RESUMEN
Breast cancer is a heterogeneous disease, and treatment is guided by biomarker profiles representing distinct molecular subtypes. Breast cancer arises from the breast ductal epithelium, and experimental data suggests breast cancer subtypes have different cells of origin within that lineage. The precise cells of origin for each subtype and the transcriptional networks that characterize these tumor-normal lineages are not established. In this work, we applied bulk, single-cell (sc), and single-nucleus (sn) multi-omic techniques as well as spatial transcriptomics and multiplex imaging on 61 samples from 37 breast cancer patients to show characteristic links in gene expression and chromatin accessibility between breast cancer subtypes and their putative cells of origin. We applied the PAM50 subtyping algorithm in tandem with bulk RNA-seq and snRNA-seq to reliably subtype even low-purity tumor samples and confirm promoter accessibility using snATAC. Trajectory analysis of chromatin accessibility and differentially accessible motifs clearly connected progenitor populations with breast cancer subtypes supporting the cell of origin for basal-like and luminal A and B tumors. Regulatory network analysis of transcription factors underscored the importance of BHLHE40 in luminal breast cancer and luminal mature cells, and KLF5 in basal-like tumors and luminal progenitor cells. Furthermore, we identify key genes defining the basal-like ( PRKCA , SOX6 , RGS6 , KCNQ3 ) and luminal A/B ( FAM155A , LRP1B ) lineages, with expression in both precursor and cancer cells and further upregulation in tumors. Exhausted CTLA4-expressing CD8+ T cells were enriched in basal-like breast cancer, suggesting altered means of immune dysfunction among breast cancer subtypes. We used spatial transcriptomics and multiplex imaging to provide spatial detail for key markers of benign and malignant cell types and immune cell colocation. These findings demonstrate analysis of paired transcription and chromatin accessibility at the single cell level is a powerful tool for investigating breast cancer lineage development and highlight transcriptional networks that define basal and luminal breast cancer lineages.
RESUMEN
OBJECTIVES: To examine time trends in glucocorticoid (GC) use among patients diagnosed with rheumatoid arthritis (RA) during the biologic era. METHODS: A population-based inception cohort of RA patients diagnosed during 1999 - 2018 was followed longitudinally through their medical records until death, migration or 12/31/2020. All patients fulfilled 1987 American College of Rheumatology classification criteria for RA. GC start and stop dates were collected along with dosages in prednisone equivalents. The cumulative incidence of GC initiation and discontinuation adjusted for the competing risk of death was estimated. Cox models adjusted for age and sex were used to compare trends between time periods. RESULTS: The study population included 399 patients (71% female) diagnosed in 1999 - 2008 and 430 patients (67% female) diagnosed in 2009 - 2018. GC use was initiated within 6 months of meeting RA criteria in 67% of patients in 1999-2008 and 71% of patients in 2009-2018, corresponding to a 29% increase in hazard for initiation of GC in 2009-2018 (adjusted hazard ratio [HR]: 1.29; 95% confidence interval [CI]: 1.09-1.53). Among GC users, similar rates of GC discontinuation within 6 months after GC initiation were observed in patients with RA incidence in 1999 - 2008 and 2009 - 2018 (39.1% versus 42.9%, respectively), with no significant association in adjusted Cox models (HR: 1.11; 95% CI: 0.93-1.31). CONCLUSION: More patients are initiating GCs early in their disease course now compared to previously. The rates of GC discontinuation were similar, despite the availability of biologics.
