Pathology, research and practice最新文献

{"title":"Molecular landscape and biomarker discovery in adrenocortical carcinoma: An integrative review of bioinformatics and translational insights","authors":"Javad Omidi","doi":"10.1016/j.prp.2025.156295","DOIUrl":"10.1016/j.prp.2025.156295","url":null,"abstract":"<div><div>Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with limited therapeutic options and poor prognosis. Recent advances in high-throughput sequencing and integrative bioinformatics have unraveled the complex molecular landscape of ACC, highlighting critical genomic, epigenomic, transcriptomic, and immune-related alterations. This review synthesizes current evidence to provide a comprehensive overview of the key molecular mechanisms driving ACC pathogenesis. The role of recurrent mutations (e.g., TP53, CTNNB1), dysregulated cell cycle genes (e.g., CDK1, CCNB1, AURKA), non-coding RNAs, and epigenetic modifications in shaping tumor behavior is discussed. Multi-omics integration and systems biology approaches have enabled the identification of robust prognostic gene signatures and protein biomarkers, offering novel tools for risk stratification. Furthermore, the tumor immune microenvironment is examined, with hypoxia, immune suppression, and checkpoint pathways highlighted as emerging targets. Finally, computational drug repositioning strategies that nominate repurposed agents such as IGF1R inhibitors and BCLAF1 modulators for therapeutic intervention are explored. Together, these insights pave the way for precision oncology in ACC, while emphasizing the need for rigorous multi-layered validation and standardized clinical integration to enable real-world translational impact.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156295"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EBF3 transcriptionally activates ACADL to block the Hippo/YAP signaling pathway and inhibits breast cancer progression","authors":"Caihong Cao ,&nbsp;Xing Feng","doi":"10.1016/j.prp.2025.156299","DOIUrl":"10.1016/j.prp.2025.156299","url":null,"abstract":"<div><h3>Objective</h3><div>Breast cancer (BC) is the chief cause of malignancy-related deaths in women. This paper investigates how the EBF3-ACADL axis inhibits BC progression through Hippo/YAP signaling.</div></div><div><h3>Methods</h3><div>The differentially expressed gene ACADL in BC was screened by the bioinformatics databases, and ACADL expression in BC tumors and cells was verified by immunohistochemistry, RT-qPCR, and western blot analysis. BC cells were infected with an overexpressing-ACADL lentivirus to examine the effect of ACADL on BC cell growth. The <em>in vivo</em> impact of ACADL was investigated by constructing a xenograft tumor model. Cells were treated with XMU-MP-1, an inhibitor of MST1/2 kinase, to study the influence of ACADL on BC progression through the Hippo/YAP pathway. The upstream mechanism of abnormally elevated ACADL expression was analyzed by bioinformatics, and EBF3 expression in BC tumors and cells was verified. Regulatory assays were performed to confirm the binding relationship between ACADL and EBF3.</div></div><div><h3>Results</h3><div>ACADL and EBF3 were poorly expressed in BC tissues and cell lines. ACADL overexpression blocked p-YAP (Ser127), nuclear YAP localization, and canonical target genes (CTGF, CYR61, and ANKRD1), thereby suppressing BC cell growth and xenograft tumor development. XMU-MP-1 reversed the suppressive effect of ACADL overexpression on BC progression. EBF3 transcriptionally activated ACADL expression by binding to its promoter. EBF3 overexpression suppressed the malignant behavior of BC cells and xenograft tumor development in mice, which was reversed by ACADL knockdown.</div></div><div><h3>Conclusion</h3><div>EBF3 transcriptionally activates ACADL and blocks the Hippo/YAP pathway to inhibit BC progression.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156299"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The clinical pathological significance of TLSs in HER2-low breast cancer","authors":"Zhixing Zhang ,&nbsp;Wei Kang ,&nbsp;Chunjun Li ,&nbsp;Dongdong Zhang ,&nbsp;Xiaoyu Chen ,&nbsp;Dan Lu ,&nbsp;Yuzhen Huang ,&nbsp;Lixia Zeng","doi":"10.1016/j.prp.2025.156300","DOIUrl":"10.1016/j.prp.2025.156300","url":null,"abstract":"<div><h3>Purpose</h3><div>To investigate the presence and clinical significance of tertiary lymphoid structures (TLSs) in HER2-low breast cancer, by focusing on their associations with clinicopathological features and prognosis.</div></div><div><h3>Methods</h3><div>Hematoxylin and eosin staining and immunohistochemical markers were used in combination with whole-slide imaging (WSI) to delineate invasive carcinoma and adjacent TLSs. WSI-based tools were subsequently utilized to annotate the location, density, and maturity of TLSs.</div></div><div><h3>Results</h3><div>Among 560 patients with HER2-low breast cancer, the median age was 53 years and the age range was 28–85 years; 34 % (189/560) had TLSs-positive tumors. TLSs were associated with high histological grade, high-grade DCIS, absence of lymphovascular invasion, ER-negative, PR-negative, HER2 2 + , high K-i67, and triple-negative breast cancer subtypes (all P &lt; 0.05). In the low-age cohort, TLSs (+), TLSs density, TLSs maturity, and peritumoral TLSs were significantly associated with poorer DFS (all P &lt; 0.05).Conversely, TLSs (+), TLSs density, TLSs maturity, and peritumoral TLSs were significantly associated with better DFS in the high-age cohort (all P &lt; 0.05).</div></div><div><h3>Conclusion</h3><div>In HER2-low breast cancer, TLSs were associated with higher histological grade, the presence of DCIS, absence of lymphovascular invasion, as well as expression of ER negative, PR negative, HER2 2 + , high K-i67, and triple-negative breast cancer. Additionally, the clinical prognosis value of TLSs (such as DFS) exhibited a correlation with the patient’s age.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156300"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative stress and neuronal alteration: Mitochondrial dysfunction as a key player in intractable epilepsy - a narrative review","authors":"Muhammad Liaquat Raza ,&nbsp;Mustafa Hussain Imam ,&nbsp;Warisha Zehra ,&nbsp;Insa Binte Anwar ,&nbsp;Rukhsar Mehdi","doi":"10.1016/j.prp.2025.156285","DOIUrl":"10.1016/j.prp.2025.156285","url":null,"abstract":"<div><div>Drug-resistant epilepsy (DRE) still poses one of the greatest therapeutic challenges, afflicting about one-third of all patients with epilepsy in the world. Despite spectacular advances in the fields of anti-seizure medications and neurostimulation techniques, treatment outcomes in DRE have reached plateau levels, signifying an urgent need for better mechanistic understanding and therapeutic strategies. New evidence increasingly elucidates mitochondrial dysfunction as a lens through which to understand seizure generation, pharmacoresistance, and disease progression. Mitochondria are regulators of ATP production, calcium buffering, and redox homeostasis; disruption of any such pathway will result in neuronal hyperexcitability, oxidative injury, and cell death. Moreover, mitochondrial DNA mutations and heteroplasmy threshold can correlate with seizure onset, seizure severity, and <strong>Response</strong> to treatment, thus being potential biomarkers for risk stratification. This narrative review surveys both preclinical and clinical evidence for mitochondrial dysfunction in epilepsy, examining oxidative stress pathways, mitophagy, and mitochondrial permeability transition pore opening as key mechanisms of neuronal vulnerability. We subsequently analyze various preclinical models of mitochondrial dysfunction, pointing out their respective strengths and weaknesses. Emerging therapeutic strategies, encompassing pharmacological agents, gene therapy, diet, and natural compounds, are then reviewed, which aim to resolve issues surrounding mitochondrial health on a molecular basis. By straddling the mechanistic and clinical narratives, this work foregrounds mitochondrial-centered approaches as promises for both the diagnostic and therapeutic arsenal in the management of DRE.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156285"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progress in nanotechnology-based strategies to enhance tamoxifen therapy for breast cancer management","authors":"Karthik Mangu ,&nbsp;Aashna Nimish Gandhi ,&nbsp;Md. Rizwanullah","doi":"10.1016/j.prp.2025.156308","DOIUrl":"10.1016/j.prp.2025.156308","url":null,"abstract":"<div><div>Breast cancer (BC) remains a major cause of cancer-related mortality among women worldwide, with estrogen receptor-positive (ER⁺) tumors representing the most common subtype. Tamoxifen (TMX), a selective estrogen receptor modulator, has been a cornerstone in ER⁺ BC therapy for decades. However, its clinical utility is hampered by its high lipophilicity, poor water solubility, systemic toxicity, off-target effects, and the emergence of resistance. In recent years, nanoparticle (NPs)-based drug delivery has emerged as a promising approach to surmount these challenges and enhance the therapeutic potential of TMX. These NPs not only improve solubility and bioavailability but also demonstrate validated outcomes such as resistance reversal, prolonged plasma half-life, significant tumor inhibition, and reduced systemic toxicity, thereby underscoring their clinical-translational potential in BC. This review critically analyzes the limitations of traditional TMX therapy and critically evaluates the role of various NPs-based strategies in overcoming these barriers. Furthermore, we explored the potential of multifunctional NPs to co-deliver TMX with other therapeutic agents to achieve synergistic effects and circumvent resistance. Overall, this review highlights the transformative potential of NPs-enabled TMX delivery systems and provides future perspectives on their clinical translation for better BC management.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156308"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-dimensional targeting of the tumor microenvironment to inhibit the invasion and metastasis of breast cancer","authors":"Yutong Wang,&nbsp;Qingshuang Wang,&nbsp;Jiahua Chang,&nbsp;Zhengrong Chen,&nbsp;Chunshuang Qi,&nbsp;Xue Jiang,&nbsp;Xiangru Feng","doi":"10.1016/j.prp.2025.156309","DOIUrl":"10.1016/j.prp.2025.156309","url":null,"abstract":"<div><div>The predominant cause of mortality in breast cancer patients arises from tumor invasion and metastasis. The tumor microenvironment (TME) plays an indispensable role in breast cancer development and progression. In recent years, intervention strategies targeting TME have become a research hotspot for suppressing breast cancer metastasis. In this review, we summarize a deep insight of therapeutic approaches against cancer by remodeling TME: (1) vascular normalization strategies to inhibit tumor invasion and metastasis by improving the structure and function of the tumor vasculature; (2) targeting cancer-associated fibroblasts (CAFs) aiming to reduce tumor invasiveness by inhibiting the pro-tumorigenic activity of CAFs; (3) targeting senescent cells to reduce the pro-invasive nature of TME by removing senescent cells or modulating their secretion of the senescence-associated secretory phenotypes (SASP); (4) targeting exosomes to inhibit tumor invasion and metastasis by interfering with exosome-mediated intercellular communication and blocking signaling between tumor cells and TME; and (5) targeting cancer-associated adipocytes (CAA) in order to intervene in tumor progression by regulating metabolism and secretion of adipocytes. We summarize TME-remodeling approaches and their recent research progress. These strategies show promising results in breast cancer treatment and may advance precision therapy.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156309"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EGCG inhibits hepatic stellate cell activity and liver fibrosis by targeting the MDM2/MUC5AC-mediated TGF-β1/Smad signaling pathway","authors":"Longbao Yang ,&nbsp;Fenrong Chen ,&nbsp;Xiong Li,&nbsp;Xiaoke Sun,&nbsp;Hong Li,&nbsp;Haitao Shi,&nbsp;Gang Zhao","doi":"10.1016/j.prp.2025.156298","DOIUrl":"10.1016/j.prp.2025.156298","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the intervention effect of epigallocatechin gallate (EGCG) on liver fibrosis and its underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>A mouse model of liver fibrosis induced by a high-fat diet was established, with groups divided into normal control, high-fat diet (HF) group, and HF + EGCG groups (low, medium, and high doses). The therapeutic effect of EGCG on liver fibrosis was evaluated by liver pathological scoring, detection of serum biochemical indicators, analysis of fibrotic markers, and Western blot for fibrotic protein expression. LX-2 cells were cultured in vitro and activated by TGF-β1. Molecular biology experiments (RT-qPCR, Western blot, immunofluorescence, co-immunoprecipitation, etc.) were used to explore the effects of EGCG on LX-2 cell activation, proliferation, migration, and its regulation of the TGF-β/Smad signaling pathway. Ubiquitination assays, molecular docking, and enzyme inhibitor interventions were performed to clarify the regulatory mechanism of EGCG on MUC5AC stability and its interaction with MDM2. Gene silencing/overexpression techniques were used to verify the critical role of the MDM2/MUC5AC axis in EGCG’s anti-fibrotic effect.</div></div><div><h3>Results</h3><div>In vivo experiments showed that EGCG dose-dependently improved liver histological damage in high-fat diet-fed mice, reduced serum levels of ALT, AST, and TBil, increased albumin and prothrombin time, decreased the expression of fibrotic markers such as hyaluronic acid (HA) and laminin (LN), and inhibited the expression of fibrotic proteins including α-SMA and collagen I. In vitro experiments confirmed that EGCG reduced activation, proliferation, and migration of LX-2 cells by inhibiting the TGF-β1/Smad signaling pathway (downregulating Smad2/3 phosphorylation and upregulating Smad7). Mechanistically, EGCG targeted and bound to MDM2, inhibiting MDM2-mediated ubiquitination and degradation of MUC5AC, thereby increasing MUC5AC protein stability. MUC5AC directly interacted with TGF-β1, further inhibiting the activation of the TGF-β1/Smad pathway. Additionally, overexpression of MDM2 reversed the upregulation of MUC5AC and the anti-fibrotic effect of EGCG, while supplementation of MUC5AC restored the intervention effect of EGCG, confirming that EGCG exerts its function through the MDM2/MUC5AC axis.</div></div><div><h3>Conclusion</h3><div>EGCG targets MDM2 to prevent MUC5AC from ubiquitination and degradation. The upregulated MUC5AC binds to TGF-β1 and inhibits the TGF-β1/Smad signaling pathway, thereby suppressing hepatic stellate cell activation and liver fibrosis progression. This study provides new potential targets and experimental basis for the prevention and treatment of liver fibrosis.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156298"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145605549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CSB6B attenuates renal inflammation and fibrosis by inhibiting the activation of NLRP3 inflammasome through the NLRP3/Caspase-1/GSDMD/IL-1β signaling pathway","authors":"Shuo Chen ,&nbsp;Yonghong Zhu ,&nbsp;Tong Chen ,&nbsp;Yanyan Xu ,&nbsp;Qiuling Fan","doi":"10.1016/j.prp.2025.156286","DOIUrl":"10.1016/j.prp.2025.156286","url":null,"abstract":"<div><h3>Context</h3><div>Diabetic Kidney Disease (DKD) is a significant complication and leading cause of death in both type 1 and type 2 diabetes, as well as the primary cause of chronic kidney disease. Macrophage migration inhibitory factor (MIF) activates the NLRP3 inflammasome. Chicago sky blue 6B (CSB6B) is a MIF inhibitor with therapeutic potential in various inflammatory diseases, but its effect on DKD remains unexplored.</div></div><div><h3>Materials and methods</h3><div>HK-2 cell was used as the in vitro cell model. For the in vivo animal model, The db/db mice were randomly divided into three subgroups: the diabetic nephropathy model group, the low-dose CSB6B intervention group (2 mg/kg), and the high-dose CSB6B intervention group (8 mg/kg), with drug administration via intraperitoneal injection twice weekly for 12 weeks. CCK-8 assessed CSB6B toxicity, while qPCR measured MIF mRNA expression. Western blot, immunohistochemistry and ELISA detected protein expression level, and LDH release assessed membrane integrity. Histological analysis evaluated renal pathological changes.</div></div><div><h3>Results</h3><div>CSB6B significantly inhibited the secretion of inflammatory cytokines interleukin-1β (IL-1β) and TGF-β1 from high-glucose-stimulated HK-2 cells without affecting their viability. CSB6B effectively inhibited the expression and secretion of MIF in high-glucose-stimulated HK-2 cells, down-regulated the expression of NLRP3, suppressed the activation of NLRP3 inflammasomes, reduced the production of cell pyroptosis-related proteins, and significantly decreased collagen I and FN expression. CSB6B treatment significantly reduced the body weight, blood glucose, blood creatinine, urine ACR, and NGAL of db/db mice, and improved the pathological damage of diabetic nephropathy. CSB6B effectively reduced the expression level of MIF protein in diabetic nephropathy mice, down-regulated the expression of NLRP3, Caspase-1, GSDMD, IL-1β, Collagen I and FN in the renal cortex of diabetic nephropathy mice.</div></div><div><h3>Conclusions</h3><div>CSB6B mitigated DKD by inhibiting the NLRP3/Caspase-1/GSDMD pyroptosis signaling pathway, suppressed cell pyroptosis, reduced cytokine secretion, and decreasd extracellular matrix accumulation. CSB6B showed promise as a potential therapeutic for DKD.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156286"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular regulation and therapeutic targeting of programmed cell death in hepatocellular carcinoma","authors":"Yu Zhao ,&nbsp;Liuxin Yang ,&nbsp;Peng Wang ,&nbsp;Shuang Huo ,&nbsp;Xingxing Yuan ,&nbsp;Jiakang Jiang","doi":"10.1016/j.prp.2025.156310","DOIUrl":"10.1016/j.prp.2025.156310","url":null,"abstract":"<div><h3>Background</h3><div>Hepatocellular carcinoma (HCC) is a global health challenge with limited treatment options, largely due to the ability of tumor cells to evade programmed cell death (PCD). Dysregulation of key PCD pathways; apoptosis, necroptosis, pyroptosis, and autophagy plays a pivotal role in hepatocarcinogenesis, progression, and therapy resistance.</div></div><div><h3>Objective</h3><div>This review comprehensively elucidates the molecular mechanisms governing these PCD pathways, their dysregulation in HCC, and the resulting therapeutic opportunities.</div></div><div><h3>Methods</h3><div>We systematically analyzed current literature to detail the core regulators of each PCD pathway, summarize how HCC cells evade them, and evaluate preclinical and clinical strategies for therapeutic targeting.</div></div><div><h3>Key findings</h3><div>HCC cells hijack multiple mechanisms to suppress apoptosis and divert necroptosis. Pyroptosis exhibits a dual role, acting as a tumor suppressor but also contributing to an immunosuppressive microenvironment in established tumors. Autophagy serves a context-dependent function, preventing tumor initiation but sustaining advanced tumors. Promisingly, preclinical studies demonstrate that resensitizing HCC cells to PCD, particularly through combination therapies, can overcome resistance. Early-phase clinical trials targeting these pathways, especially with autophagy inhibitors, have shown manageable safety profiles and hints of efficacy, though larger trials are needed.</div></div><div><h3>Conclusion</h3><div>The precise modulation of PCD pathways represents a promising frontier in HCC therapy. Future efforts must focus on patient stratification, biomarker development, and rational combination strategies that exploit the crosstalk between different PCD modalities to improve clinical outcomes.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156310"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pitfalls in MLH1 promoter methylation assessment, including POLEmut/MLH1meth endometrial adenocarcinoma","authors":"Amelia Flaus ,&nbsp;Zhi Cui ,&nbsp;Mirko Miladinovic ,&nbsp;Ju-Yoon Yoon","doi":"10.1016/j.prp.2025.156303","DOIUrl":"10.1016/j.prp.2025.156303","url":null,"abstract":"<div><div><em>MLH1</em> promoter methylation status may serve as an important diagnostic, prognostic, and predictive biomarker in management of mismatch repair (MMR)-deficient cancers. A new commercial assay for detection of <em>MLH1</em> promoter hyper-methylation (EntroGen), which interrogates regions C and D, was assessed for its performance characteristics. False positive results were obtained in 5/21 non-lesional cases, with signals limited to region C. Three were explained by overloaded reactions. Two unexplained cases were both muscle samples (2/6 muscle samples, one each of skeletal and smooth). The assay was 100 % concordant (52/52) for lesional samples with expected <em>MLH1</em> promoter methylation status. These included two exceptional cases—one Lynch-associated, and one <em>POLE</em>-mutated endometrial carcinoma; thus expanding the spectrum of extreme cases, and demonstrate neither germline or somatic NGS results completely rule out <em>MLH1</em> promoter methylation, and vice versa. The <em>POLE</em>^mut/<em>MLH1</em>^meth carcinoma was notable for molecular features in keeping with POLE dysfunction, accompanied by multiple, additional genetic lesions in the MMR pathway. Exploring the TCGA dataset, 1/8 cases of POLE (ultramutated) endometrial carcinoma was notable for <em>MLH1</em> silencing. Comprehensive genomic profiling assay was informative, allowing for correlation of <em>MLH1</em> methylation and <em>POLE</em> genotype results with tumor mutation burden and mutational signature. Taken together, our data highlight the need for integrated approach in endometrial carcinoma biomarker testing, integrating NGS and <em>MLH1</em> promoter methylation status, the latter of which benefits from assessing both regions C and D. Finding of <em>MLH1</em> promoter methylation does not rule out either Lynch syndrome or ultramutated (POLE) carcinoma.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156303"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}