The Journal of Pathology最新文献

{"title":"Runt-related transcription factor 1 (RUNX1) is a mediator of acute kidney injury","authors":"Miguel Fontecha-Barriuso,&nbsp;Natalia Villar-Gomez,&nbsp;Juan Guerrero-Mauvecin,&nbsp;Julio M Martinez-Moreno,&nbsp;Susana Carrasco,&nbsp;Diego Martin-Sanchez,&nbsp;María Rodríguez-Laguna,&nbsp;Manuel J Gómez,&nbsp;María D Sanchez-Niño,&nbsp;Marta Ruiz-Ortega,&nbsp;Alberto Ortiz,&nbsp;Ana B Sanz","doi":"10.1002/path.6355","DOIUrl":"10.1002/path.6355","url":null,"abstract":"<p>Treatment for acute kidney injury (AKI) is suboptimal. A better understanding of the pathogenesis of AKI may lead to new therapeutic approaches. Kidney transcriptomics of folic acid-induced AKI (FA-AKI) in mice identified <i>Runx1</i> as the most upregulated RUNX family gene. We then examined the expression of RUNX1 in FA-AKI, in bacterial lipopolysaccharide (LPS)-induced cytokine storm-AKI (CS-AKI), and in human AKI. In cultured mouse tubule cells, we explored the expression and role of RUNX1 in response to the cytokine TWEAK or LPS. A chemical inhibitor of RUNX1 (Ro5-3335) was used in animal models of AKI to test its potential as a therapeutic target. RUNX1 overexpression in FA-AKI was validated at the mRNA and protein levels and localized mainly to tubule cell nuclei. CS-AKI also upregulated kidney RUNX1. Increased tubule and interstitial RUNX1 expression were also observed in human AKI. In cultured mouse tubule cells, the pro-inflammatory cytokine TWEAK and LPS increased RUNX1 and IL-6 expression. Mechanistically, RUNX1 bound to the <i>Il6</i> gene promoter and RUNX1 targeting with the chemical inhibitor Ro5-3335, or a specific small interfering RNA (siRNA), prevented the TWEAK- and LPS-induced upregulation of IL6 through a RUNX1/NFκB1 p50 pathway. <i>In vivo</i>, preventive Ro5-3335 improved kidney function and reduced inflammation in FA-AKI and CS-AKI. However, Ro5-3335 administration after the insult only improved kidney function in CS-AKI. Kidney transcriptomics identified inflammatory genes and transcription factor mRNAs such as <i>Yap1</i> and <i>Trp53</i> as key targets of Ro5-3335 in CS-AKI. In conclusion, RUNX1 contributes to AKI by driving the expression of genes involved in inflammation and represents a novel therapeutic target in AKI. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 4","pages":"396-410"},"PeriodicalIF":5.6,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6355","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the molecular landscape of cutaneous mixed tumors characterized by TRPS1::PLAG1 gene fusion","authors":"Ziyad Alsugair,&nbsp;Marie Donzel,&nbsp;Nicolas Macagno,&nbsp;Juliet Tantot,&nbsp;Olivier Harou,&nbsp;Maxime Battistella,&nbsp;Pierre Sohier,&nbsp;Thibault Kervarrec,&nbsp;Arnaud de la Fouchardière,&nbsp;Brigitte Balme,&nbsp;Anne Champagnac,&nbsp;Marie-Delphine Lanic,&nbsp;Jonathan Lopez,&nbsp;Marick Laé,&nbsp;Françoise Descotes,&nbsp;Franck Tirode,&nbsp;Daniel Pissaloux,&nbsp;Brice Thamphya,&nbsp;Valérie Costes-Martineau,&nbsp;Nazim Benzerdjeb","doi":"10.1002/path.6359","DOIUrl":"10.1002/path.6359","url":null,"abstract":"<p>The histological similarities between pleomorphic adenomas (PAs) and cutaneous mixed tumors (CMTs) found in certain facial regions can create a diagnostic challenge. Molecular findings reveal common genetic profiles, particularly <i>PLAG1</i> rearrangements in both PA and CMT. Although molecular distinctions have received limited attention, our observations indicate multiple cases of CMTs carrying the <i>TRPS1</i>::<i>PLAG1</i> fusion. This clinical experience has driven our investigation into the potential diagnostic utility of <i>TRPS1</i>::<i>PLAG1</i> fusions for determining tumor origin. Two cohorts consisting of 46 cases of CMT and 45 cases of PA of the salivary glands were obtained from French institutions and reviewed by specialists in each subspecialty. RNA sequencing analysis was conducted to identify the molecular features of cases harboring <i>PLAG1</i>. Clinical, pathological, and molecular data were collected. In this study, cases of CMT exhibited recurrent gene fusions, primarily <i>TRPS1</i>::<i>PLAG1</i> (74%). These tumors shared characteristic histological features, including tubuloductal differentiation in 55% of cases and squamous metaplasia in varying proportions. In contrast, cases of PA had gene fusions involving <i>PLAG1</i> with various gene partners, with only one case in which <i>TRPS1</i>::<i>PLAG1</i> was identified. This disparity was also observed at the transcriptomic level between <i>TRPS1</i>::<i>PLAG1</i> CMTs and other tumors. However, TRPS1 immunostaining did not correlate with <i>TRPS1</i>::<i>PLAG1</i> fusion. In conclusion, we report that recurrent <i>TRPS1</i>::<i>PLAG1</i> fusion CMTs exhibit similar characteristic histological features, including tubuloductal differentiation that is associated with squamous metaplasia in around half of cases. Detection of this fusion could be valuable in correctly identifying the origin of these tumors. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 4","pages":"448-456"},"PeriodicalIF":5.6,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6359","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-VEGFR2 neutralising antibody slows the progression of multistep oral carcinogenesis","authors":"Yoichiro Shirogane,&nbsp;Yu Usami,&nbsp;Masashi Okumura,&nbsp;Katsutoshi Hirose,&nbsp;Kohei Naniwa,&nbsp;Kazunori Ikebe,&nbsp;Satoru Toyosawa","doi":"10.1002/path.6357","DOIUrl":"10.1002/path.6357","url":null,"abstract":"<p>Angiogenesis plays an important role in cancer growth and metastasis, and it is considered a therapeutic target to control tumour growth following anti-angiogenic therapy. However, it is still unclear when tissues initiate angiogenesis during malignant transformation from premalignant condition and whether this premalignant condition could be a therapeutic target of anti-angiogenic therapy. In this study, we aimed to analyse the onset of angiogenesis by evaluating morphological and functional alterations of microvessels during oral multistep carcinogenesis using a 4-nitroquinoline 1-oxide (4NQO)-induced oral carcinogenesis mouse model. In the study, we initially confirmed that with the use of 4NQO, oral lesions develop in a stepwise manner from normal mucosa through oral epithelial dysplasia (OED) to oral squamous cell carcinoma (OSCC). Evaluation of CD31-immunostained specimens revealed that microvessel density (MVD) increases in a stepwise manner from OEDs. Histological and functional analyses revealed the structural abnormalities and leakage of blood vessels had already taken place in OED. Then we evaluated the expression profiles of <i>Hif1a</i> and <i>Vegfa</i> along with hypoxic status and found that OED exhibited increased <i>Vegfa</i> expression under hypoxic conditions. Finally, we tested the possibility of OEDs as a target of anti-angiogenic therapy and found that anti-VEGFR2 neutralising antibody in OED slowed the disease progression from OED to OSCC. These data indicate that an angiogenic switch occurs at the premalignant stage and morphological, and functional alterations of microvessels already exist in OED. These findings also elucidate the tumour microenvironment, which gradually develops along with carcinogenic processes, and highlight usefulness of the 4NQO-induced carcinogenesis model in the study of epithelial and stromal components, which will support epithelial carcinogenesis. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 4","pages":"423-433"},"PeriodicalIF":5.6,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6357","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive luminal breast cancer patient-derived xenografts (PDX) library to capture tumor heterogeneity and explore the mechanisms of resistance to CDK4/6 inhibitors","authors":"Ilenia Segatto,&nbsp;Maria Chiara Mattevi,&nbsp;Gian Luca Rampioni Vinciguerra,&nbsp;Nicole Crestan,&nbsp;Lorena Musco,&nbsp;Andrea Favero,&nbsp;Alessandra Dall'Acqua,&nbsp;Gabriele Di Giustino,&nbsp;Giorgia Mungo,&nbsp;Sara D'Andrea,&nbsp;Chiara Gava,&nbsp;Federica Ruggiero,&nbsp;Matteo Dugo,&nbsp;Lorenzo Gerratana,&nbsp;Fabio Puglisi,&nbsp;Samuele Massarut,&nbsp;Riccardo Bomben,&nbsp;Maurizio Callari,&nbsp;Tiziana Perin,&nbsp;Gustavo Baldassarre,&nbsp;Barbara Belletti","doi":"10.1002/path.6358","DOIUrl":"10.1002/path.6358","url":null,"abstract":"<p>Breast cancer (BC) is marked by significant genetic, morphological and clinical heterogeneity. To capture this heterogeneity and unravel the molecular mechanisms driving tumor progression and drug resistance, we established a comprehensive patient-derived xenograft (PDX) biobank, focusing particularly on luminal (estrogen receptor, ER+) and young premenopausal patients, for whom PDX models are currently scarce. Across all BC subtypes, our efforts resulted in an overall success rate of 17% (26 established PDX lines out of 151 total attempts), specifically 15% in luminal, 12% in human epidermal growth factor receptor 2 positive (HER2+) and 35% in triple negative BC. These PDX mirrored morphologic and genetic features of BC from which they originated, serving as a reliable tool to investigate drug resistance and test therapeutic strategies. We focused on understanding resistance to CDK4/6 inhibitors (CDK4/6i), which are crucial in the treatment of patients with advanced luminal BC. Treating a sensitive luminal BC PDX with the CDK4/6i palbociclib revealed that, despite initial tumor shrinkage, some tumors might eventually regrow under drug treatment. RNA sequencing, followed by gene set enrichment analyses, unveiled that these PDXs have become refractory to CDK4/6i, both at biological and molecular levels, displaying significant enrichment in proliferation pathways, such as <i>MTORC1</i>, <i>E2F</i> and <i>MYC</i>. Using organoids derived from these PDX (PDxO), we observed that acquisition of CDK4/6i resistance conferred cross-resistance to endocrine therapy and that targeting MTORC1 was a successful strategy to overcome CDK4/6i resistance. Considered together, these results indicate that our PDX models may serve as robust tools to elucidate the molecular basis of BC disease progression and, by providing the possibility to simultaneously test different therapies on the same tumor, to surmount treatment resistance. While this approach is of course not feasible in the clinic, its exploitation in PDX may expedite the identification and development of more successful therapies for patients with advanced luminal BC. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 4","pages":"434-447"},"PeriodicalIF":5.6,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6358","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of dystroglycan function accompanies pancreatic acinar-to-ductal metaplasia and favours dysplasia development","authors":"Ge Huang,&nbsp;Luke Ternes,&nbsp;Christian Lanciault,&nbsp;Kevin MacPherson-Hawthorne,&nbsp;Young Hwan Chang,&nbsp;Rosalie C Sears,&nbsp;John L Muschler","doi":"10.1002/path.6356","DOIUrl":"10.1002/path.6356","url":null,"abstract":"<p>The basement membrane (BM) is among the predominant microenvironmental factors of normal epithelia and of precancerous epithelial lesions. Evidence suggests that the BM functions not only as a barrier to tumour invasion but also as an active tumour-suppressing signalling substrate during premalignancy. However, the molecular foundations of such mechanisms have not been elucidated. Here we explore potential tumour-suppressing functions of the BM during precancer evolution, focusing on the expression and function of the extracellular matrix receptor dystroglycan in the pancreas and pancreatic disease. We show that the dystroglycan protein is highly expressed in the acinar compartment of the normal pancreas but lower in the ductal compartment. Moreover, there is a strong suppression of dystroglycan protein expression with acinar-to-ductal metaplasia in chronic pancreatitis and in all stages of pancreatic precancer and cancer evolution, from acinar-to-ductal metaplasia to dysplasia to adenocarcinoma. The conditional knockout of dystroglycan in the murine pancreas produced little evidence of developmental or functional deficiency. However, conditional deletion of dystroglycan expression in the context of oncogenic <i>Kras</i> expression led to a clear acceleration of pancreatic disease evolution, including accelerated dysplasia development and decreased survival. These data establish dystroglycan as a suppressor of pancreatic dysplasia development and one that is muted in chronic pancreatitis and at the earliest stages of oncogene-induced transformation. We conclude that dystroglycan is an important mediator of the tumour-suppressing functions of the BM during precancer evolution and that reduced dystroglycan function increases cancer risk, highlighting the dynamics of cell–BM interactions as important determinants of early cancer progression. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 4","pages":"411-422"},"PeriodicalIF":5.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454406","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":"Correction to ‘Hourglass, a compass navigating global and regional heterogeneity of pancreatic cancer’","authors":"","doi":"10.1002/path.6361","DOIUrl":"10.1002/path.6361","url":null,"abstract":"<p>\u0000 <span>Derya Bakırdöğen</span>, <span>Kıvanç Görgülü</span>, <span>Hana Algül</span>. <i>J Pathol</i> <span>2024</span>; <span>263</span><b>:</b> <span>5</span>–<span>7</span>. https://doi.org/10.1002/path.6268\u0000 </p><p>In this published Invited Commentary, there was an error regarding the affiliation shown for all three authors.</p><p>Instead of ‘Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, Munich, Germany’ the affiliation should have been ‘Comprehensive Cancer Center Munich TUM, Institute for Tumor Metabolism, Technical University of Munich (TUM), Klinikum rechts der Isar, Munich, Bavaria, Germany’.</p><p>The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 4","pages":"457"},"PeriodicalIF":5.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6361","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APRIL/BAFF upregulation is associated with clonal B-cell expansion in Hunner-type interstitial cystitis","authors":"Masafumi Horie,&nbsp;Yoshiyuki Akiyama,&nbsp;Hiroto Katoh,&nbsp;Satoru Taguchi,&nbsp;Masaki Nakamura,&nbsp;Keishi Mizuguchi,&nbsp;Yukinobu Ito,&nbsp;Takashi Matsushita,&nbsp;Tetsuo Ushiku,&nbsp;Shumpei Ishikawa,&nbsp;Akiteru Goto,&nbsp;Haruki Kume,&nbsp;Yukio Homma,&nbsp;Daichi Maeda","doi":"10.1002/path.6353","DOIUrl":"10.1002/path.6353","url":null,"abstract":"<p>Hunner-type interstitial cystitis (HIC) is a chronic inflammatory disease of the urinary bladder with an unknown etiology. We conducted comprehensive immunogenomic profiling of bladder specimens obtained by biopsy and cystectomy from 37 patients with HIC. Next-generation RNA sequencing demonstrated abundant plasma cell infiltration with frequent light chain restriction in HIC-affected bladder tissue. Subsequent analysis of the B-cell receptor repertoire revealed spatial and temporal expansion of B-cell clones. The extent of B-cell clonal expansion was significantly correlated with the gene expression levels of <i>TNFSF13</i> and <i>TNFSF13B</i>, which encode APRIL and BAFF, respectively. These findings indicate that APRIL and BAFF are the key regulators of clonal B-cell expansion in HIC and might serve as therapeutic targets in this debilitating disease. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 4","pages":"383-395"},"PeriodicalIF":5.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6353","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The evolutionary history of metastatic pancreatic neuroendocrine tumours reveals a therapy driven route to high-grade transformation","authors":"Samuel Backman,&nbsp;Johan Botling,&nbsp;Helena Nord,&nbsp;Suman Ghosal,&nbsp;Peter Stålberg,&nbsp;C. Christofer Juhlin,&nbsp;Jonas Almlöf,&nbsp;Anders Sundin,&nbsp;Liang Zhang,&nbsp;Lotte Moens,&nbsp;Barbro Eriksson,&nbsp;Staffan Welin,&nbsp;Per Hellman,&nbsp;Britt Skogseid,&nbsp;Karel Pacak,&nbsp;Kazhan Mollazadegan,&nbsp;Tobias Åkerström,&nbsp;Joakim Crona","doi":"10.1002/path.6348","DOIUrl":"10.1002/path.6348","url":null,"abstract":"<p>Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular may progress from a low/intermediate to a high-grade disease. The aim of this work was to understand the molecular mechanisms underlying metastatic progression as well as PanNET transformation from a low/intermediate to a high-grade disease. We performed multi-omics analysis (genome/exome sequencing, total RNA-sequencing and methylation array) of 32 longitudinal samples from six patients with metastatic low/intermediate grade PanNET. The clonal composition of tumour lesions and underlying phylogeny of each patient were determined with bioinformatics analyses. Findings were validated in post-alkylating chemotherapy samples from 24 patients with PanNET using targeted next generation sequencing. We validate the current PanNET evolutionary model with <i>MEN1</i> inactivation that occurs very early in tumourigenesis. This was followed by pronounced genetic diversity on both spatial and temporal levels, with parallel and convergent tumour evolution involving the ATRX/DAXX and mechanistic target of the rapamycin (mTOR) pathways. Following alkylating chemotherapy treatment, some PanNETs developed mismatch repair deficiency and acquired a hypermutational phenotype. This was validated among 16 patients with PanNET who had high-grade progression after alkylating chemotherapy, of whom eight had a tumour mutational burden &gt;50 (50%). In comparison, among the eight patients who did not show high-grade progression, 0 had a tumour mutational burden &gt;50 (0%; odds ratio ‘infinite’, 95% confidence interval 1.8 to ‘infinite’, <i>p</i> = 0.02). Our findings contribute to broaden the understanding of metastatic/high-grade PanNETs and suggests that therapy driven disease evolution is an important hallmark of this disease. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 4","pages":"357-370"},"PeriodicalIF":5.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6348","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aristolochic acid-related renal cell carcinoma exhibits a distinct tumor-immune microenvironment favoring response to immune checkpoint blockade","authors":"Po-Hung Lin,&nbsp;Jason Yongsheng Chan,&nbsp;Peiyong Guan,&nbsp;Jing Han Hong,&nbsp;Abner Herbert Lim,&nbsp;Cedric Chuan-Young Ng,&nbsp;Joe Poh Sheng Yeong,&nbsp;Jing Yi Lee,&nbsp;Wei Liu,&nbsp;Jeffrey Chun Tatt Lim,&nbsp;See-Tong Pang,&nbsp;Bin Tean Teh","doi":"10.1002/path.6349","DOIUrl":"10.1002/path.6349","url":null,"abstract":"<p>Immune checkpoint blockade (ICB) is currently the standard of care for metastatic renal cell carcinoma (RCC), but treatment responses remain unpredictable. Aristolochic acid (AA), a prevalent supplement additive in Taiwan, has been associated with RCC and induces signature mutations, although its effect on the tumor-immune microenvironment (TIME) is unclear. We aimed to investigate the immune profile of AA-positive RCCs and explore its potential role as a susceptible candidate for ICB. Tissue samples from 22 patients with clear cell RCC (ccRCC) were collected for whole-exome sequencing to determine the genetic features and AA mutational signature (the discovery cohort). The corresponding RNA was sent for NanoString PanCancer IO 360 gene expression analysis to explore the immunological features. The formalin-fixed, parafilm-embedded slides of ccRCCs were sent for multiplex immunohistochemistry/immunofluorescence stain using Vectra system to evaluate the TIME. Tissues from two patients with metastatic RCC demonstrating complete response to ICB were sent for studies to validate the findings (the index patients). The results showed that AA mutational signatures with high tumor mutational burden (TMB) were present in 31.81% of the tumors in the discovery cohort. Three distinct clusters were observed through NanoString analysis. Clusters 1 and 3 were composed mainly of AA-positive RCCs. Cluster 3 RCCs exhibited higher tumor inflammation signature scores and higher immune cell type scores. Vectra analysis revealed a higher percentage of CD15+ and BATF3+ cells in cluster 1, whereas the percentage of CD8+ cells was potentially higher in cluster 3. Strong AA mutational signatures were found in the tumors of two index patients, and both were grouped to cluster 3. In conclusion, AA may induce higher TMB and alter the immune microenvironment in RCCs, which makes the tumors more susceptible to ICB. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 4","pages":"371-382"},"PeriodicalIF":5.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6349","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the clinicopathologic spectrum and genomic landscape of tumors with SMARCA2/4::CREM fusions","authors":"Joanna Cyrta,&nbsp;Josephine K Dermawan,&nbsp;Arnault Tauziède-Espariat,&nbsp;Ting Liu,&nbsp;Marc Rosenblum,&nbsp;Seema Shroff,&nbsp;Nora Katabi,&nbsp;Liesbeth Cardoen,&nbsp;Delphine Guillemot,&nbsp;Julien Masliah-Planchon,&nbsp;Owen Hoare,&nbsp;Olivier Delattre,&nbsp;Tejus Bale,&nbsp;Franck Bourdeaut,&nbsp;Cristina R Antonescu","doi":"10.1002/path.6350","DOIUrl":"10.1002/path.6350","url":null,"abstract":"<p><i>CREB</i> gene family (<i>ATF1</i>, <i>CREB1</i>, <i>CREM</i>) fusions with either <i>EWSR1</i> or <i>FUS</i> gene partners drive the pathogenesis of a wide range of neoplasms, including various soft tissue tumors, intracranial myxoid mesenchymal tumors (IMMTs), hyalinizing clear cell carcinoma (HCCC), and rare mesotheliomas. Recently, a <i>SMARCA2</i>::<i>CREM</i> fusion was reported in one case each of IMMT and HCCC. In this study, we expand the clinicopathologic and molecular spectrum of these neoplasms by describing three additional cases with <i>SMARCA2</i>::<i>CREM</i> and one with a novel <i>SMARCA4</i>::<i>CREM</i> fusion, highlighting the recurrent potential of additional CREB gene fusion partners beyond FET family members. To evaluate if these fusions define a new pathologic entity, we performed a comprehensive genomic and methylation analysis and compared the results to other related tumors. Tumors occurred in children and young adults (median age 20 years) and spanned a broad anatomic distribution, including soft tissue, intracranial, head and neck, and prostatic urethra. Microscopically, the tumors shared an undifferentiated round to epithelioid cell phenotype and a hyalinized fibrous stroma. Immunohistochemically, a polyphenotypic profile was observed, with variable expression of SOX10, desmin, and/or epithelial markers. No targetable genomic alterations were found using panel-based DNA sequencing. By DNA methylation and transcriptomic analyses, tumors grouped closely to <i>FET</i>::<i>CREB</i> entities, but not with <i>SMARCA4</i>/<i>SMARCB1</i>-deficient tumors. High expression of CREM by immunohistochemistry was also documented in these tumors. Patients experienced local recurrence (<i>n</i> = 2), locoregional lymph node metastases (<i>n</i> = 2), and an isolated visceral metastasis (<i>n</i> = 1). Overall, our study suggests that <i>SMARCA2/4</i>::<i>CREM</i> fusions define a distinct group of neoplasms with round cell to epithelioid histology, a variable immunoprofile, and a definite risk of malignancy. Larger studies are needed to further explore the pathogenetic relationship with the <i>FET</i>::<i>CREB</i> family of tumors. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 3","pages":"305-317"},"PeriodicalIF":5.6,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338066","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}