Data from Transcriptional Reprogramming Differentiates Active from Inactive ESR1 Fusions in Endocrine Therapy-Refractory Metastatic Breast Cancer
Year: 2023
Type: other
Abstract: Genomic analysis has recently identified multiple ESR1 gene translocations in estrogen receptor alpha–positive (ERα+) metastatic breast cancer (MBC) that encode chimeric proteins whereby the ESR1 ligand binding domain (LBD) is replaced by C-terminal sequences from many different gene partners. Here we functionally screened 15 ESR1 fusions and identified 10 that promoted estradiol-independent cell growth, motility, invasion, epithelial-to-mesenchymal transition, and resistance to fulvestrant. RNA sequencing identified a gene expression pattern specific to functionally active ESR1 gene fusions that was subsequently reduced to a diagnostic 24-gene signature. This signature was further examined in 20 ERα+ patient-derived xenografts and in 55 ERα+ MBC samples. The 24-gene signature successfully identified cases harboring ESR1 gene fusions and also accurately diagnosed the presence of activating ESR1 LBD point mutations. Therefore, the 24-gene signature represents an efficient approach to screening samples for the presence of diverse somatic ESR1 mutations and translocations that drive endocrine treatment failure in MBC. Significance: This study identifies a gene signature diagnostic for functional ESR1 fusions that drive poor outcome in advanced breast cancer, which could also help guide precision medicine approaches in patients harboring ESR1 mutations.
Authors: Xuxu Gou, Meenakshi Anurag, Jonathan T. Lei, Beom-Jun Kim, Purba Singh, Sinem Seker, Diana Fandino, Airi Han, Saif Rehman, Jianhong Hu, Viktoriya Korchina, Harshavardhan Doddapaneni, Lacey E. Dobrolecki, Nicholas Mitsiades, Michael T. Lewis, Alana L. Welm, Shunqiang Li, Adrian V. Lee, Dan R. Robinson, Charles E. Foulds, Matthew J. Ellis
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4362663103