变异、基因表达水平及末次治疗方案进行比较。层次聚类分析揭示出两个特征迥异的亚群：其中一个亚群以ESR1及其靶基因的高表达为特征，该组样本中ESR1突变及FGFR1和TSPYL扩增显著富集；另一亚群则呈现相对较低的ESR1及其靶基因表达水平（与ER阴性样本相当），且更多患者在活检前接受过内分泌治疗作为末次治疗方案。MAPK通路相关基因（包括NF1）及ESR1转录调控因子的分布则相对均衡。综上所述，RNA测序鉴定出一个具有明确ESR1及其下游靶基因表达的亚群，该亚群患者可能仍能从ER靶向治疗中获益。另一亚群较低的ER表达可能部分归因于近期内分泌治疗对ER活性的持续抑制，这表明在解读转录组数据时需充分考虑活检时间与内分泌治疗的时间关联性。

原文链接：

Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling