The Journal of Pathology最新文献

{"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}

{"title":"Dissecting the immune infiltrate of primary luminal B-like breast carcinomas in relation to age","authors":"Sigrid Hatse,&nbsp;Yentl Lambrechts,&nbsp;Asier Antoranz Martinez,&nbsp;Maxim De Schepper,&nbsp;Tatjana Geukens,&nbsp;Hanne Vos,&nbsp;Lieze Berben,&nbsp;Julie Messiaen,&nbsp;Lukas Marcelis,&nbsp;Yannick Van Herck,&nbsp;Patrick Neven,&nbsp;Ann Smeets,&nbsp;Christine Desmedt,&nbsp;Frederik De Smet,&nbsp;Francesca Maria Bosisio,&nbsp;Hans Wildiers,&nbsp;Giuseppe Floris","doi":"10.1002/path.6354","DOIUrl":"10.1002/path.6354","url":null,"abstract":"<p>The impact of aging on the immune landscape of luminal breast cancer (Lum-BC) is poorly characterized. Understanding the age-related dynamics of immune editing in Lum-BC is anticipated to improve the therapeutic benefit of immunotherapy in older patients. To this end, here we applied the ‘multiple iterative labeling by antibody neo-deposition’ (MILAN) technique, a spatially resolved single-cell multiplex immunohistochemistry method. We created tissue microarrays by sampling both the tumor center and invasive front of luminal breast tumors collected from a cohort of treatment-naïve patients enrolled in the prospective monocentric IMAGE (IMmune system and AGEing) study. Patients were subdivided into three nonoverlapping age categories (35–45 = ‘young’, <i>n</i> = 12; 55–65 = ‘middle’, <i>n</i> = 15; ≥70 = ‘old’, <i>n</i> = 26). Additionally, depending on localization and amount of cytotoxic T lymphocytes, the tumor immune types ‘desert’ (<i>n</i> = 22), ‘excluded’ (<i>n</i> = 19), and ‘inflamed’ (<i>n</i> = 12) were identified. For the MILAN technique we used 58 markers comprising phenotypic and functional markers allowing in-depth characterization of T and B lymphocytes (T&amp;B-lym). These were compared between age groups and tumor immune types using Wilcoxon's test and Pearson's correlation. Cytometric analysis revealed a decline of the immune cell compartment with aging. T&amp;B-lym were numerically less abundant in tumors from middle-aged and old compared to young patients, regardless of the geographical tumor zone. Likewise, desert-type tumors showed the smallest immune-cell compartment and were not represented in the group of young patients. Analysis of immune checkpoint molecules revealed a heterogeneous geographical pattern of expression, indicating higher numbers of PD-L1 and OX40-positive T&amp;B-lym in young compared to old patients. Despite the numerical decline of immune infiltration, old patients retained higher expression levels of OX40 in T helper cells located near cancer cells, compared to middle-aged and young patients. Aging is associated with important numerical and functional changes of the immune landscape in Lum-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 3","pages":"344-356"},"PeriodicalIF":5.6,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6354","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338064","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":"DNA methylation as a new tool for the differential diagnosis between T-LBL and lymphocyte-rich thymoma","authors":"Mehdi Latiri,&nbsp;Mohamed Belhocine,&nbsp;Charlotte Smith,&nbsp;Nathalie Garnier,&nbsp;Estelle Balducci,&nbsp;Antoine Pinton,&nbsp;Guillaume P Andrieu,&nbsp;Julie Bruneau,&nbsp;Salvatore Spicuglia,&nbsp;Stéphane Jamain,&nbsp;Violaine Latapie,&nbsp;Vincent Thomas de Montpreville,&nbsp;Lara Chalabreysse,&nbsp;Alexander Marx,&nbsp;Nicolas Girard,&nbsp;Benjamin Besse,&nbsp;Christoph Plass,&nbsp;Laure Gibault,&nbsp;Cécile Badoual,&nbsp;Elizabeth Macintyre,&nbsp;Vahid Asnafi,&nbsp;Thierry Jo Molina,&nbsp;Aurore Touzart","doi":"10.1002/path.6346","DOIUrl":"10.1002/path.6346","url":null,"abstract":"<p>T-lymphoblastic lymphoma (T-LBL) and thymoma are two rare primary tumors of the thymus deriving either from T-cell precursors or from thymic epithelial cells, respectively. Some thymoma subtypes (AB, B1, and B2) display numerous reactive terminal deoxynucleotidyl transferase-positive (TdT⁺) T-cell precursors masking epithelial tumor cells. Therefore, the differential diagnosis between T-LBL and TdT⁺ T-lymphocyte-rich thymoma could be challenging, especially in the case of needle biopsy. To distinguish between T-LBL and thymoma-associated lymphoid proliferations, we analyzed the global DNA methylation using two different technologies, namely MeDIP array and EPIC array, in independent samples series [17 T-LBLs compared with one TdT⁺ lymphocyte-rich thymoma (B1 subtype) and three normal thymi, and seven lymphocyte-rich thymomas compared with 24 T-LBLs, respectively]. In unsupervised principal component analysis (PCA), T-LBL and thymoma samples clustered separately. We identified differentially methylated regions (DMRs) using MeDIP-array and EPIC-array datasets and nine overlapping genes between the two datasets considering the top 100 DMRs including <i>ZIC1</i>, <i>TSHZ2</i>, <i>CDC42BPB</i>, <i>RBM24</i>, <i>C10orf53</i>, and <i>MACROD</i>2. In order to explore the DNA methylation profiles in larger series, we defined a classifier based on these six differentially methylated gene promoters, developed an MS-MLPA assay, and demonstrated a significant differential methylation between thymomas (hypomethylated; <i>n</i> = 48) and T-LBLs (hypermethylated; <i>n</i> = 54) (methylation ratio median 0.03 versus 0.66, respectively; <i>p</i> &lt; 0.0001), with <i>MACROD2</i> methylation status the most discriminating. Using a machine learning strategy, we built a prediction model trained with the EPIC-array dataset and defined a cumulative score taking into account the weight of each feature. A score above or equal to 0.4 was predictive of T-LBL and conversely. Applied to the MS-MLPA dataset, this prediction model accurately predicted diagnoses of T-LBL and thymoma. © 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 3","pages":"284-292"},"PeriodicalIF":5.6,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6346","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338065","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":"Spatial analysis of microRNA regulation at defined tumor hypoxia levels reveals biological traits of aggressive prostate cancer","authors":"Vilde E Skingen,&nbsp;Unn Beate Salberg,&nbsp;Tord Hompland,&nbsp;Christina S Fjeldbo,&nbsp;Hanna Helgeland,&nbsp;Kari-Anne M Frikstad,&nbsp;Harald B Ragnum,&nbsp;Ljiljana Vlatkovic,&nbsp;Knut Håkon Hole,&nbsp;Therese Seierstad,&nbsp;Heidi Lyng","doi":"10.1002/path.6344","DOIUrl":"10.1002/path.6344","url":null,"abstract":"<p>Mechanisms regulating the gene expression program at different hypoxia severity levels in patient tumors are not understood. We aimed to determine microRNA (miRNA) regulation of this program at defined hypoxia levels from moderate to severe in prostate cancer. Biopsies from 95 patients were used, where 83 patients received the hypoxia marker pimonidazole before prostatectomy. Forty hypoxia levels were extracted from pimonidazole-stained histological sections and correlated with miRNA and gene expression profiles determined by RNA sequencing and Illumina bead arrays. This identified miRNAs associated with moderate (<i>n</i> = 7) and severe (<i>n</i> = 28) hypoxia and predicted their target genes. The scores of miRNAs or target genes showed prognostic significance, as validated in an external cohort of 417 patients. The target genes showed enrichment of gene sets for cell proliferation and MYC activation at all hypoxia levels and PTEN inactivation at severe hypoxia. This was confirmed by RT-qPCR for <i>MYC</i> and <i>PTEN</i>, by Ki67 immunohistochemistry, and by gene set analysis in an external cohort. To assess whether miRNA regulation occurred within the predicted hypoxic regions, a method to quantify co-localization of multiple histopathology parameters at defined hypoxia levels was applied. A high Ki67 proliferation index co-localized significantly with hypoxia at all levels. The co-localization index was strongly associated with poor prognosis. Absence of PTEN staining co-localized significantly with severe hypoxia. The scores for miRNAs correlated with the co-localization index for Ki67 staining and hypoxia, consistent with miRNA regulation within the overlapping regions. This was confirmed by showing miR-210-3p expression within severe hypoxia by <i>in situ</i> hybridization. Cell line experiments (22Rv1, PC3) were conducted to determine whether miRNAs and target genes were regulated directly by hypoxia. Most of them were hypoxia-unresponsive, and probably regulated by other mechanisms such as MYC activation. In conclusion, in aggressive, hypoxic prostate tumors, cancer cells exhibit different proliferative gene expression programs that is regulated by miRNAs and depend on whether the cells reside in moderate or severe hypoxic regions. © 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 3","pages":"270-283"},"PeriodicalIF":5.6,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6344","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338068","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}