Luminal breast cancer (BC) is generally associated with a lower risk of recurrence compared with other subtypes. However, patients with luminal BC can still experience recurrence, which remains a significant concern and contributes to BC-related mortality. Current clinical practice for recurrence risk prognosis relies on prognostic tests based on tumor gene expression profiles. In this study, we aimed to investigate the association between different genetic alterations with the likelihood of recurrence and gene expression prognostic prediction (Oncotype DX®, MammaPrint®, and PAM50-ROR) in luminal BC patients. We constructed three transcriptome-based predictive models, based on these widely used clinical tests, to evaluate the recurrence risk of patients with luminal BC, using RNA-seq data from 1527 samples across 11 datasets. We further classified 1780 patients from the TCGA and METABRIC datasets into risk groups and detected distinct recurrence risk patterns. Our analysis revealed that low-risk groups had higher frequencies of mutations in PIK3CA, MAP3K1, CDH1, KMT2C, and CBFB, as well as co-mutations in PIK3CA-MAP3K1, PIK3CA-CBFB, and KMT2C-MAP3K1. In contrast, high-risk groups showed enrichment of TP53, RB1, and PTPN22 mutations compared with the whole cohort, with notable co-mutations in TP53-PIK3CA and TP53-KMT2C. Furthermore, mutations in TP53 and BRCA2, and deletions in the 7p22.3 region were at least threefold more frequent in high-risk patients compared with low-risk patients. Using an independent dataset, we validated our finding of higher frequency of BRCA2 mutations in Oncotype DX® high-risk patients. Notably, PIK3CA mutations had an unexpected negative impact on recurrence and survival among high-risk patients. Our study reveals key genetic factors associated with recurrence risk in luminal BC. Identifying these mutations and copy number alterations provides a basis for refined prognostic models and suggests avenues for further research, potentially improving treatment strategies and follow-up care for patients with luminal BC.

Over recent decades, marine microorganisms have increasingly adapted to plastic debris, forming distinct plastic-attached microbial communities. Despite this, the colonization and succession processes on plastic surfaces in marine environments remain poorly understood. To address this knowledge gap, we conducted a microbiome succession experiment using four common plastic polymers (PE, PP, PS, and PET), as well as glass and wood, in a temperature-controlled seawater system over a 2- to 90-day period. We employed long-read 16S rRNA metabarcoding to profile the prokaryotic microbiome’s taxonomic composition at five time points throughout the experiment. By applying Weighted Gene Co-expression Network Analysis (WGCNA) to our 16S metabarcoding data, we identified unique succession signatures for 77 bacterial genera and observed polymer-specific enrichment in 39 genera. Our findings also revealed that the most significant variations in microbiome composition across surfaces occurred during the initial succession stages, with potential intra-genus relationships that are linked to surface preferences. This research advances our understanding of microbial succession dynamics on marine plastic debris and introduces a robust statistical approach for identifying succession signatures of specific bacterial taxa.

Purpose: One-half of hormone receptor-positive (HR +) breast cancer (BC) patients have low expression of HER2 (HER2-low) and may benefit from trastuzumab deruxtecan (TDXd). This study aimed to identify parameters associated with HER2-low levels in primary and metastatic tumors. We specifically sought to determine whether OncotypeDX and HER2 mRNA levels could identify patients who would otherwise be considered HER2-negative by immunohistochemistry (IHC). Methods: This retrospective analysis of all consecutive HR + patients who underwent OncotypeDX from January 2004 to December 2020 was conducted in a single medical center (n = 1429). We divided HER2-negative cases into HER2-low (IHC = 1 + or 2 + and non-amplified fluorescent situ hybridization) and HER2-0 (IHC = 0). HER2 RT-PCR was evaluated from the OncotypeDX results. Results: HER2-low cases exhibited significantly higher HER2 RT-PCR scores (p = 2.1e-9), elevated estrogen receptor (ER) levels (p = 0.0114), and larger tumor sizes compared to HER2-0 cases (> 2 cm; 36.6% vs. 22.1%, respectively, p < 0.00001). Primary tumors > 2 cm were more likely to be HER2-low (OR = 2.07, 95% CI: 1.6317 to 2.6475, p < 0.0001). Metastatic BCs expressed higher HER2 IHC scores compared with primary BCs (Wilcoxon signed-rank, p = 0.046). HER2 IHC scores were higher for low-risk vs. medium-risk OncotypeDX (p = 0.0067). No other clinical or pathological parameters were associated with the increase in HER2 levels in the metastatic samples. Conclusion: It might be beneficial to use clinical data from the primary tumor, including the HER2 RT-PCR score, to determine a HER2-low status.

Background: Fumarate hydratase (FH) deficiency is a rare metabolic alteration in breast cancer that may drive tumor progression through angiogenic remodeling. However, its role in shaping the tumor microenvironment remains poorly defined, limiting our understanding of metabolism-driven angiogenesis and its therapeutic significance. Methods: We analyzed genomic and transcriptomic profiles from thousands of breast cancer samples, including the TCGA cohort, to identify FH mutations and copy number alterations. Differential expression, pathway enrichment, and weighted gene co-expression network analysis (WGCNA) were performed to characterize metabolic and signaling changes. Clinical relevance was examined in a triple-negative breast cancer patient with an FH mutation treated with bevacizumab. Results: FH alterations were enriched in larger, primary tumors and in older patients. FH-deficient tumors displayed metabolic reprogramming, with reduced oxidative phosphorylation and TCA cycle activity, accompanied by upregulation of angiogenesis, VEGF signaling, and epithelial–mesenchymal transition pathways. WGCNA identified 11 hub genes (including CDH5, CLDN5, VWF, and PECAM1) linked to a pro-angiogenic microenvironment. A clinical case illustrated a durable and exceptional response to bevacizumab-based therapy in an FH-mutant patient. Conclusions: FH deficiency promotes an angiogenic tumor microenvironment and may serve as a predictive biomarker for VEGF-targeted therapies. These findings underscore the therapeutic potential of exploiting metabolic vulnerabilities to inform precision oncology.

Thyroid hormones (THs) regulate metabolism, proliferation, and genomic stability. Clinical studies have linked levothyroxine therapy with higher Oncotype DX Recurrence Scores in breast cancer (BC), suggesting a potential effect of thyroid hormone signaling on genomic risk. Here, we investigated the impact of triiodothyronine (T3) on DNA damage and repair pathways in estrogen receptor-positive T47D breast cancer and non-tumorigenic MCF10A cells. RNA sequencing revealed significant upregulation of RAD51 and enrichment of DNA repair pathways following 24 h T3 exposure. Consistently, T3 increased γH2AX and 53BP1 nuclear foci, indicating transient activation of the DNA damage response (DDR). These effects were transient, returning to baseline after 48 h, suggesting cellular adaptation. T3 also enhanced proliferation at 10 μM but inhibited growth at higher concentrations. Our findings indicate that acute exposure to T3 induces transient genomic stress, providing a potential mechanistic basis for the observed association between thyroid hormone therapy and increased BC recurrence risk.

Psoriasis, a chronic inflammatory skin disease affecting men and women equally, presents distinct gender-based differences in severity and treatment response. While molecular mechanisms underlying psoriasis are well-studied, sex-specific differences remain largely unexplored. To address this, we conducted a comprehensive analysis of transcriptomic data from lesional psoriasis skin and healthy controls, comparing male and female cohorts. Our findings reveal 2760 overlapping differentially expressed genes (DEGs) between sexes, highlighting shared pathways like IL-17 signaling and Th17 differentiation. However, sex-specific pathways emerged, including male-enriched PI3K-Akt signaling and chemokine receptor activity, and female-enriched glycolysis and AHR-NRF2 pathways. Upstream regulator analysis identified sex-specific drivers, including VEGFA activation and CFTR inhibition in males, and AHR activation and FGF21 inhibition in females. Notably, Regulatory T cells (Tregs) and neutrophil abundance differed by sex, aligning with disease severity trends. These results highlight sex-associated molecular and cellular disparities that may be relevant to understanding differences in disease manifestation and treatment response. As an exploratory, hypothesis-generating transcriptomic analysis, this study lays the groundwork for future experimental and clinical validation of sex-specific mechanisms in psoriasis.