The Journal of Pathology最新文献

{"title":"Enhanced diagnostic potential of CSPG4 in melanoma and nevi: a comparative study with PRAME, CDC7 and Ki67","authors":"Elias AT Koch,&nbsp;Christina Seidel,&nbsp;Ramona Erber,&nbsp;Michael Erdmann,&nbsp;Markus V Heppt,&nbsp;Stefan Schliep,&nbsp;Carola Berking,&nbsp;Jan Dörrie,&nbsp;Niels Schaft","doi":"10.1002/path.6450","DOIUrl":"10.1002/path.6450","url":null,"abstract":"<p>Chondroitin sulfate proteoglycan 4 (CSPG4) is a promising target for melanoma immunotherapy, but its expression in benign melanocytic lesions and its diagnostic value remain unexplored. This study assessed CSPG4 expression in benign nevi (BN), dysplastic nevi (DN), and superficial spreading melanomas (SSM), comparing it with PRAME (PReferentially expressed Antigen in MElanoma) and evaluating the cell division cycle 7-related protein kinase (CDC7) and the proliferation marker Ki67. Histological sections were stained using automated instruments, digitized, and analyzed using QuPath. Cohorts of BN, DN, and SSM were created, and positive cells/mm² and H-scores were determined. A total of 336 IHC stainings from 84 specimens were analyzed. CSPG4 expression was readily detected in SSM and was significantly stronger in DN (<i>p</i> = 0.005), with the highest intensity observed in BN (<i>p</i> &lt; 0.001). PRAME showed the highest density of positive cells/mm² in SSM, was significantly reduced in DN (<i>p</i> &lt; 0.001), and was lowest in BN (<i>p</i> &lt; 0.001). Ki67 expression was strong in SSM, moderate in DN (<i>p</i> = 0.62), and low in BN (<i>p</i> = 0.008). CDC7 expression was most intense in DN, less in SSM (<i>p</i> = 0.39), and weakest in BN (<i>p</i> = 0.002). ROC AUC values for SSM versus DN and SSM versus BN were 0.764 and 0.921 for CSPG4, 0.85 and 0.889 for PRAME, 0.735 and 0.742 for Ki67, and 0.425 and 0.767 for CDC7. While PRAME was the most reliable marker for differentiating DN and SSM, CSPG4 was superior for distinguishing BN from SSM due to its high expression in BN. However, CSPG4-targeting therapies may trigger on-target/off-tumor effects due to its high expression in melanocytic nevi. © 2025 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":"267 1","pages":"69-78"},"PeriodicalIF":5.2,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6450","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697223","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":"BIRC3 deficiency blocks the ubiquitination and degradation of GOT2 to impede antitumor immune responses in lung squamous cell carcinoma","authors":"Qiang Zhang,&nbsp;Hongxu Sheng,&nbsp;Dongnan Ping,&nbsp;Jixiang Gao","doi":"10.1002/path.6448","DOIUrl":"10.1002/path.6448","url":null,"abstract":"<p>In lung squamous cell carcinoma (LUSC), the proportion of exhausted CD8⁺ T cells is considerably higher than in lung adenocarcinoma (LUAD). The exhaustion of CD8⁺ T cells is responsible for the failure of immunotherapies, as terminally exhausted CD8⁺ T cells do not respond to immune checkpoint blockade. Therefore, investigating the regulatory mechanisms underlying CD8⁺ T-cell exhaustion in LUSC is essential for potentiating the efficacy of immunotherapy in this context. In our study, cellular assays revealed that elevated expression of <i>GOT2</i> in LUSC reinforced the exhaustion of cocultured CD8⁺ T cells, as evidenced by elevated levels of TIGIT and TIM-3, while simultaneously impairing tumor-killing capabilities, as indicated by reduced LDH activity and diminished apoptosis. Animal experiments confirmed that knockdown of <i>GOT2</i> effectively curbed tumor growth and boosted the CD8⁺ T cell infiltration and tumor-killing function. Mechanistic studies demonstrated that BIRC3, acting as an E3 ubiquitin ligase, can recognize the 366–372 sequence of GOT2, mediating its ubiquitination and degradation. The deficiency of <i>BIRC3</i> in LUSC interrupted ubiquitination and subsequent degradation of GOT2, leading to elevated GOT2 protein levels, which in turn facilitated CD8⁺ T-cell exhaustion and ultimately compromised their antitumor immune responses. Collectively, our findings elucidated the regulatory role of protein ubiquitination in CD8⁺ T cell functionality, highlighting a novel approach to enhance the sensitivity of LUSC to immunotherapy through the intervention of the BIRC3/GOT2 ubiquitination axis. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"267 2","pages":"142-154"},"PeriodicalIF":5.2,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673515","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":"Overexpression of m7G writers METTL1 and BUD23 confers oncogenicity in kidney renal clear cell carcinoma","authors":"Anni Su,&nbsp;Jessica Tieng,&nbsp;Xueying S Xu,&nbsp;Richard P Tan,&nbsp;Yuchen Feng,&nbsp;Justin J-L Wong","doi":"10.1002/path.6453","DOIUrl":"10.1002/path.6453","url":null,"abstract":"<p>Emerging evidence shows that N7-methylguanosine (m⁷G) modification and its writers contribute to the development of diverse cancers. However, the role of m⁷G writers in kidney renal clear cell carcinoma (KIRC) remains unclear. In this study we show that the catalytic components of m⁷G writers, METTL1 and BUD23, are overexpressed in advanced KIRC and are associated with worse overall survival. Knockdown of <i>METTL1</i> or <i>BUD23</i> inhibited cell proliferation, colony formation, and migration in KIRC cell lines, indicating their oncogenic role in KIRC. Furthermore, we observed that <i>METTL1</i> and <i>BUD23</i> expression was negatively correlated with the expression of key tumor suppressor genes commonly dysregulated in KIRC. We observed METTL1-mediated m⁷G methylation in mRNAs expressed by these tumor suppressor genes, indicating that METTL1 may regulate these genes <i>via</i> m⁷G modification. Overall, our study highlights the oncogenic role of METTL1 and BUD23 in KIRC and their potential as prognostic biomarkers and therapeutic targets in KIRC. © 2025 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":"267 1","pages":"1-9"},"PeriodicalIF":5.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6453","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144809276","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":"Overexpression of m7G writers METTL1 and BUD23 confers oncogenicity in kidney renal clear cell carcinoma","authors":"Anni Su,&nbsp;Jessica Tieng,&nbsp;Xueying S Xu,&nbsp;Richard P Tan,&nbsp;Yuchen Feng,&nbsp;Justin J-L Wong","doi":"10.1002/path.6453","DOIUrl":"https://doi.org/10.1002/path.6453","url":null,"abstract":"<p>Emerging evidence shows that N7-methylguanosine (m⁷G) modification and its writers contribute to the development of diverse cancers. However, the role of m⁷G writers in kidney renal clear cell carcinoma (KIRC) remains unclear. In this study we show that the catalytic components of m⁷G writers, METTL1 and BUD23, are overexpressed in advanced KIRC and are associated with worse overall survival. Knockdown of <i>METTL1</i> or <i>BUD23</i> inhibited cell proliferation, colony formation, and migration in KIRC cell lines, indicating their oncogenic role in KIRC. Furthermore, we observed that <i>METTL1</i> and <i>BUD23</i> expression was negatively correlated with the expression of key tumor suppressor genes commonly dysregulated in KIRC. We observed METTL1-mediated m⁷G methylation in mRNAs expressed by these tumor suppressor genes, indicating that METTL1 may regulate these genes <i>via</i> m⁷G modification. Overall, our study highlights the oncogenic role of METTL1 and BUD23 in KIRC and their potential as prognostic biomarkers and therapeutic targets in KIRC. © 2025 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":"267 1","pages":"1-9"},"PeriodicalIF":5.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6453","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144809277","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 case for homebrew AI in diagnostic pathology","authors":"Julien Calderaro,&nbsp;Helen Morement,&nbsp;Frédérique Penault-Llorca,&nbsp;Stephen Gilbert,&nbsp;Jakob Nikolas Kather","doi":"10.1002/path.6438","DOIUrl":"10.1002/path.6438","url":null,"abstract":"<p>Artificial intelligence (AI) methods for digital pathology have tremendous potential to improve cancer diagnostics, biomarkers, and ultimately patient care. These AI methods, if marketed and sold, require authorisation or clearance as <i>in vitro</i> diagnostic (IVD) devices by regulatory bodies like the Food and Drug Administration (FDA) in the USA or Notified Bodies in the European Union (EU). Many AI tools for digital pathology are unlikely to be commercially viable and taken up by commercial entities ready to navigate these complex and costly processes. However, a longstanding quality framework already exists that allows for lab-developed tests, colloquially known as ‘homebrew’ tests, that are locally validated and performed under the responsibility and oversight of the pathologist. Here we argue for advancing homebrew AI systems within this existing framework to enhance patients' access to supportive digital diagnostic tools. We outline how homebrew AI models are currently permitted under regulatory provisions in the USA and the European Union, how a new US FDA rule may effectively regulate them out of existence, and propose steps to facilitate the safe and effective integration of homebrew AI models in pathology practice. © 2025 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":"266 4-5","pages":"390-394"},"PeriodicalIF":5.2,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6438","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558664","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":"Involvement of KEAP1/NRF2 pathway in non-BRAF mutated squamous cell carcinoma of the thyroid","authors":"Elin Schoultz,&nbsp;Jakob Dahlberg,&nbsp;Lisa M Nilsson,&nbsp;Jozefina J Dzanan,&nbsp;Therese Carlsson,&nbsp;Niklas Dahr,&nbsp;Ellinor Andersson,&nbsp;Ghayeb Muhammad,&nbsp;Andreas Muth,&nbsp;Erik Elias,&nbsp;Henrik Fagman,&nbsp;Volkan I Sayin,&nbsp;Jonas A Nilsson,&nbsp;Mikael Nilsson","doi":"10.1002/path.6444","DOIUrl":"10.1002/path.6444","url":null,"abstract":"<p>Squamous cell carcinoma (SCC) of the thyroid is a rare tumor that is classified as an anaplastic thyroid cancer (ATC) due to its similar unresponsiveness to chemoradiotherapy and an outstandingly poor prognosis. Due to its rarity, current knowledge about this tumor is mostly based on single-case reports. The tumor-cell-origin and molecular pathogenesis remain unclear, although the presence of <i>BRAF</i> mutations in some cases suggest it may evolve from papillary thyroid carcinoma (PTC). Here we provide direct evidence of derivation of SCC of the thyroid from PTC, based on a unique combination of likely pathogenic mutations in <i>KEAP1</i>, <i>STK11</i> (<i>LKB1</i>), and <i>RB1</i> found in both tumor components, along with loss of one copy of chromosome 11 and additional somatic mutations in the SCC tumor. Transdifferentiation from PTC to SCC was also evident by immunohistochemistry. Out of eight attempted patient-derived xenografts (PDX) from advanced thyroid cancers, only one derived from thyroid SCC successfully engrafted in immunodeficient NOG mice. Untreated PDXs showed high Ki67 indices but did not reproduce the conspicuous stromal invasion of CDH1^low/SNAI2⁺/CDH2⁺ cells that characterized the primary tumor. Based on the mutation profile (<i>NFE2L2</i>, <i>PIK3CA</i>, <i>CDKN2A</i>, and <i>TP53</i>), experiments were designed to evaluate targeted drug therapy using third-passage PDX transplants. The combination of TRK and PI3K inhibitors, cabozantinib and GDC-0326, additively reduced PDX growth by nearly 90%. Remarkably, CB-839 (telaglenastat), a glutaminase inhibitor targeting metabolic rewiring downstream of NRF2 activation, was equally effective. Both combined treatment with cabozantinib + GDC-0326 and CB-839 monotherapy diminished the expression of NQO1, an NRF2 transcriptional target, in tumor cells. Glutaminase inhibition further promoted squamous differentiation in engrafted tumors. Both investigated SCC tumors were negative for BRAFV600E or any other common driver mutation of thyroid cancer. Collectively, these findings indicate that aberrant activation of the KEAP1/NRF2 pathway due to somatic mutations is a previously unrecognized feature of thyroid SCC and suggest that glutaminase inhibition may serve as a potential therapeutic option for this subgroup of ATC patients. © 2025 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":"266 4-5","pages":"481-494"},"PeriodicalIF":5.2,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6444","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537605","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":"Correction to ‘CC chemokine receptor-like 1 functions as a tumour suppressor by impairing CCR7-related chemotaxis in hepatocellular carcinoma’","authors":"","doi":"10.1002/path.6445","DOIUrl":"10.1002/path.6445","url":null,"abstract":"<p>\u0000 <span>Jie-Yi Shi</span>, <span>Liu-Xiao Yang</span>, <span>Zhi-Chao Wang</span>, <span>Ling-Yan Wang</span>, <span>Jian Zhou</span>, <span>Xiao-Ying Wang</span>, <span>Guo-Ming Shi</span>, <span>Zhen-Bin Ding</span>, <span>Ai-Wu Ke</span>, <span>Zhi Dai</span>, <span>Shuang-Jian Qiu</span>, <span>Qi-Qun Tang</span>, Qiang Gao* and Jia Fan*. <i>J Pathol</i> <span>2015</span>; <span>235</span><b>:</b> <span>546</span>–<span>558</span>. https://doi.org/10.1002/path.4450\u0000 </p><p>The authors apologise for any inconvenience this error may have caused.</p><p>While considering the request to make a correction, the editors realised that two of the seven cell lines used in the article are listed as problematic in Cellosaurus (https://www.cellosaurus.org/). When the studies were performed, the cell line SMMC-7721 was considered to be an hepatocellular carcinoma cell line, and HL-7702/L02 was considered to originate from normal foetal liver; both are listed in Cellosaurus as derivatives of HeLa (a human papillomavirus-related endocervical adenocarcinoma cell line). Limited use was made of these two cell lines in the article, but readers should consider the possibility that they were contaminated.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"267 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6445","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537604","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":"Mucinous cystic neoplasms of the pancreas and liver share a similar DNA methylation profile with mucinous ovarian tumors","authors":"Zoe Leoni,&nbsp;Teodor G Calina,&nbsp;Tobias Janik,&nbsp;Elena Grafenhorst,&nbsp;Eliane T Taube,&nbsp;Christopher CM Neumann,&nbsp;BaoQing Chen,&nbsp;Elena I Braicu,&nbsp;Jalid Sehouli,&nbsp;Thomas Malinka,&nbsp;Wenzel Schöning,&nbsp;Johann Pratschke,&nbsp;George A Calin,&nbsp;David S Klimstra,&nbsp;Jamal K Benhamida,&nbsp;Irene Esposito,&nbsp;Markus Möbs,&nbsp;David Horst,&nbsp;Simon Schallenberg,&nbsp;David Capper,&nbsp;Mihnea P Dragomir","doi":"10.1002/path.6439","DOIUrl":"10.1002/path.6439","url":null,"abstract":"<p>The origin of mucinous cystic neoplasms (MCNs) remains a major challenge in hepato-pancreato-biliary pathology. These cystic tumors are defined by their mucinous epithelium and ovarian-like stroma, with an estimated 10% risk of progression to invasive carcinoma. The origin of the ovarian-like stroma remains a subject of debate. In this study, we conducted immunohistochemical profiling, targeted DNA sequencing, and genome-wide DNA methylation analysis on a cohort of 15 pancreatic MCNs (MCN-P) and six hepatic MCNs (MCN-L). Using immunohistochemistry and targeted DNA sequencing, we unequivocally established the diagnosis of MCN. Unsupervised DNA methylation profile analysis of reference classes of pancreatic neoplasms (11 entities and normal pancreatic tissue from 224 unique samples) revealed that MCN-P predominantly forms a distinct group. In the DNA methylation landscape of liver tumors, encompassing five tumor types and normal bile duct tissue from 136 unique samples, MCN-L demonstrated a specific methylation profile when compared with all other entities. Furthermore, within the DNA methylation landscape of ovarian tumors – featuring five tumor types, normal Fallopian tube, and normal ovarian tissue from 90 unique samples – we found that both MCN-P and MCN-L grouped with mucinous ovarian carcinoma and mucinous borderline ovarian tumors (mBOTs). Notably, low-grade MCNs exhibited greater DNA methylation similarities to mBOTs, while high-grade or invasive MCNs were primarily associated with mucinous ovarian carcinomas. When analyzing all samples together (19 tumor types and four normal tissue types, <i>n</i> = 430), MCNs similarly grouped with mucinous ovarian tumors and normal ovarian tissue. Additionally, in a network analysis of differentially methylated probes, MCN-P and MCN-L share significant methylation traits, closely resembling mucinous ovarian tumors. In conclusion, our findings highlight that MCN-P and MCN-L are distinct entities in the landscape of pancreatic and hepatic tumors and show DNA methylation profile similarities with mucinous ovarian tumors, suggesting a potential common origin. © 2025 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":"267 1","pages":"10-24"},"PeriodicalIF":5.2,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6439","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482749","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":"Analysis of IDH1 and IDH2 mutations as causes of the hypermethylator phenotype in colorectal cancer","authors":"Joseph C Ward,&nbsp;Melissa Morgan,&nbsp;James Wood,&nbsp;Connor Woolley,&nbsp;Albert Antao Nobre de Menezes,&nbsp;Alina Finch,&nbsp;Kitty Sherwood,&nbsp;Qiwen Huang,&nbsp;Chloe S Henry,&nbsp;Juan Fernández-Tajes,&nbsp;Ignacio Soriano,&nbsp;Steve Thorn,&nbsp;Isabelle Legge,&nbsp;James McCullagh,&nbsp;David Kerr,&nbsp;Rachel Kerr,&nbsp;Rahul K Hejmadi,&nbsp;Mark J Arends,&nbsp;The S:CORT Consortium,&nbsp;Enric Domingo,&nbsp;Timothy Maughan,&nbsp;Chiara Bardella,&nbsp;Ian Tomlinson","doi":"10.1002/path.6446","DOIUrl":"10.1002/path.6446","url":null,"abstract":"<p>The CpG island methylator phenotype (CIMP) occurs in many colorectal cancers (CRCs). CIMP is closely associated with global hypermethylation and tends to occur in proximal tumours with microsatellite instability (MSI), but its origins have been obscure. A few CRCs carry oncogenic (gain-of-function) mutations in isocitrate dehydrogenase <i>IDH1</i>. Whilst <i>IDH1</i> is an established CRC driver gene, the low frequency of <i>IDH1</i>-mutant CRCs (about 0.5%) has meant that the effects and molecular covariates of those mutations have not been established. We first showed computationally that <i>IDH2</i> is also a CRC driver. Using multiple public and in-house CRC datasets, we then identified IDH mutations at the hotspots (<i>IDH1</i> codons 132 and <i>IDH2</i> codons 140 and 172) frequently mutated in other tumour types. Somatic IDH mutations were associated with <i>BRAF</i> mutations and expression of mucinous/goblet cell markers, but not with <i>KRAS</i> mutations or MSI. All IDH-mutant CRCs were CIMP-positive, mostly at a high level. Cell and mouse models showed that IDH mutation was plausibly causal for DNA hypermethylation. Whilst the aetiology of hypermethylation generally remains unexplained, IDH-mutant tumours did not form a discrete methylation subcluster, suggesting that different underlying mechanisms can converge on similar final methylation phenotypes. Although further analysis is required, IDH mutations may be the first cause of hypermethylation to be identified in a common cancer type, providing evidence that CIMP and DNA methylation represent more than aging-related epiphenomena. Cautious exploration of mutant IDH inhibitors and DNA demethylating agents is suggested in managing IDH-mutant CRCs. © 2025 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":"267 1","pages":"40-55"},"PeriodicalIF":5.2,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6446","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367754","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":"Circulating metabolomics reveals guanosine monophosphate synthetase (GMPS) as a novel therapeutic target in lung adenocarcinoma","authors":"Mengjie Yu,&nbsp;Dou Yang,&nbsp;Danxia Zhu,&nbsp;Yue Wang,&nbsp;Minmin Cao,&nbsp;Jingfeng Zhu,&nbsp;Wei Zhu,&nbsp;Guangji Wang,&nbsp;Jiye Aa","doi":"10.1002/path.6442","DOIUrl":"10.1002/path.6442","url":null,"abstract":"<p>Metabolic reprogramming is pivotal in the initiation and progression of lung adenocarcinoma (LUAD). However, a substantial gap remains in the understanding of the primary drivers of metabolic reprogramming and alterations in early-stage LUAD. Using an unbiased, large-scale metabolomics analysis of 2,531 plasma and serum samples from three independent clinical centers, we identified significant perturbations in purine metabolism that characterized reprogrammed metabolism in early-stage LUAD. Additionally, hypoxanthine (<i>p</i> &lt; 0.001) and xanthine (<i>p</i> &lt; 0.05) were identified as two typical early risk indicators, with odd ratios (ORs) more than 2.8 and 1.45, respectively. Guanosine monophosphate synthetase (GMPS) was identified as a pivotal factor in the early development and malignant progression of LUAD. Progression of LUAD was significantly attenuated by <i>GMPS</i> knockdown and markedly exacerbated by its overexpression. Further data indicated that GMPS primarily contributed to the reprogrammed metabolic phenotypes of LUAD through its enzymatic activity and subsequent production of purine nucleotides, based on the relative abundance of the labeled isotope metabolites. Collectively, dysregulated purine metabolism emerged as a key characteristic of early-stage LUAD, and targeting GMPS activity may offer a promising therapeutic potential for LUAD treatment. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 4-5","pages":"465-480"},"PeriodicalIF":5.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332223","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}