Alinés, a junior studying Biology with a minor in Genomics at Davidson College, characterized the transcriptomic of ESR1 fusions in endocrine therapy-resistant metastatic breast cancers.
Hormone-receptor (HR)-positive / HER2-negative metastatic breast cancer (MBC) presents significant challenges due to eventual resistance to endocrine therapy (ET), contributing to its incurability. Participating in the Broad Summer Research Program has been a life-altering experience, fostering my scientific and personal growth. This unique opportunity allowed me to tackle challenges, connect with prominent researchers, and share my passion for making an impact with like-minded peers. What sets the Broad apart is its unwavering support for individuality. I've flourished in an environment where I can be my true self, benefiting from incredible mentorship. The transformative experiences I've gained here will undoubtedly influence the communities I become a part of in the future. While ESR1 activating mutations are recognized as critical drivers of ET resistance, recent evidence suggests that ESR1 gene fusions also contribute. The molecular consequences and landscape of these fusions remain poorly understood–which is unfortunate, given that ESR1 fusions resist all current ETs in model systems. Using a transcriptomics-based approach, we characterized the frequency, structural features, potential downstream consequences, and PAM50 subtype enrichments of ESR1 fusions. Analyzing RNA-sequencing data from the Dana-Farber Cancer Institute CCPM retrospective cohort (n = 252 cases, 276 specimens), we identify 10 cases harboring 5' ESR1 fusions. All fusions were in-frame with breakpoints within exons 6/7 of ESR1's ligand binding domain. These ESR1 fusions were exclusively identified in Luminal B (LumB) metastases–defining an ESR1 fusion frequency of 6.7% in LumB disease (10 of 149 LumB Mets). A differential expression analysis between LumB samples with and without ESR1 fusions revealed significant expression loss of a suite of genes previously shown to be downregulated in basal breast cancers–including GRIA2, PIP, CAPN9, BRINP2, BRINP3, CEACAM5, CX3CR1. Additionally, we identify differential expression in immune-related genes–which will be discussed. These findings–albeit limited by a small sample size–suggest that ESR1 fusions in MBC are enriched in LumB-like disease and may have unique transcriptomic features. We propose that additional analyses of ESR1 fusion-positive cases will reveal a distinct biology that will inform future translational studies.
Project: Transcriptomic characterization of ESR1 fusions in endocrine therapy-resistant metastatic breast cancers
Mentors: Nolan Priedigkeit
PI: Golub Lab, Cancer Program