Laboratory Investigation最新文献

{"title":"Prevalence, immune checkpoint expression and spatial interplay of immune cells is linked to favourable tumor phenotype in 4915 human carcinomas.","authors":"Zhihao Huang, Tim Mandelkow, Jonas B Raedler, Elena Bady, Jan H Müller, Ronald Simon, Eik Vettorazzi, Guido Sauter, Julia Ebner, Niclas C Blessin","doi":"10.1016/j.labinv.2025.104248","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104248","url":null,"abstract":"<p><p>Although there is raising evidence that immune cell subpopulations that are in direct contact to the tumor cells (intraepithelial) can predict response to immune checkpoint therapy and patient's outcome, a comprehensive assessment of intraepithelial immune cells and their spatial interplay is lacking. To assess intraepithelial leukocyte densities, immune checkpoint expression, and spatial interactions in 43 carcinoma entities, 4915 tumor samples in a tissue microarray format were analyzed using a deep learning framework and BLEACH&STAIN multiplex fluorescence immunohistochemistry (mfIHC). This approach enabled single-cell resolution quantification of 21 biomarkers through seven sequential staining and imaging rounds. Immune and tumor cells were classified into 54 subpopulations. The mean intraepithelial immune cell density of CD8⁺cytotoxic T-cells, CD4⁺T-helper cells, FOXP3⁺Tregs, CD20⁺B-cells, M1/M2-macrophages and CD11c⁺dendritic cells varied markedly between tumor entities and individual tumors. For instance, 88(±90) cells/mm² were found in tubular breast cancer, 661(±729) cells/mm² in colorectal cancer, and up to 2325(±2131) cells/mm² in squamous cell cancers from various origins. Unsupervised cluster analysis revealed a \"cluster a\" of 634 patients from almost all different tumor entities with an exceptionally high density of intraepithelial immune cells that was characterized by a unique interaction profile along with the highest immune checkpoint expression. Across all analyzed tumor entities, the intraepithelial highly inflamed cluster a was significantly linked to low pT (p<0.001). The data from this study provide a comprehensive characterization of intraepithelial immune cells across 43 different human carcinomas and identify an inflamed pan-cancer phenotype characterized by strong interactions of intraepithelial CD8⁺cytotoxic T-cells, CD4⁺T-cells, dendritic cells, and M2 macrophages along with highest levels of TIM3, PD-1, and CTLA-4 expression that is linked to favorable tumor phenotype.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104248"},"PeriodicalIF":4.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Tumor Necrosis Factor-α–Dependent Inflammation Upregulates High Mobility Group Box 1 To Induce Tumor Promotion and Anti–Programmed Cell Death Protein-1 Immunotherapy Resistance in Lung Adenocarcinoma” [Laboratory Investigation 105 (2025) 102164]","authors":"Lifei Kang ,&nbsp;Jingjing Cao ,&nbsp;Wenli Guo ,&nbsp;Xiaohui Cui ,&nbsp;Yangxuan Wei ,&nbsp;Jiayu Zhang ,&nbsp;Feiran Liu ,&nbsp;Chenyang Duan ,&nbsp;Qiang Lin ,&nbsp;Ping Lvx ,&nbsp;Zhiyu Ni ,&nbsp;Jing Zuo ,&nbsp;Haitao Shen","doi":"10.1016/j.labinv.2025.104228","DOIUrl":"10.1016/j.labinv.2025.104228","url":null,"abstract":"","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104228"},"PeriodicalIF":4.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145219929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultra-Rapid EGFR Testing in Non-Small Cell Lung Carcinoma Patients: Findings from a Canadian Clinical Testing Workflow.","authors":"Kate Fitzsimmons, Curtis Hughesman, Reka Pataky, Deirdre Weymann, Marie-Frédérique D'Amours, Deepu Alex, Diana N Ionescu, Barb Melosky, Hannah Carolan, Kelly McNeil, Cheryl Ho, Anna McGuire, Stephen Yip, Julia R Naso","doi":"10.1016/j.labinv.2025.104245","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104245","url":null,"abstract":"<p><p>Single versus multigene molecular testing modalities for lung cancer offer distinct advantages and risks. We examined lung cancer cases with clinically requested ultra-rapid EGFR testing to (i) identify clinical features of rapid tested cases and their association with EGFR mutations, (ii) evaluate performance of single and multigene panel testing for ultra-rapid tested patients; and (iii) estimate laboratory costs and clinical outcomes. We include all retrospectively identified lung cancer patients who had ultra-rapid Idylla EGFR testing during the study period. Demographic data were retrieved from clinical charts and cost estimates were obtained from the BC Cancer Genetics and Genomics Laboratory. Of the 109 ultra-rapid tests, 94 (86%) were technically successful, yielding a positive or negative result. Of these, 62 tests (66%) identified an EGFR mutation. Patients with negative or failed testing were offered panel sequencing (n=47, 43%). Ultra-rapid testing had a median 1-day turnaround time and 95% sensitivity for EGFR mutation detection relative to panel sequencing. East/Southeast Asian ethnicity and female sex were significantly associated with EGFR mutation positivity in a multivariate logistic regression model (P=0.0001 and 0.029, respectively). The mean molecular testing cost per ultra-rapid tested patient, including panel sequencing for cases with negative/failed rapid tests, was $550.53 (standard deviation $284), slightly less than the $571 cost for panel sequencing. Single gene testing of patients with urgent clinical need or high probability of mutation may allow rapid time to treatment at similar testing costs.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104245"},"PeriodicalIF":4.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of QuPath and HALO platforms for analysis of the tumor microenvironment in prostate cancer.","authors":"Wei Zhang, Qin Zhou, Jonathan V Nguyen, Erika Egal, Qian Yang, Michael R Freeman, Siwen Hu-Lieskovan, Gita Suneja, Anna Coghill, Beatrice S Knudsen","doi":"10.1016/j.labinv.2025.104246","DOIUrl":"10.1016/j.labinv.2025.104246","url":null,"abstract":"<p><p>QuPath, an open-source digital pathology platform, has gained widespread use for image analysis in biomedical research since its release in 2016. However, its reproducibility and reliability compared to commercial software, such as HALO, requires further validation, particularly for multiplex immunofluorescence (mIF) analysis. In this study, we performed a direct comparison of QuPath and HALO using a mIF-stained prostate cancer tissue microarray (TMA) inclusive of 192 unique cores. We evaluated performance across three key analytical modules: immune cell phenotyping, tumor infiltration with immune cells, and nearest neighbor analysis. Furthermore, we integrated QuPath with CytoMap, an open-source spatial analysis tool, to perform unsupervised clustering of immune cell infiltration-a feature not available in HALO. Our results demonstrated high concordance between two platforms, with correlation coefficients exceeding 0.89 for immune cell density, distance and pattern of cell organization in tumor microenvironment (TME). A neighborhood analysis using CytoMap was further performed and provided a more detailed spatial analysis of immune cell distribution across different prostate cancer grades. A significant increase of CD103+ T cell infiltration into TME was observed in prostate cancer. In conclusion, our findings validate QuPath as a robust and reproducible alternative to commercial platforms for fluorescence-based digital pathology. By demonstrating QuPath's capability to perform high-quality quantitative analysis with additional flexibility for integration with external tools, our study underscores its potential for advancing tumor microenvironment research in translational oncology.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104246"},"PeriodicalIF":4.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MMP13- and COL11A1-expressing cancer-associated fibroblasts: key drivers of esophageal squamous cell carcinoma progression and prognostic indicators.","authors":"Shu Kato, Yuki Kato, Makoto Kodama, Kouhei Yamamoto, Asuka Furukawa, Yoshihiro Nagase, Rinka Miyashiro, Minako Takagi, Masayoshi Sakano, Hisashi Fujiwara, Kenro Kawada, Yusuke Kinugasa, Kenichi Ohashi","doi":"10.1016/j.labinv.2025.104247","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104247","url":null,"abstract":"<p><p>The tumor microenvironment comprises various cell types, and cancer-associated fibroblasts are crucial contributors to cancer progression and metastasis. Cancer-associated fibroblasts also play an important role in esophageal squamous cell carcinoma and have been extensively studied in this context. However, the association between cancer-associated fibroblasts and progression across pathological stages has not yet been reported. To identify these specific cancer-associated fibroblasts, we used a case-oriented approach for single-cell RNA sequencing. Consequently, we identified three cancer-associated fibroblast clusters, classified as myofibroblastic cancer-associated fibroblasts, which increased in number as the cancer progressed. Pathway analysis revealed that the three cancer-associated fibroblast clusters had distinct properties. These cancer-associated fibroblasts were named MMP13⁺, COL11A1⁺, and SFRP4⁺ myofibroblastic cancer-associated fibroblasts based on their characteristic gene expression. We also investigated the distribution of various immune cells within the tumor microenvironment associated with the three different cancer-associated fibroblast clusters. The results revealed the presence of different types of immune cells, including M2 macrophages, regulatory T cells, and interferon-γ⁺ programmed death-1⁺ T cells and interferon-γ⁺ programmed death-1^- T cells. Next, we evaluated the presence of these three cancer-associated fibroblast subtypes in surgically resected specimens from patients with advanced esophageal squamous cell carcinoma using RNA in situ hybridization. Analysis of the association between these three cancer-associated fibroblast subtypes and prognosis showed that two subtypes (MMP13⁺ and COL11A1⁺ myofibroblastic cancer-associated fibroblasts) were associated with poor prognosis. MMP13⁺ myofibroblastic cancer-associated fibroblasts were associated with poorly differentiated infiltration patterns, whereas COL11A1⁺ myofibroblastic cancer-associated fibroblasts were associated with lymph node metastasis. These results suggest that future treatments targeting these cancer-associated fibroblasts and patient stratification based on these cancer-associated fibroblasts are warranted.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104247"},"PeriodicalIF":4.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Replication Stress-Related Genes in Cervical Cancer Radiotherapy Resistance: A Bioinformatic and Experimental Validation.","authors":"Hongyan Qian, Min Tang, Tianqi Wu, Zhouna Sun, Junjie Mao, Juanjuan Cui, Feng Sun, Yunyan Lu, Hua Jin, Aiguo Shen","doi":"10.1016/j.labinv.2025.104244","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104244","url":null,"abstract":"<p><p>Cervical cancer (CC) remains a major global health challenge, with radiotherapy resistance (RR) representing a critical impediment to treatment efficacy. This study investigated the underlying mechanisms of replication stress (RS) in RR and identified potential therapeutic targets for CC. A comprehensive bioinformatics workflow was applied to analyze the expression profiles and prognostic significance of RS-related differentially expressed genes (RSRDs) in patients with RR. The prognostic utility of an RS-based risk score model was subsequently evaluated in the context of the tumor microenvironment, somatic mutation landscape, etc. The clinical relevance of the identified hub RSRDs was validated through immunohistochemistry (IHC), univariate and multivariate Cox regression analyses, and a prognostic nomogram using data from a real-world patient cohort. Functional assays conducted both in vitro and in vivo further confirmed the role of the key RSRD. Thus, enrichment analysis of the 124 common differentially expressed genes showed RS related biological processes were enriched. The RS risk score model, constructed using two hub RSRDs (AXIN1 and CTBP1) identified through LASSO regression, showed strong diagnostic and prognostic performance. Enrichment analysis showed the risk score model influenced CC prognosis by tumor microenvironment and mutation, etc. IHC analysis of tissue microarrays explored a significant downregulation of AXIN1 in RR samples. AXIN1 was also an independent prognosis biomarker for CC patients, particularly among patients receiving radiotherapy. Knock-down of AXIN1 significantly inhibited the radiosensitivity in CC cell lines, and in vivo experiments showed AXIN1 knockdown led to increased tumor volume following radiotherapy. Molecular docking analysis illustrated JQ1 may promote AXIN1 expression. This study is the first to identify AXIN1 as a replication stress associated gene with prognostic value in CC, specifically in the context of radiotherapy. These findings may support personalized treatment strategies and provide a foundation for future investigations into RS-targeted therapies in CC.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104244"},"PeriodicalIF":4.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CBX4 is a novel interactor of SS18::SSX in synovial sarcoma.","authors":"Ainiah Rushdiana Raquib, Torsten O Nielsen","doi":"10.1016/j.labinv.2025.104243","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104243","url":null,"abstract":"<p><p>Synovial sarcoma is an aggressive cancer generally affecting adolescents and young adults, and is characterized by high rates of recurrence and metastasis. It is primarily driven by the fusion oncoprotein SS18::SSX, the product of a pathognomonic chromosomal translocation t(X;18), which facilitates widespread epigenetic dysregulation through interactions with complexes such as the BAF complex and polycomb repressive complexes. Previous attempts to perform mass spectrometry of the SS18::SSX interactome has been limited by the lack of an antibody to detect the endogenous protein, hence relying on single cell lines with exogenous tags. We previously used a monoclonal antibody which specifically detects SS18::SSX containing the canonical fusion junction (seen in 95% of cases) and established its utility in several applications. Using that antibody, mass spectrometry analysis revealed that the SS18::SSX protein undergoes alternative splicing of exon 8 in SS18. We next performed immunoprecipitation mass spectrometry of SS18::SSX in six immortalized human synovial sarcoma cell lines and identified the canonical polycomb repressive complex member chromobox 4, CBX4, as a novel interactor of the oncoprotein. Immunohistochemical staining of several epigenetic factors on a human synovial sarcoma tissue microarray showed association of synovial sarcoma samples with higher CBX4 expression. Lastly, analysis of CBX4 expression across 337 samples from 12 sarcoma subtypes, carcinomas and normal tissue demonstrates higher expression in synovial sarcoma samples as compared to other tissue types. These results highlight a crucial approach in identifying important partners of SS18::SSX in synovial sarcoma to establish new biological pathways that contribute to the disease.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104243"},"PeriodicalIF":4.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined multi-color immunofluorescence staining and spatial in situ mRNA expression analysis identifies potential fibrosis drivers in acute lymphoblastic leukemia.","authors":"Sandro Bräunig, Carl Dencker, Dang Nghiem Vo, Rong Fan, Alba Lillo Sierras, Jens Enoksson, Anne Hultquist, Hongzhe Li, Stefan Scheding","doi":"10.1016/j.labinv.2025.104241","DOIUrl":"https://doi.org/10.1016/j.labinv.2025.104241","url":null,"abstract":"<p><p>Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer. Bone marrow (BM) fibrosis in ALL has been associated with adverse outcomes, however, little is known about the mechanisms that cause fibrosis in ALL. Therefore, we established a novel and advanced analysis method by combining multi-color immunofluorescence staining with in-situ RNA expression analysis (RNAscope®) investigate the spatial expression of putative fibrotic drivers in ALL bone marrows. We analyzed standard BM biopsies from pediatric ALL patients. Sequential 5-color immunofluorescence (IF) staining with CD45, CD271, CD31, CD34 and DAPI was used to identify different BM cell types. Combined RNAscope® and IF staining was established for spatial mRNA expression analysis of transforming growth factor beta 1 (TGFB1) and platelet-derived growth factor alpha 1 (PDGFA1), which are known to play major roles in primary myelofibrosis (PMF). PMF and normal BM samples served as controls. As expected, ALL bone marrows showed high cellularities and prominent populations of blast cells. CD271⁺ MSC density was increased in ALL and was associated with fibrosis in a similar manner as observed for PMF. TGFB1 and PDGFA1 expression was considerably increased in ALL megakaryocytes (MKs) compared to PMF patients and normal controls. Furthermore, MK TGFB1 and PDGFA1 expression intensities in fibrotic ALL correlated with fibrosis grade. TGFB1 and PDGFA1 were also expressed in leukemic blasts, however at lower intensities compared to ALL MKs. Taken together, advanced in-situ RNA and IF staining not only revealed increased expression of TGFB1 and PDGFA1 in fibrotic pediatric ALL, but also identified ALL blasts and MKs as their cellular origin at the single cell level. These novel data strongly suggest a role of these cytokines as potential fibrosis drivers in ALL. More broadly, our findings demonstrate that combined RNA and surface marker analysis is a powerful tool to provide new and valuable insights into bone marrow pathophysiology.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104241"},"PeriodicalIF":4.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detailed Characterization and Comparison of Mouse Models for Cholangiocarcinoma","authors":"Margaret Tulessin ,&nbsp;Ludwig Beer ,&nbsp;Stephanie Roessler ,&nbsp;Anika Beckers ,&nbsp;Darko Castven ,&nbsp;Diego Francesco Calvisi ,&nbsp;Xin Chen ,&nbsp;Sebastian Lange ,&nbsp;Nicole Pfarr ,&nbsp;Jens Marquardt ,&nbsp;Theresa Hildegard Wirtz ,&nbsp;Marie-Luise Berres ,&nbsp;Katja Steiger ,&nbsp;Tanja Groll ,&nbsp;Carolin Mogler","doi":"10.1016/j.labinv.2025.104242","DOIUrl":"10.1016/j.labinv.2025.104242","url":null,"abstract":"<div><div>Cholangiocarcinoma (CCA) is an aggressive malignancy that originates in the bile ducts and is characterized by late-stage diagnosis and limited treatment options. CCA accounts for approximately 10% to 15% of primary liver tumors. Recent genetic studies have shed new light on this disease, exploring CCA’s complexity and finding more effective treatment strategies, particularly based on identifying actionable mutations. Various mouse models for CCA have been established; however, the extent to which these models reflect the complexity of human is not well investigated. Therefore, this study aimed to characterize the available mouse models for CCA studies and compare their characteristics, advantages, and challenges in resemblance to human CCA. We applied tissue-based techniques using classical hematoxylin and eosin, Sirius red, and immunohistochemistry of 16 markers for in-depth characterization of tumor cells, and the tumor microenvironment of 11 different mouse models. Our findings demonstrate that CCAs present with various tumor subtypes, tumor growth patterns, morphologic subtypes, and tumor microenvironment activity. Furthermore, we report here that neoplastic lesions other than CCA, such as hepatocellular carcinoma and nonneoplastic changes in the liver parenchyma (eg, steatosis), occur with significant differences among the investigated models. Nine out of 11 investigated models were suitable for CCA studies as they resemble human CCA features. Overall, our data show that mouse models of CCA represent a valid tool to investigate this deadly disease, but they should be carefully selected, depending on the study’s aims and targets in advance.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 12","pages":"Article 104242"},"PeriodicalIF":4.2,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of Human Epidermal Growth Factor Receptor 2 (HER2) Heterogeneity at the Protein and Gene Levels in Endometrial Cancer: Refining HER2 Reporting and HER2-Directed Therapies","authors":"Ekaterina Menshikova ,&nbsp;Kristin Deeb ,&nbsp;Elizabeth M. Genega ,&nbsp;Krisztina Hanley ,&nbsp;Gulisa Turashvili","doi":"10.1016/j.labinv.2025.104240","DOIUrl":"10.1016/j.labinv.2025.104240","url":null,"abstract":"<div><div>Targeted therapy directed against human epidermal growth factor receptor 2 (HER2) has shown promising results in HER2-positive endometrial cancer. Recent limited data suggest significant intratumoral heterogeneity in HER2 expression in serous carcinomas. We aimed to evaluate HER2 heterogeneity at the protein and gene levels and the impact of variable definitions in endometrial carcinomas including nonserous subtypes. We retrospectively identified biopsies and surgical specimens with available HER2 immunohistochemical (IHC) stains and fluorescence in situ hybridization (FISH) results. IHC stains and FISH data were reevaluated to assess variability in the HER2 protein expression and gene amplification. The overall HER2-positivity rate was 31% using the endometrial criteria, and 42.6% by the gastric criteria. Heterogeneous IHC staining was observed in 45.7% of tumors, predominating in 2+/3+ scores (<em>P</em> &lt; .001). Re-evaluation of FISH revealed a 31% rate of heterogeneous gene amplification. Our study demonstrates a high frequency of HER2 heterogeneity at both the protein and the gene levels. Further studies on HER2 heterogeneity and treatment response are warranted for refining standardized testing and reporting algorithms.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 12","pages":"Article 104240"},"PeriodicalIF":4.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}