Journal of Pathology Clinical Research最新文献

{"title":"A genome-wide study of gastric intramucosal neoplasia based on somatic copy number alterations, gene mutations, and mRNA expression patterns","authors":"Yoshihiko Koike,&nbsp;Mitsumasa Osakabe,&nbsp;Ryo Sugimoto,&nbsp;Noriyuku Uesugi,&nbsp;Takayuki Matsumoto,&nbsp;Hiromu Suzuki,&nbsp;Naoki Yanagawa,&nbsp;Tamotsu Sugai","doi":"10.1002/2056-4538.12368","DOIUrl":"10.1002/2056-4538.12368","url":null,"abstract":"<p>We performed comprehensive analyses of somatic copy number alterations (SCNAs) and gene expression profiles of gastric intramucosal neoplasia (IMN) using array-based methods in 97 intestinal-type IMNs, including 39 low-grade dysplasias (LGDs), 37 high-grade dysplasias (HGDs), and 26 intramucosal carcinomas (IMCs) with stromal invasion of the lamina propria to identify the molecular mechanism of IMN. In addition, we examined gene mutations using gene panel analyses. We used cluster analyses for exclusion of arbitrariness to identify SCNA patterns and expression profiles. IMNs were classified into two distinct subgroups (subgroups 1 and 2) based on SCNA patterns. Subgroup 1 showed a genomic stable pattern due to the low frequency of SCNAs, whereas subgroup 2 exhibited a chromosomal instability pattern due to the high frequencies of SCNAs and <i>TP53</i> mutations. Interestingly, although the frequencies of LGD and HGD were significantly higher in subgroup 1 than in subgroup 2, IMC was commonly found in both types. Although the expression profiles of specific mRNAs could be used to categorise subgroups 1 and 2, no clinicopathological findings correlated with either subgroup. We examined signalling pathways specific to subgroups 1 and 2 to identify the association of each subgroup with signalling pathways based on gene ontology tree visualisation: subgroups 1 and 2 were associated with haem metabolism and chromosomal instability, respectively. These findings reveal a comprehensive genomic landscape that highlights the molecular complexity of IMNs and provide a road map to facilitate our understanding of gastric IMNs.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 2","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.12368","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140060910","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":"Macrophage migration inhibitory factor (MIF) predicts survival in patients with clear cell renal cell carcinoma","authors":"Martyna Parol-Kulczyk,&nbsp;Justyna Durślewicz,&nbsp;Laura Blonkowska,&nbsp;Radosław Wujec,&nbsp;Arkadiusz Gzil,&nbsp;Daria Piątkowska,&nbsp;Joanna Ligmanowska,&nbsp;Dariusz Grzanka","doi":"10.1002/2056-4538.12365","DOIUrl":"10.1002/2056-4538.12365","url":null,"abstract":"<p>Clear cell renal cell carcinoma (ccRCC) is one of the most common subtypes of renal cancer, with 30% of patients presenting with systemic disease at diagnosis. This aggressiveness is a consequence of the activation of epithelial–mesenchymal transition (EMT) caused by many different inducers or regulators, signaling cascades, epigenetic regulation, and the tumor environment. Alterations in EMT-related genes and transcription factors are associated with poor prognosis in ccRCC. EMT-related factors suppress E-cadherin expression and are associated with tumor progression, local invasion, and metastasis. The aim of this study was to investigate the expression levels and prognostic significance of macrophage migration inhibitory factor (MIF), β-catenin, and E-cadherin in ccRCC patients. We examined these proteins immunohistochemically in tumor areas and adjacent normal tissues resected from patients with ccRCC. Analysis of the cancer genome atlas (TCGA) cohort was performed to verify our results. Kaplan–Meier analysis showed that median overall survival (OS) was significantly shorter in patients with tumors exhibiting high MIFⁿ and MIF^m-c levels compared to those with low MIFⁿ and MIF^m-c levels (<i>p</i> = 0.03 and <i>p</i> = 0.007, respectively). In the TCGA cohort, there was a significant correlation between MIF expression and OS (<i>p</i> &lt; 0.0001). In conclusion, this study provides further evidence for the biological and prognostic value of MIF in the context of EMT as a potential early prognostic marker for advanced-stage ccRCC.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 2","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.12365","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140023063","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":"Aberrant PRDM2 methylation as an early event in serrated lesions destined to evolve into microsatellite-instable colorectal cancers","authors":"David EFWM van Toledo,&nbsp;Arne GC Bleijenberg,&nbsp;Andrea Venema,&nbsp;Mireille J de Wit,&nbsp;Susanne van Eeden,&nbsp;Gerrit A Meijer,&nbsp;Beatrice Carvalho,&nbsp;Evelien Dekker,&nbsp;Peter Henneman,&nbsp;Joep EG IJspeert,&nbsp;Carel JM van Noesel","doi":"10.1002/cjp2.348","DOIUrl":"10.1002/cjp2.348","url":null,"abstract":"<p>Up to 30% of colorectal cancers (CRCs) develop from sessile serrated lesions (SSLs). Within the serrated neoplasia pathway, at least two principally distinct oncogenetic routes exist generating microsatellite-stable and microsatellite-instable CRCs, respectively. Aberrant DNA methylation (DNAm) is found early in the serrated pathway and might play a role in both oncogenetic routes. We studied a cohort of 23 SSLs with a small focus (&lt;10 mm) of dysplasia or cancer, 10 of which were MLH1 deficient and 13 MLH1 proficient. By comparing, for each SSL, the methylation status of (1) the region of dysplasia or cancer (SSL-D), (2) the nondysplastic SSL (SSL), and (3) adjacent normal mucosa, differentially methylated probes (DMPs) and regions (DMRs) were assessed both genome-wide as well as in a tumor-suppressor gene-focused approach. By comparing DNAm of MLH1-deficient SSL-Ds with their corresponding SSLs, we identified five DMRs, including those annotating for <i>PRDM2</i> and, not unexpectedly, <i>MLH1</i>. <i>PRDM2</i> gene promotor methylation was associated with MLH1 expression status, as it was largely hypermethylated in MLH1-deficient SSL-Ds and hypomethylated in MLH1-proficient SSL-Ds. Significantly increased DNAm levels of <i>PRDM2</i> and <i>MLH1</i>, in particular at ‘critical’ <i>MLH1</i> probe sites, were to some extent already visible in SSLs as compared to normal mucosa (<i>p</i> = 0.02, <i>p</i> = 0.01, <i>p</i> &lt; 0.0001, respectively). No DMRs, nor DMPs, were identified for SSLs destined to evolve into MLH1-proficient SSL-Ds. Our data indicate that, within both arms of the serrated CRC pathway, the majority of the epigenetic alterations are introduced early during SSL formation. Promoter hypermethylation of <i>PRDM2</i> and <i>MLH1</i> on the other hand specifically initiates in SSLs destined to transform into MLH1-deficient CRCs suggesting that the fate of SSLs may not necessarily result from a stochastic process but possibly is already imprinted and predisposed.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 2","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.348","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139913798","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":"NDRG1 is a prognostic biomarker in breast cancer and breast cancer brain metastasis","authors":"Vaibhavi Joshi,&nbsp;Andrew Stacey,&nbsp;Yufan Feng,&nbsp;Priyakshi Kalita-de Croft,&nbsp;Pascal HG Duijf,&nbsp;Peter T Simpson,&nbsp;Sunil R Lakhani,&nbsp;Amy E McCart Reed","doi":"10.1002/2056-4538.12364","DOIUrl":"https://doi.org/10.1002/2056-4538.12364","url":null,"abstract":"<p>Brain metastases are secondary brain tumours characterised by their aggressive nature and poor prognosis. Breast cancer is one of the most common primary tumours in women to spread to the brain. A lack of biomarkers predicting likely spread to the brain and limited therapeutic interventions represents major areas of clinical unmet need. We investigated N-myc downregulated gene-1 (NDRG1) as a clinically relevant biomarker in breast cancer brain metastasis patients. NDRG1 expression was investigated using immunohistochemistry on tissue microarrays of two clinical cohorts: (i) brain metastatic breast cancers (<i>n</i> = 48) and brain metastases (<i>n</i> = 64; including a subset of 39 patient-matched breast and brain metastasis cases) and (ii) unselected primary breast cancers (<i>n</i> = 336). NDRG1 was highly expressed in breast-to-brain metastases, as well as in high-grade primary breast cancers. High NDRG1 expression and also an absence of expression were associated with worse survival outcomes in both breast cancer and breast cancer brain metastasis patients. This establishes NDRG1 as a ‘Goldilocks’ protein, where too much or too little has a negative effect on survival. We pose that this accounts for its previous categorisation as both tumour suppressor and oncoprotein. Additionally, a shift in NDRG1 localisation with a gain of nuclear expression was seen at the brain metastasis stage. Significant survival benefit in cases expressing cytoplasmic NDRG1 was observed, whereas NDRG1 localisation in the nucleus showed a clear association with poorer survival. <i>In vitro</i> analyses revealed that hypoxic stress significantly elevated NDRG1 expression and resulted in its nuclear localisation. Our findings suggest NDRG1 expression and subcellular localisation are clinically relevant biomarkers for poor prognosis in breast cancer and breast cancer brain metastasis.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 2","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.12364","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139682995","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":"Verification of molecular subtyping of bladder cancer in the GUSTO clinical trial","authors":"Jon Griffin,&nbsp;Jenny Down,&nbsp;Lewis A Quayle,&nbsp;Paul R Heath,&nbsp;Ewan A Gibb,&nbsp;Elai Davicioni,&nbsp;Yang Liu,&nbsp;Xin Zhao,&nbsp;Jayne Swain,&nbsp;Dennis Wang,&nbsp;Syed Hussain,&nbsp;Simon Crabb,&nbsp;James WF Catto,&nbsp;the GUSTO Trial Management Group","doi":"10.1002/2056-4538.12363","DOIUrl":"https://doi.org/10.1002/2056-4538.12363","url":null,"abstract":"<p>The GUSTO clinical trial (Gene expression subtypes of Urothelial carcinoma: Stratified Treatment and Oncological outcomes) uses molecular subtypes to guide neoadjuvant therapies in participants with muscle-invasive bladder cancer (MIBC). Before commencing the GUSTO trial, we needed to determine the reliability of a commercial subtyping platform (Decipher Bladder; Veracyte) when performed in an external trial laboratory as this has not been done previously. Here, we report our pre-trial verification of the TCGA molecular subtyping model using gene expression profiling. Formalin-fixed paraffin-embedded tissue blocks of MIBC were used for gene expression subtyping by gene expression microarrays. Intra- and inter-laboratory technical reproducibilities, together with quality control of laboratory and bioinformatics processes, were assessed. Eighteen samples underwent analysis. RNA of sufficient quality and quantity was successfully extracted from all samples. All subtypes were represented in the cohort. Each sample was subtyped twice in our laboratory and once in a separate reference laboratory. No clinically significant discordance in subtype occurred between intra- or inter-laboratory replicates. Examination of sample histopathology showed variability of morphological appearances within and between subtypes. Overall, these results show that molecular subtyping by gene expression profiling is reproducible, robust and suitable for use in the GUSTO clinical trial.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 2","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.12363","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139676540","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":"ERBB2-amplified lobular breast carcinoma exhibits concomitant CDK12 co-amplification associated with poor prognostic features","authors":"Miriam Forster-Sack,&nbsp;Martin Zoche,&nbsp;Bernhard Pestalozzi,&nbsp;Isabell Witzel,&nbsp;Esther Irene Schwarz,&nbsp;Joel Julien Herzig,&nbsp;Hisham Fansa,&nbsp;Christoph Tausch,&nbsp;Jeff Ross,&nbsp;Holger Moch,&nbsp;Zsuzsanna Varga","doi":"10.1002/2056-4538.12362","DOIUrl":"10.1002/2056-4538.12362","url":null,"abstract":"<p>Most invasive lobular breast carcinomas (ILBCs) are luminal-type carcinomas with an HER2-negative phenotype (<i>ERBB2 or HER2</i> un-amplified) and <i>CDH1</i> mutations. Rare variants include <i>ERBB2</i>-amplified subtypes associated with an unfavorable prognosis and less response to anti-HER2 targeted therapies. We analyzed the clinicopathological and molecular features of <i>ERBB2</i>-amplified ILBC and compared these characteristics with <i>ERBB2</i>-unamplified ILBC. A total of 253 patients with ILBC were analyzed. Paraffin-embedded formalin-fixed tumor samples from 250 of these patients were added to a tissue microarray. Protein expression of prognostic, stem cell and breast-specific markers was tested by immunohistochemistry (IHC). Hybrid capture-based comprehensive genomic profiling (CGP) was performed for 10 ILBCs that were either fluorescent <i>in situ</i> hybridization (FISH) or IHC positive for <i>HER2</i> amplification/overexpression and 10 ILBCs that were either FISH or IHC negative. Results were compared with a CGP database of 44,293 invasive breast carcinomas. The CGP definition of <i>ERBB2</i> amplification was five copies or greater. A total of 17 of 255 ILBC (5%) were <i>ERBB2</i> amplified. <i>ERBB2</i>-amplified ILBC had higher tumor stage (<i>p</i> &lt; 0.0001), more frequent positive nodal status (<i>p</i> = 0.00022), more distant metastases (<i>p</i> = 0.012), and higher histological grade (<i>p</i> &lt; 0.0001), and were more often hormone receptor negative (<i>p</i> &lt; 0.001) and more often SOX10 positive (<i>p</i> = 0.005). <i>ERBB2</i> short variant sequence mutations were more often detected in <i>ERBB2</i>-unamplified tumors (6/10, <i>p</i> = 0.027), whereas <i>CDH1</i> mutations/copy loss were frequently present in both subgroups (9/10 and 7/10, respectively). Amplification of pathogenic genes were more common in HER2-positive ILBC (<i>p</i> = 0.0009). <i>CDK12</i> gene amplification (≥6 copies) was detected in 7 of 10 <i>ERBB2</i>-amplified ILBC (<i>p</i> = 0.018). There were no <i>CDK12</i> gene amplifications reported in 44,293 invasive breast carcinomas in the FMI Insights CGP database. <i>ERBB2</i>-amplified ILBC is a distinct molecular subgroup with frequent coamplification of <i>CDK12</i>, whereas <i>ERBB2</i> sequence mutations occur only in <i>ERBB2</i>-unamplified ILBC. <i>CDK12</i>/<i>ERBB2</i> co-amplification may explain the poor prognosis and therapy resistance of <i>ERBB2</i>-amplified ILBC.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 2","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.12362","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139523782","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":"Microenvironment-induced restoration of cohesive growth associated with focal activation of P-cadherin expression in lobular breast carcinoma metastatic to the colon","authors":"Malte Gronewold,&nbsp;Isabel Grote,&nbsp;Stephan Bartels,&nbsp;Henriette Christgen,&nbsp;Leonie D Kandt,&nbsp;Maria Jose Brito,&nbsp;Gàbor Cserni,&nbsp;Maximilian E Daemmrich,&nbsp;Franz Fogt,&nbsp;Burkhard M Helmke,&nbsp;Natalie ter Hoeve,&nbsp;Corinna Lang-Schwarz,&nbsp;Michael Vieth,&nbsp;Axel Wellmann,&nbsp;Elna Kuehnle,&nbsp;Ulf Kulik,&nbsp;Gesa Riedel,&nbsp;Tanja Reineke-Plaass,&nbsp;Ulrich Lehmann,&nbsp;Thijs Koorman,&nbsp;Patrick WB Derksen,&nbsp;Hans Kreipe,&nbsp;Matthias Christgen","doi":"10.1002/2056-4538.12361","DOIUrl":"https://doi.org/10.1002/2056-4538.12361","url":null,"abstract":"<p>Invasive lobular carcinoma (ILC) is a special breast cancer type characterized by noncohesive growth and E-cadherin loss. Focal activation of P-cadherin expression in tumor cells that are deficient for E-cadherin occurs in a subset of ILCs. Switching from an E-cadherin deficient to P-cadherin proficient status (EPS) partially restores cell–cell adhesion leading to the formation of cohesive tubular elements. It is unknown what conditions control EPS. Here, we report on EPS in ILC metastases in the large bowel. We reviewed endoscopic colon biopsies and colectomy specimens from a 52-year-old female (index patient) and of 18 additional patients (reference series) diagnosed with metastatic ILC in the colon. EPS was assessed by immunohistochemistry for E-cadherin and P-cadherin. <i>CDH1</i>/E-cadherin mutations were determined by next-generation sequencing. The index patient's colectomy showed transmural metastatic ILC harboring a <i>CDH1</i>/E-cadherin p.Q610* mutation. ILC cells displayed different growth patterns in different anatomic layers of the colon wall. In the tunica muscularis propria and the tela submucosa, ILC cells featured noncohesive growth and were E-cadherin-negative and P-cadherin-negative. However, ILC cells invading the mucosa formed cohesive tubular elements in the intercryptal stroma of the lamina propria mucosae. Inter-cryptal ILC cells switched to a P-cadherin-positive phenotype in this microenvironmental niche. In the reference series, colon mucosa infiltration was evident in 13 of 18 patients, one of which showed intercryptal EPS and conversion to cohesive growth as described in the index patient. The large bowel is a common metastatic site in ILC. In endoscopic colon biopsies, the typical noncohesive growth of ILC may be concealed by microenvironment-induced EPS and conversion to cohesive growth.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 2","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2056-4538.12361","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139494593","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":"Anaplastic and poorly differentiated thyroid carcinomas: genetic evidence of high-grade transformation from differentiated thyroid carcinoma","authors":"Haiyan Gu,&nbsp;Jingnan Wang,&nbsp;Wenwen Ran,&nbsp;Guangqi Li,&nbsp;Shasha Hu,&nbsp;Han Zhao,&nbsp;Xiaonan Wang,&nbsp;Jigang Wang","doi":"10.1002/cjp2.356","DOIUrl":"https://doi.org/10.1002/cjp2.356","url":null,"abstract":"<p>Anaplastic thyroid carcinoma (ATC) is the most advanced and aggressive thyroid cancer, and poorly differentiated thyroid carcinoma (PDTC) lacks anaplastic histology but has lost architectural and cytologic differentiation. Only a few studies have focused on the genetic relationship between the two advanced carcinomas and coexisting differentiated thyroid carcinomas (DTCs). In the present study, we investigated clinicopathologic features and genetic profiles in 57 ATC and PDTC samples, among which 33 cases had concomitant DTC components or DTC history. We performed immunohistochemistry for BRAF V600E, p53, and PD-L1 expression, Sanger sequencing for <i>TERT</i> promoter and <i>RAS</i> mutations, and fluorescence <i>in situ</i> hybridization for <i>ALK</i> and <i>RET</i> rearrangements. We found that ATCs and PDTCs shared similar gene alterations to their coexisting DTCs, and most DTCs were aggressive subtypes harboring frequent <i>TERT</i> promoter mutations. A significantly higher proportion of ATCs expressed p53 and PD-L1, and a lower proportion expressed PAX-8 and TTF-1, than the coexisting DTCs. Our findings provide more reliable evidence that ATCs and PDTCs are derived from DTCs.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 2","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.356","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139494591","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":"Immune checkpoint CD161/LLT1-associated immunological landscape and diagnostic value in oral squamous cell carcinoma","authors":"Xinyang Hu,&nbsp;Yuexin Dong,&nbsp;Shixin Xie,&nbsp;Yuxian Song,&nbsp;Chenhang Yu,&nbsp;Yijia He,&nbsp;Zhiyong Wang,&nbsp;Qingang Hu,&nbsp;Yanhong Ni,&nbsp;Liang Ding","doi":"10.1002/cjp2.353","DOIUrl":"https://doi.org/10.1002/cjp2.353","url":null,"abstract":"<p>An active host adaptive response is characterized by the existence of programmed cell death protein 1 (PD-1)⁺/IFN-γ⁺ cytotoxic T cells and IFN-γ-induced PD-L1⁺ tumor cells (TCs), which predicts high response rate to anti-PD-1/L1 therapy. Recently, CD161 and its ligand LLT1 (CLEC2D) have been identified as an emerging checkpoint for immunotherapy. Clarifying its heterogeneous clinical expression pattern and its immune landscape is a prerequisite for maximizing the response rate of CD161 blockade therapy in a specific population of oral squamous cell carcinoma (OSCC) patients. Here, we investigated the expression pattern of CD161/LLT1 and its association with major immunocytes (T cells, B cells, NK cells, and macrophages) by multiplex immunofluorescence, immunohistochemistry, and flow cytometry in 109 OSCC tissues and 102 peripheral blood samples. TCs showed higher LLT1 levels than tumor infiltrating lymphocytes (TILs), whereas CD161 was highly expressed in CD8⁺ T cells at the tumor front, which was decreased in paracancerous tissue. High expression of TC-derived LLT1 (LLT1^TC) conferred poor clinical outcomes, whereas higher CD161⁺ and LLT1⁺ TILs were associated with better prognosis. Meanwhile, patients with high LLT1^TC showed a decreased ratio of CD8⁺/Foxp3⁺ T cells <i>in situ</i>, but CD161⁺ TILs correlated with more peripheral CD3⁺ T cells. Interestingly, treatment of OSCC patients with nivolumab (anti-PD-1) could restore tumoral CD161/LLT1 signal. Furthermore, an OSCC subgroup characterized by high LLT1⁺ TCs and low CD161⁺CD8⁺ T cells showed fewer peripheral T cells and a higher risk of lymph node metastasis, leading to a shorter 5-year survival time (29%). More LLT1^TC at the invasive front was another risk characteristic of exhausted T cells. In conclusion, in view of this heterogeneity, the LLT1/CD161 distribution pattern should be determined before CD161-based immunotherapy.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 2","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.353","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139480551","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":"Genomic heterogeneity at baseline is associated with T790M resistance mutations in EGFR-mutated lung cancer treated with the first-/second-generation tyrosine kinase inhibitors","authors":"Michael Menzel,&nbsp;Martina Kirchner,&nbsp;Klaus Kluck,&nbsp;Markus Ball,&nbsp;Susanne Beck,&nbsp;Michael Allgäuer,&nbsp;Christin Assmann,&nbsp;Johannes Schnorbach,&nbsp;Anna-Lena Volckmar,&nbsp;Timothy Kwang Yong Tay,&nbsp;Hannah Goldschmid,&nbsp;Daniel SW Tan,&nbsp;Michael Thomas,&nbsp;Daniel Kazdal,&nbsp;Jan Budczies,&nbsp;Albrecht Stenzinger,&nbsp;Petros Christopoulos","doi":"10.1002/cjp2.354","DOIUrl":"https://doi.org/10.1002/cjp2.354","url":null,"abstract":"<p>This study analyzed whether extended molecular profiling can predict the development of epidermal growth factor receptor (<i>EGFR</i>) gene T790M mutation, which is the most frequent resistance alteration in non-small cell lung cancer (NSCLC) after treatment with the first-/second-generation (1G/2G) EGFR inhibitors (tyrosine kinase inhibitors [TKIs]), but only weakly associated with clinical characteristics. Whole exome sequencing (WES) was performed on pretreatment tumor tissue with matched normal samples from NSCLC patients with (<i>n</i> = 25, detected in tissue or blood rebiopsies) or without (<i>n</i> = 14, negative tissue rebiopsies only) subsequent <i>EGFR</i> p.T790M mutation after treatment with 1G/2G EGFR TKI. Several complex genetic biomarkers were assessed using bioinformatic methods. After treatment with first-line afatinib (44%) or erlotinib/gefitinib (56%), median progression-free survival and overall survival were 12.1 and 33.7 months, respectively. Clinical and tumor genetic characteristics, including age (median, 66 years), sex (74% female), smoking (69% never/light smokers), <i>EGFR</i> mutation type (72% exon 19 deletions), and <i>TP53</i> mutations (41%) were not significantly associated with T790M mutation (<i>p</i> &gt; 0.05). By contrast, complex biomarkers including tumor mutational burden, the clock-like mutation signature SBS1 + 5, tumor ploidy, and markers of subclonality including mutant-allele tumor heterogeneity, subclonal copy number changes, and median tumor-adjusted variant allele frequency were significantly higher at baseline in tumors with subsequent T790M mutation (all <i>p</i> &lt; 0.05). Each marker alone could predict subsequent development of T790M with an area under the curve (AUC) of 0.72–0.77, but the small number of cases did not allow confirmation of better performance for biomarker combinations in leave-one-out cross-validated logistic regression (AUC 0.69, 95% confidence interval: 0.50–0.87). Extended molecular profiling with WES at initial diagnosis reveals several complex biomarkers associated with subsequent development of T790M resistance mutation in NSCLC patients receiving first-/second-generation TKIs as the first-line therapy. Larger prospective studies will be necessary to define a forecasting model.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"10 2","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.354","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139480552","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}