Histopathological examination is a cornerstone in the diagnosis, prognostic stratification, and therapeutic planning of breast cancer. It combines morphological, immunophenotypic, and molecular data to guide clinical decision-making. This article provides a comprehensive overview of the main histological types, technical modalities, and conventional and emerging biomarkers in breast cancer pathology. Breast carcinomas are categorized into in situ (DCIS, LCIS) and invasive forms. The most frequent invasive types are invasive carcinoma of no special type (NST) and invasive lobular carcinoma (ILC). Rare histologic variants (e.g., mucinous, micropapillary, metaplastic) exhibit distinct biological and prognostic features. The diagnostic workflow includes standardized steps: sampling, formalin fixation, paraffin embedding, H&E staining, immunohistochemistry (ER, PR, HER2, Ki-67), and molecular testing when needed (FISH, PCR, NGS). Routine biomarkers help define surrogate molecular subtypes (luminal A/B, HER2-positive, triple-negative) and guide systemic therapies. The emergence of the HER2-low category exemplifies how biomarker refinement impacts clinical practice. Additional markers such as PIK3CA and ESR1 mutations, BRCA/HRD status, PD-L1 expression, and tumor-infiltrating lymphocytes (TILs), along with multigene signatures (e.g., Oncotype DX, MammaPrint), further individualize prognostic assessment and treatment selection. Innovative approaches such as liquid biopsy and next-generation sequencing (NGS) enable minimally invasive monitoring and personalized care, especially in advanced disease. Breast cancer pathology is thus a dynamic, integrative discipline central to precision oncology, driven by ongoing technological and molecular advances, and essential to multidisciplinary cancer care.

IntroductionThe expression of Human Epidermal Growth Factor Receptor-2 (HER2/neu) has shown significant therapeutic implications in malignancies, particularly in breast and gastric cancer. Therefore, the interest in studying HER2 in other malignancies, including colorectal cancer (CRC), has increased. However, the prevalence of HER2 overexpression in CRC remains debatable, with conflicting data. To address this uncertainty, this study aimed to investigate HER2 expression in CRC in Jordanian patients and to assess its association with clinicopathological characteristics, as well as the survival outcome.MethodsSixty-nine formalin-fixed, paraffin-embedded tissue blocks of CRC cases were included along with their corresponding patient's clinicopathological data. Tissue-microarray (TMA) were constructed and stained using anti-HER2/neu monoclonal antibody. HER2 scoring was performed using the HERACLES criteria. Fisher's exact test/Chi-squared test were used to investigate the association between HER2 scores and the clinicopathological data. Survival analysis was evaluated using Kaplan-Meier curves.ResultsHER2/neu positivity of any degree was expressed in 30 cases (43.5%). Twenty-five cases (36.2%) were scored 1 + and 4 (5.8%) scored 2+. Only one case (1.5%) was scored as 3+, representing the single positive case. In comparison, 39 cases (56.5%) showed no HER2/neu protein expression and were scored as (0). Two of the four cases that were scored (2+) required FISH testing to confirm the positivity for HER2 overexpression, which was not available. No significant associations were found between HER2/neu expression and clinicopathological parameters or survival rates. However, cases with either 2+ or 3+ HER2/neu scores were associated with worse overall survival (OS) and event-free survival compared to cases with a score of 1+ or no expression (score 0).ConclusionsThe prevalence of HER2/neu overexpression in CRC among Jordanian patients is low, with only 1.5% of the study sample exhibiting HER2/neu overexpression. A trend towards poor outcome was observed in patients with HER2/neu overexpression.

BackgroundHepatocellular carcinoma (HCC) is a major global health burden, with limited tools for early diagnosis and prognosis. This study explores serum-derived exosomal miR-1275 as a potential non-invasive biomarker for HCC.MethodsExosomes were isolated from serum samples of 50 HCC patients and 50 matched healthy controls. miR-1275 expression was quantified by qRT-PCR and compared with traditional biomarkers (AFP, CEA, CA199, DCP, AFP-L3%). Diagnostic performance was evaluated using ROC curves. Bioinformatic analyses, including TCGA pan-cancer data, target gene prediction, and pathway enrichment, were performed to explore regulatory mechanisms.ResultsExosomal miR-1275 levels were significantly reduced in HCC patients and correlated with advanced clinical stage, tumor burden, and metastasis. miR-1275 showed strong diagnostic value (AUC = 0.869), outperforming CEA and CA199, and improved significantly when combined with other biomarkers (AUC = 0.982). UBE2V1 was identified as a key miR-1275 target involved in cancer-related pathways, including ubiquitination and mTOR signaling.ConclusionSerum exosomal miR-1275 is a promising biomarker for early diagnosis and prognosis of HCC. Its integration into multimarker panels could enhance clinical decision-making and patient management.

Cancer genes break free from the regulatory constraints of chromosomes.

Epigenetic and transcriptional dysregulation plays a fundamental role in tumor lineage plasticity (LP). However, the underlying mechanisms, especially for the initial events of LP development, are still poorly understood. Here, we report that in progression of prostate cancer from adenocarcinoma to treatment-induced neuroendocrine prostate cancer (t-NEPC), anti-androgen receptor (AR) signaling inhibitors (ARSIs) reprogram the function of circadian regulator/nuclear receptor REV-ERBα by switching its target gene programs from kinase signaling and metabolic programs to programs of LP, which includes neurogenesis, stem cell, and epithelial-mesenchymal transition as well as over fifteen LP drivers including POU3F2/BRN2, ASCL1, FOXA2, ONECUT2, and MYCN. Unexpectedly, REV-ERBα facilitates the chromatin occupancy of BRN2, ASCL1, and FOXA1 in their activation of LP programs, thus functioning as a master regulator of ARSI-induced LP driver network. Mechanistically, REV-ERBα induces chromatin accessibility and H3K27ac modification at promoters of LP genes through its recruitment of BRD4 and p300. Overexpression of REV-ERBα alone is sufficient to induce LP and neuroendocrine phenotype and confers resistance to ARSI in adenocarcinoma cells. Loss of REV-ERBα potently inhibits NEPC cell growth and abolishes the expression of LP drivers and gene programs. Pharmacological inhibition of REV-ERBα exhibits high potency in blocking the growth of NEPC tumors including patient-derived xenografts. Our findings reveal that therapy-induced LP development entails a coordinated induction of a network of LP drivers and that REV-ERBα is an unexpected master regulator of the network and a promising therapeutic target for treatment of advanced prostate cancer such as NEPC.

The information-theoretic approach can shed light on the role of groups of correlated elements within a network. While there are already established methods for measuring new information, storage and transmission, the definition and application of methods for measuring information change remains an unresolved challenge. The change of information in a network is associated with redundancy and synergy between systems that share information about a target. Redundancy involves shared information about the target that can be retrieved using the individual source systems, while synergy involves information that can only be obtained by sharing the systems. A more refined approach, called partial information decomposition (PID), separates the unique, redundant and synergetic contributions of the shared information. However, these contributions cannot be directly derived from the classical measures of information theory. In this work, we apply PID approach to publicly available microarray gene expression data from 2 different experiments derived from patients affected by HCC and ASD. By comparing sample and gene synergy clusters with classical correlation clusters, we uncover higher order behaviours, such as differential genes and enriched functions closely linked to diseases phenotype, that emerge with this novel approach. These findings and further applications of this approach to gene expression data could shed light on the genetic aspects related to physiological aspects of complex diseases.

Vestibular schwannoma (VS) is a benign tumor originating from Schwann cells, and its molecular pathogenesis remains poorly understood. Increasing evidence suggests oxidative stress (OS) plays a critical role in tumor development, but its involvement in VS is largely unexplored.

Osteosarcoma is the most common malignant bone tumor in children and adolescents, characterized by high heterogeneity and a complex tumor microenvironment (TME). Despite multimodal treatments, survival rates have stagnated, highlighting the need for new therapeutic options. Single-cell RNA sequencing (scRNA-seq) offers a powerful tool to dissect heterogeneity and uncover mechanisms of progression and immune evasion. A narrative literature review, guided by PRISMA principles, was conducted through October 2024 via PubMed and Scopus databases to assess scRNA-seq contributions to osteosarcomagenesis. A total of 107 studies were analyzed to highlight the identification of tumor subpopulations, signaling pathways, diagnostic and prognostic biomarkers, and therapeutic assessments. Our analysis highlights the critical role of scRNA-seq in revealing the complexity of the osteosarcoma TME. Studies identified distinct immune and non-immune cell subpopulations, with TXNIP+ and IFIT1+ macrophages, KAZALD1, EGFL7, TNFSF11, and TRAIL receptors emerging as potential therapeutic targets. scRNA-seq has elucidated mechanisms of tumor progression and metastasis, including CD24 expression, and enabled the discovery of immune and stromal biomarkers within the TME. It also revealed novel therapeutic strategies, such as targeting Tregs via CXCR4 inhibition, CAFs through LOX and SERPINE1 modulation, and MCL1 in metastatic niches. Additionally, it uncovered promising drug candidates-etoposide, mevastatin, oxfendazole, HDAC inhibitors, and TIGIT blockade-as well as immunotherapies like PD-1 inhibition and adoptive CD8+ T cell therapy. scRNA-seq has transformed insights into osteosarcoma by exposing key cellular dynamics and potential therapeutic targets. While technical challenges remain, it paves the way for more personalized and effective treatment strategies. However, the current findings are subject to limitations, including technical biases in single-cell protocols and the exclusion of non-English literature, which may affect generalizability.

Although low-grade glioma (LGG) patients usually enjoy an active familial and socio-professional life, their ability to practice sports was poorly studied. Here, the capability to resume high-level sports following awake surgery (AS) in LGG patients who performed intensive sport activities before resection was investigated.

Non-small-cell lung cancer (NSCLC) is associated with high mortality. Beclin 1 (BECN1), an autophagy regulator, and ferroptosis, a lipid peroxidation-driven cell death, are both linked to cancer suppression. This study examines whether the BECN1 activator peptide, Tat-Beclin 1, induces ferroptosis in NSCLC by targeting solute carrier family 7 member 11 (SLC7A11). BECN1 expression in NSCLC tissues and cells was assessed using RT-qPCR, western blot, and immunohistochemistry. Functional assays included CCK-8 for cell viability, C11-BODIPY for lipid peroxidation, glutathione (GSH) and glutamate release, glutathione peroxidase 4 (GPX4) activity, and western blotting for iron metabolism markers (ferritin heavy chain 1 [FTH1], ferritin light chain [FTL], and transferrin receptor [TFRC]). BECN1-SLC7A11 interactions were examined using co-immunoprecipitation and immunofluorescence. BECN1 was knocked down using small hairpin RNA (shRNA), and its effects on ferroptosis were evaluated. System Xc⁻ activity was assessed in control, Tat-beclin 1, Tat-beclin 1 + shRNA-NC, and Tat-Beclin 1 + shRNA-BECN1 groups. Tumor suppression by Tat-beclin 1, erastin, and their combination was assessed in vivo using xenograft models. BECN1 expression was downregulated in NSCLC tissues and cells. Treating NSCLC cells with Tat-beclin 1 upregulated BECN1 expression and promoted ferroptosis, as evidenced by increased lipid peroxidation and malondialdehyde content, reduced GSH and GPX4 activity, and decreased cell viability, without affecting Fe2+ levels or the expression of iron metabolism-related proteins (FTH1, FTL, and TFRC). Knocking down BECN1 attenuated these effects, confirming its central role. BECN1 interacted with SLC7A11 to inhibit system Xc⁻, an effect abolished by knocking down BECN1. Co-treatment with Tat-beclin 1 and erastin enhanced BECN1-SLC7A11 complex formation, more strongly inhibited system Xc⁻, enhanced lipid peroxidation, inhibited the Nrf2-Keap1 signaling pathway and significantly suppressed tumor growth in vivo. Tat-beclin 1 promotes ferroptosis and tumor suppression in NSCLC by activating BECN1 and inhibiting SLC7A11-mediated system Xc⁻ activity.

This study aims to investigate the epigenetic regulation of TIPE3 in nasopharyngeal carcinoma (NPC) and its role in tumor progression, with a focus on enhancer elements and associated histone modifications, as well as the involvement of the Hedgehog signaling pathway.

Despite efforts to understand breast cancer biology, metastatic disease remains a clinical challenge. Identifying suppressors of breast cancer progression and mechanisms of transition to more invasive phenotypes could provide game changing therapeutic opportunities. Transcriptional dysregulation is central to all malignancies, highlighted by the extensive reprogramming of regulatory elements that underlie oncogenic programs. Among these, super-enhancers (SEs) stand out due to their enrichment in genes controlling cancer hallmarks. To reveal novel breast cancer dependencies, we integrated the analysis of the SE landscape with master regulator activity inference for a series of breast cancer cell lines. As a result, we identified T-helper-inducing Poxviruses and Zinc-finger (POZ)/Krüppel-like factor (ThPOK, ZBTB7B), a CD4+ cell lineage commitment factor, as a breast cancer master regulator that is recurrently associated with a SE. ThPOK expression is highest in luminal breast cancer but is significantly reduced in the basal subtype. Manipulation of ThPOK levels in cell lines shows that its repressive function restricts breast cancer cells to an epithelial phenotype by suppressing the expression of genes involved in the epithelial-mesenchymal transition (EMT), WNT/β-catenin target genes, and the pro-metastatic TGFβ pathway. Our study reveals ThPOK as a master transcription factor that restricts the acquisition of metastatic features in breast cancer cells.

Imatinib is a small molecule that inhibits receptor tyrosine kinases KIT and platelet-derived growth factor receptor α (PDGFRA). It was approved by the U.S. Food and Drug Administration (FDA) in 2002 for the treatment of advanced, unresectable gastrointestinal stromal tumours (GISTs). Since then, additional kinase inhibitors targeting multiple pathways have also been introduced. However, as treatment with imatinib is prolonged, its effectiveness gradually declines, with 50% of patients experiencing relapse within 2-5 years. This decline in effectiveness is largely attributed to the development of both initial and acquired resistance. Due to these mechanisms of resistance, many advanced GIST patients struggle to achieve long-term benefits from systemic treatment. This review aims to summarise the mechanisms of resistance to imatinib and their relationship with GIST molecular subtypes, while also exploring the latest strategies to overcome resistance. We discuss the alterations in signalling pathways following imatinib resistance, the disruption of autophagy and glycolysis, the role of microRNAs and immunotherapy in resistant GISTs, and combination therapies. Furthermore, we examine ongoing clinical trials and potential future therapies that could be integrated into clinical practice, offering guidance for new treatment strategies that aim to enhance the prognosis of advanced GIST patients.

To explore the impact of age on the genetic variant spectrum and prognosis of patients with previously untreated Diffuse large B-cell lymphoma (DLBCL).

Testicular germ cell tumors (TGCTs), though typically responsive to therapy, may rarely develop somatic-type malignancy (STM), a transformation associated with poor prognosis and chemoresistance. This study presents two cases of postpubertal-type teratoma with intestinal-type adenocarcinoma as STM, offering insights into their clinical, histopathological, immunophenotypic, and molecular profiles. The first patient, a 63-year-old male, presented with pulmonary and retroperitoneal metastases and underwent orchiectomy, revealing an intratesticular intestinal-type adenocarcinoma. Molecular testing confirmed 12p overrepresentation and pathogenic mutations in CTNNB1, STK11, and MDM2. The second patient, initially diagnosed at age 35 with a mixed TGCT, developed STM as a late recurrence 16 years post-orchiectomy, manifesting as a retroperitoneal mass with vertebral invasion. Histology again confirmed intestinal-type adenocarcinoma, and molecular testing revealed amplification of ERBB2, KRAS, along with mutations in TP53 and PIK3CA. Both cases were managed with capecitabine-oxaliplatin plus bevacizumab, followed by maintenance therapy, achieving disease stabilization for at least 9 months. These cases illustrate the diagnostic and therapeutic complexities of STM, particularly with adenocarcinoma morphology that may mimic primary gastrointestinal neoplasms. Accurate diagnosis required exclusion of alternate primary sites and demonstration of chromosome 12 aberrations using FISH and next-generation sequencing. Our findings emphasize the importance of long-term follow-up in TGCT patients, particularly those with teratomatous elements, and highlight the value of cytogenetic and molecular profiling in confirming STM and identifying potential therapeutic targets. Given the rarity of STM, especially in metastatic or recurrent settings, there is an urgent need for standardized diagnostic protocols and evidence-based treatment strategies. These cases support the use of tumor-specific chemotherapy regimens guided by the histological and molecular characteristics of STM.

This short review highlights recent findings related to transcription factor-mediated RNA polymerase II (Pol II) pause release at enhancers and its role in regulating cell identity. We discuss how the transcriptional state of Pol II, either paused or released, shapes enhancer-promoter interactions, thereby influencing gene expression programs that define cell identity. We further summarize current knowledge of DNA-binding transcription factors that regulate Pol II pause release at enhancers and explore how this process influences cell identity. We propose a novel concept of therapy-induced molecular amnesia, where temporary inhibition of enhancer-proximal Pol II pause release and enhancer RNA transcription affects enhancer-promoter interactions differently in distinct cellular contexts. In some contexts, preservation of enhancer-promoter interactions allows rapid transcriptional reactivation and maintenance of cell identity upon recovery. In other contexts, repeated inhibition of enhancer RNA transcription leads to the permanent dissociation of enhancer-promoter interactions and loss of cell identity. Our model suggests that manipulating Pol II pause release at enhancers could selectively reverse certain aggressive tumor cell identities, limit tumor cell plasticity, and improve therapy responsiveness.

The treatment of patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) whose disease progresses after tyrosine-kinase inhibitors (TKIs) treatment has become a research hotspot.

Gastric cancer immunotherapy, recognized as the fourth primary treatment modality after surgery, radiotherapy, and chemotherapy, encompasses strategies such as immune checkpoint inhibitors and cellular immunotherapy and provides new avenues for cancer control. Recent studies have revealed that non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, piRNAs, siRNAs, and circRNAs, drive the progression of gastric cancer primarily through three regulatory axes: epigenetic modification, transcriptional reprogramming, and tumor microenvironment remodeling. These processes are closely linked to tumor immunity and the efficacy of immunotherapy in gastric cancer (GC). Building on an overview of current immunotherapy regimens for GC, this review provides a comprehensive summary of the molecular mechanisms by which ncRNAs regulate immune cell infiltration, modulate immune checkpoints, and reshape the immunosuppressive microenvironment to influence immunotherapeutic outcomes. Furthermore, the potential translational applications of ncRNAs as prognostic biomarkers and therapeutic targets within the context of GC immunology are discussed. Collectively, these mechanistic insights and clinical perspectives offer a theoretical foundation for overcoming the limitations of current immunotherapy approaches and improving the long-term prognosis of patients with GC.

Current prognostic evaluation in melanoma primarily relies on traditional histopathological and clinical staging evaluation; however, these conventional approaches exhibit limited accuracy and fail to account for individual patient heterogeneity. To address these limitations, we developed a machine learning-driven prognostic signature, with the objectives of identifying pivotal biomarkers and establishing a precision medicine framework for prognostic assessment in melanoma management. Bulk RNA-seq data of 636 melanoma patients were obtained from TCGA and GEO databases, followed by univariate Cox regression to identify prognosis-associated genes. Intersecting results across cohorts identified consistently prognostic genes. Heterogeneity of the selected genes was assessed between primary and metastatic melanoma using scRNA-seq data. The consensus prognosis-related signature was developed by systematically integrating 101 machine learning algorithms, with model performance rigorously evaluated through multidimensional metrics. Finally, molecular experiments validated the prognostic relevance of the model's hub genes, and the biological role of CUL2 was investigated in melanoma. 53 protective prognosis-related genes (PRGs) were identified in melanoma. Single-cell analysis revealed elevated PRGs activity in primary melanoma tissues compared to metastatic lesions. A 14-gene consensus prognosis-related signature was developed using LASSO and RSF algorithms. The model achieved a C-index of 0.908 in the TCGA-SKCM cohort and a mean C-index of 0.758 across four independent validation cohorts. Furthermore, the model outperformed 19 existing prognostic models across multiple cohorts. This study developed a 14-gene consensus prognosis-related signature validated for robust prognostic performance across cohorts. CUL2, identified as a pivotal protective biomarker in melanoma, demonstrates potent tumour-suppressive activity through significant inhibition of proliferation and migration potential.

Glioma is the most prevalent primary brain tumor, causing significant mortality and morbidity. lncRNAs have great potential in tumor-targeted therapy, including for glioma via sponging microRNAs. Previous studies have shown that LINC00900 and miR-186-5p likely play a significant role in glioma progression. However, the relationship between them has not been elucidated. The purpose of this study was to explore the role of LINC00900 in the prognosis of gliomas and its underlying molecular mechanisms.