Aihua Guo , Yilin Yu , Qinpeng Guo , Enhuan Zhang , Huaqin Lin , Mei Feng , Peilin Zhong , Jie Lin , Linghua Wang , Xiurong Lin , Haixia Wu , Yang Sun
{"title":"Potential Role of PARVB in Macrophage-Mediated Immunosuppression and Cervical Cancer Progression","authors":"Aihua Guo , Yilin Yu , Qinpeng Guo , Enhuan Zhang , Huaqin Lin , Mei Feng , Peilin Zhong , Jie Lin , Linghua Wang , Xiurong Lin , Haixia Wu , Yang Sun","doi":"10.1016/j.labinv.2025.104223","DOIUrl":"10.1016/j.labinv.2025.104223","url":null,"abstract":"<div><div>This study aimed to identify and characterize novel macrophage–related molecular mechanisms underlying immunosuppression and tumor progression in cervical cancer. Through a systematic integrative analysis guided by immune-related gene signatures and robust regression modeling, we identified PARVB as a novel macrophage–associated prognostic gene with strong predictive value across multiple data sets. Further validation using large-scale transcriptomic data and single-cell RNA-sequencing profiles revealed that PARVB likely activates the SMAD signaling axis, leading to the upregulation of TNFSF13, a key driver of M2 macrophage polarization. This PARVB-SMAD3-TNFSF13 axis enhances interactions between M2 macrophages and TNFSF13<sup>+</sup> subsets, promoting regulatory T-cell induction and fostering an immunosuppressive tumor microenvironment. Functional assays and multiplex immunohistochemistry further confirmed that this axis drives tumor proliferation and immune evasion. Collectively, our findings uncover a critical PARVB-driven signaling cascade that reprograms macrophages into an immunosuppressive M2 phenotype, facilitating immune escape and cervical cancer progression. Targeting this axis presents a promising therapeutic strategy to reshape the tumor microenvironment and improve immunotherapeutic outcomes.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104223"},"PeriodicalIF":4.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760482","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":"Prevalence of Atypical and Subclonal p53 Immunohistochemistry Expression in Mismatch Repair Deficient and/or POLE-Mutant Endometrial Carcinomas with TP53 Mutation.","authors":"Jing Wang, Yumeng Cai, Jun Wang, Jiuyuan Fang, Junyi Pang, Hui Zhang, Junliang Lu, Zijuan Zhang, Huanwen Wu, Zhiyong Liang","doi":"10.1016/j.labinv.2025.104216","DOIUrl":"10.1016/j.labinv.2025.104216","url":null,"abstract":"<p><p>p53 Immunohistochemistry (IHC) is a reliable surrogate for determining TP53 mutation status in endometrial carcinomas (ECs). However, the correlation of p53 IHC patterns and TP53 mutation characteristics in mismatch repair deficiency (MMRd) and/or POLE-mutant ECs was not comprehensively investigated. In this study, we identified 4 p53 expression patterns in 40 MMRd and/or POLE-mutant ECs with TP53 mutations. Thirteen cases (33%) displayed a wild-type pattern. Nine cases (23%) showed atypical pattern, characterized by the presence of eye-catching clustered cells with strong nuclear staining or weak-to-moderate cytoplasmic staining, which were patchily distributed with blurred boundaries. Fourteen cases (35%) demonstrated subclonal pattern with distinct regions of wild-type and mutation-type staining, of which 3 cases were originally misdiagnosed as \"mixed EC.\" Only 4 (10%) cases exhibited typical aberrant pattern. Tumors with wild-type and atypical patterns were predominantly associated with MMRd and POLE mutations, respectively. Among 52 TP53 mutations identified, 75% were missense and 25% were truncating, predominantly in DNA-binding domain. Gain-of-function missense mutations were more frequent in cases with subclonal patterns, whereas non-gain-of-function missense mutations predominated in wild-type or atypical patterns. Concurrent mutations were present in 25% of cases and were more common in aberrant or atypical patterns. Interestingly, 2 POLE wild-type cases with subclonal MMR expression showed p53 overexpression across the entire tumor, complicating molecular subtyping. These findings highlight the prevalence of atypical and subclonal p53 expression patterns in MMRd and/or POLE-mutant ECs with TP53 mutations, aiding in accurate IHC interpretation and thus more precise EC histological and molecular classification.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104216"},"PeriodicalIF":4.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667953","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}
Anne Tuomisto, Päivi Sirniö, Hanna Elomaa, Henna Karjalainen, Ville K Äijälä, Meeri Kastinen, Vilja V Tapiainen, Maarit Ahtiainen, Olli Helminen, Erkki-Ville Wirta, Jukka Rintala, Sanna Meriläinen, Juha Saarnio, Tero Rautio, Toni T Seppälä, Jan Böhm, Jukka-Pekka Mecklin, Markus J Mäkinen, Juha P Väyrynen
{"title":"Integrating Tumor Intraepithelial CD8<sup>+</sup> and Stromal FOXP3<sup>+</sup> T-Cell Densities as an Enhanced Immune Prognostic Index in Colorectal Cancer.","authors":"Anne Tuomisto, Päivi Sirniö, Hanna Elomaa, Henna Karjalainen, Ville K Äijälä, Meeri Kastinen, Vilja V Tapiainen, Maarit Ahtiainen, Olli Helminen, Erkki-Ville Wirta, Jukka Rintala, Sanna Meriläinen, Juha Saarnio, Tero Rautio, Toni T Seppälä, Jan Böhm, Jukka-Pekka Mecklin, Markus J Mäkinen, Juha P Väyrynen","doi":"10.1016/j.labinv.2025.104213","DOIUrl":"10.1016/j.labinv.2025.104213","url":null,"abstract":"<p><p>High immune cell infiltration is generally associated with better survival in colorectal cancer (CRC). Recently, a prognostic score called CD8<sup>IE</sup>-FOXP3<sup>IS</sup>, which integrates the densities of tumor intraepithelial CD8<sup>+</sup> and intrastromal FOXP3<sup>+</sup> cells, was introduced using multiplex immunofluorescence. In this study, we developed a triple chromogenic immunohistochemistry assay to evaluate the CD8<sup>IE</sup>-FOXP3<sup>IS</sup> score and assessed its prognostic value in comparison with the CD3-CD8 T-cell density score (based on the principles of the Immunoscore) and conventional prognostic parameters. Multiplex immunohistochemistry combined with machine learning-assisted image analysis was used to quantify CD8<sup>IE</sup> and FOXP3<sup>IS</sup> densities in 2 independent cohorts comprising 1724 CRC patients. Multivariable Cox regression models were used to evaluate the prognostic value of the CD8<sup>IE</sup>-FOXP3<sup>IS</sup> score. We found that a low CD8<sup>IE</sup>-FOXP3<sup>IS</sup> score was associated with higher disease stage, more frequent lymphovascular invasion, and mismatch repair proficient status. In addition, a low CD8<sup>IE</sup>-FOXP3<sup>IS</sup> score was associated with higher CRC-specific mortality independent of the CD3-CD8 T-cell density score and other tumor and patient characteristics (cohort 1: hazard ratio [HR] for low vs high CD8<sup>IE</sup>-FOXP3<sup>IS</sup> score, 3.08; 95% CI, 1.54-6.15; P<sub>trend</sub> = 6.0E-4; cohort 2: HR, 4.30; 95% CI, 2.58-7.17; P<sub>trend</sub> = 3.2E-9). These findings indicate that triple chromogenic immunohistochemistry combined with digital pathology is an applicable method for quantifying tumor intraepithelial CD8<sup>+</sup> and stromal FOXP3<sup>+</sup> cell densities, allowing for the determination of the CD8<sup>IE</sup>-FOXP3<sup>IS</sup> score. The CD8<sup>IE</sup>-FOXP3<sup>IS</sup> score shows a strong prognostic value, which appears superior to overall CD3<sup>+</sup> and CD8<sup>+</sup> T-cell density measurement.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"104213"},"PeriodicalIF":4.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667952","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}
Yehan Zhou , Jiayu Li , Chengmin Zhou , Jun Hou , Jieyu Wang , Ting Lan , Dan Wan , Yuan Tu , Yungchang Chen , Qiao Yang , Jincheng Luo , Dan Luo , Lin Shi , Yang Liu
{"title":"Deep Learning–Guided Quantitative Analysis Establishes Optimized BRAF V600E Immunohistochemical Criteria for Colorectal Cancer: A Multiplatform Validation Study","authors":"Yehan Zhou , Jiayu Li , Chengmin Zhou , Jun Hou , Jieyu Wang , Ting Lan , Dan Wan , Yuan Tu , Yungchang Chen , Qiao Yang , Jincheng Luo , Dan Luo , Lin Shi , Yang Liu","doi":"10.1016/j.labinv.2025.104215","DOIUrl":"10.1016/j.labinv.2025.104215","url":null,"abstract":"<div><div>Accurate detection of BRAF V600E mutation is critical for guiding therapeutic strategies. Unlike other solid tumors, colorectal cancer (CRC) lacks reliable immunohistochemical (IHC) interpretation criteria. This study aimed to establish CRC-specific IHC criteria through quantitative analysis. A cohort of 250 CRC cases with paired IHC and genetic testing (qPCR and next-generation sequencing) results was analyzed. Cross-platform generalization capability of 3 BRAF V600E antibodies was validated. Previously reported IHC criteria were applied and discordant cases were analyzed. A deep learning–based digital pathology platform quantified IHC parameters (H-score, staining intensity, and percentage). Receiver-operating characteristic analysis identified optimal thresholds, which were translated into practical criteria. External validation was performed to confirm generalizability. Cross-platform validation revealed consistent antibody performance across platforms, with absorbance optical density (2.0-2.3) and H-scores (145-160) showing no significant intergroup differences (<em>P</em> > .05). Initial comparison of existing criteria demonstrated 80.4% to 84.8% concordance with molecular testing. Discordant cases exhibited 5 distinct abnormal staining patterns. Artificial intelligence–driven quantification identified H-score 52.675 as the optimal upper cutoff (area under the curve [AUC], 0.938), translated into a positive criterion of >25% 2+ or >15% 3+ stained cells. A negative criterion of <20% 1+ cells was established. Cases with atypical staining patterns required molecular confirmation. The optimized criteria achieved superior concordance in internal (AUC, 0.932) and external validation (AUC, 0.977). This study established refined BRAF V600E IHC criteria for colorectal cancer using precision quantitative analysis. The optimized protocol significantly improves accuracy and standardization in complex real-world scenarios, demonstrating strong potential for broad clinical adoption.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104215"},"PeriodicalIF":4.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667951","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}
Lina Liu , Zhuoyan Zai , Xuewen Qian , Yuemin Tao , Huifang Lv , Meng Wang , Chuanzhu Zhang , Juan Wang , Yinci Zhang , Yihao Zhang
{"title":"Acid Sensor Acid-Sensing Ion Channel 1a Promotes Malignant Cell Proliferation Through the Transcription Factor 7/c-Myc Pathway in Liver Cancer","authors":"Lina Liu , Zhuoyan Zai , Xuewen Qian , Yuemin Tao , Huifang Lv , Meng Wang , Chuanzhu Zhang , Juan Wang , Yinci Zhang , Yihao Zhang","doi":"10.1016/j.labinv.2025.104212","DOIUrl":"10.1016/j.labinv.2025.104212","url":null,"abstract":"<div><div>The extracellular acidic microenvironment plays a pivotal role in driving tumor initiation and sustaining its malignant progression. Therefore, understanding its regulatory mechanism is crucial for the treatment of liver cancer. Acid-sensing ion channel 1a (ASIC1a) serves as the primary acid sensor, transmitting the extracellular low pH signal into the cell to initiate downstream signaling pathways. In this study, we have investigated the pathogenic role of ASIC1a in liver cancer and elucidated its molecular mechanism. Our findings suggest that ASIC1a facilitates the proliferation of liver cancer cells and enhances their malignant characteristics in the acidic microenvironment. Relevantly, this deleterious characteristic was notably repressed upon the inhibition of ASIC1a activity. Transcription factor 7 acts as a crucial mediator, transmitting the activation signals from ASIC1a to upregulate c-Myc expression, thereby promoting the proliferation of liver cancer cells. In conclusion, our results provide new insights into how the extracellular acidic microenvironment contributes to the advancement of liver cancer.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 10","pages":"Article 104212"},"PeriodicalIF":5.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567615","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":"Clinicopathologic, Cellular, and Molecular Analyses of Pulmonary Neuroendocrine Carcinoma With High Expression of Hepatocyte Nuclear Factor 4 Alpha","authors":"Kei Asayama , Ryota Matsuoka , Suzuka Tachi , Aya Shiba-Ishii , Yoshihiko Murata , Tomoki Nakagawa , Yosuke Furuhashi , Hitomi Kawai , Ayako Suzuki , Yutaka Suzuki , Naohiro Kobayashi , Yukio Sato , Nobuyuki Hizawa , Yoshinori Murakami , Toshiro Niki , Daisuke Matsubara","doi":"10.1016/j.labinv.2025.104210","DOIUrl":"10.1016/j.labinv.2025.104210","url":null,"abstract":"<div><div>Pulmonary neuroendocrine carcinoma (NEC), including small cell carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC), is highly aggressive and has a poor prognosis. The molecular subtyping of NECs has recently attracted attention, and we identified a new NEC subtype, the hepatocyte nuclear factor 4α (HNF4α) subtype. HNF4α, a transcription factor associated with gastrointestinal differentiation, and TTF-1 are mutually and exclusively expressed in lung adenocarcinomas; however, the characteristics of HNF4α-high NEC and TTF-1-high NEC have yet to be compared. We immunohistochemically examined the characteristics of HNF4α-high NEC in 83 surgically resected specimens (37 SCLCs and 46 LCNECs) and revealed that HNF4α-high and TTF-1-high NEC accounted for 15% (12/83) and 47% (39/83), respectively. In SCLCs, HNF4α-high cases (n = 3) and TTF-1-high cases (n = 20) were almost confined to the neuroendocrine phenotype with high ASCL1 expression, and the expressions of HNF4α, TTF-1, and POU2F3 were mutually exclusive. Similar results were obtained for LCNECs; however, some HNF4α-high cases were positive for TTF-1 or YAP1, possibly due to the heterogeneity of LCNEC. Therefore, we investigated the heterogeneity of LCNEC and performed a spatial transcriptome analysis of 1 HNF4α-high LCNEC case, which revealed a mutually exclusive mixture of different subgroups characterized by HNF4A and NKX2-1 (TTF-1) expressions. A whole-genome analysis of 10 LCNECs showed that <em>NFE2L2/KEAP1</em> mutations were characteristic of HNF4α-positive LCNECs. A prognostic analysis revealed a significantly worse prognosis in HNF4α-high LCNECs than in HNF4α-low LCNECs. A cell line analysis showed that TTF-1-high-expressing (Lu139/H889/H510A) and HNF4α-high-expressing (VMRC-LCD/H810) lines were consistent with ASCL1-high-expressing lines. HNF4α knockdown/knock-in experiments in VMRC-LCD and SBC5 (HNF4α-negative) revealed that HNF4α promoted cell proliferation by inhibiting apoptosis. The HNF4α-subtype of pulmonary NEC is a unique subtype, characterized by a neuroendocrine phenotype with high ASCL1 expression and mutual exclusivity with the TTF-1/POU2F3 subtypes. <em>NFE2L2/KEAP1</em> mutations and HNF4α itself are potential therapeutic targets for this subtype.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 10","pages":"Article 104210"},"PeriodicalIF":5.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564870","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}
João Costa , Van-Linh Le , Antonio De Leo , Caterina Ravaioli , Valérie Velasco , Ben Davidson , Tone Skeie-Jensen , Mojgan Devouassoux-Shisheboran , Alexis Trecourt , Carla Bartosch , Elisabete Rios , Catherine Genestie , Patricia Pautier , Coriolan Lebreton , Frédéric Guyon , Guillaume Babin , Jean-Michel Coindre , Francois Le Loarer , Olivier Saut , Sabrina Croce
{"title":"Deep Learning Can Accurately Predict the Prognosis of Gynecologic Smooth Muscle Tumors of Uncertain Malignant Potential: A Multicenter Pilot Study","authors":"João Costa , Van-Linh Le , Antonio De Leo , Caterina Ravaioli , Valérie Velasco , Ben Davidson , Tone Skeie-Jensen , Mojgan Devouassoux-Shisheboran , Alexis Trecourt , Carla Bartosch , Elisabete Rios , Catherine Genestie , Patricia Pautier , Coriolan Lebreton , Frédéric Guyon , Guillaume Babin , Jean-Michel Coindre , Francois Le Loarer , Olivier Saut , Sabrina Croce","doi":"10.1016/j.labinv.2025.104211","DOIUrl":"10.1016/j.labinv.2025.104211","url":null,"abstract":"<div><div>Smooth muscle tumors of uncertain malignant potential (STUMP) of the gynecologic tract are a heterogeneous group of tumors, with ambiguous or worrisome features, whose biological behavior is difficult to predict. Several ancillary techniques have been used to try to predict their prognosis, with limited success. This study aimed to explore whether deep learning (DL)-based features can be used to predict progression-free survival (PFS) in STUMP and identify high-risk patients, directly from histological slides. A cohort of 95 STUMP was collected from 7 academic centers (79 for training and 16 for external validation). Nonoverlapping tiles were extracted from the tumor area and used to train a DL model to predict PFS. Python’s scikit-learn library and the R software environment were used for data analysis. After 4-fold cross-validation, mean C-indexes of 0.7052 (95% CI, 0.4951-0.9152) and 1.0 (95% CI, 1.0-1.0) were achieved, in the training and external validation cohorts, respectively. The predicted PFS probabilities were used to classify the patients into low-risk and high-risk groups, based on the thresholds of the median and the first quartile of predicted PFS probabilities. Significant differences between both groups were observed, at 10 years, with both thresholds. Cox regression analysis showed that the output of the DL model was associated with a worse prognosis (<em>P</em> = .0356). Both STUMP groups were compared with a cohort of leiomyomas (<em>n</em> = 160) and leiomyosarcomas (<em>n</em> = 58). The lowest hazard ratio was observed in leiomyomas, followed, consecutively, by low-risk STUMP, high-risk STUMP, and leiomyosarcomas. The Cox model showed good discriminatory potential between the 4 groups (all pairwise comparisons were statistically significant). These findings suggest that DL-based features can be used for outcome prediction of STUMP. Additional work is needed to establish whether this “high-risk” group can be identified via molecular markers and used to tailor patient surveillance.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 10","pages":"Article 104211"},"PeriodicalIF":4.2,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553922","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}
Martin Loveček , Ondřej Strouhal , Lenka Červenková , Simona Šůsová , Viktor Hlaváč , Magdalena Chottova Dvorakova , Petr Holý , Václav Liška , Pavel Skalický , Daniela Skanderová , Aleš Langer , Beatrice Mohelníková-Duchoňová , Pavel Souček
{"title":"Potential for Clinical Management of Pancreatic Cancer Through Whole Exome Profiling of Site-Specific Metastases and Matched Primary Tumors","authors":"Martin Loveček , Ondřej Strouhal , Lenka Červenková , Simona Šůsová , Viktor Hlaváč , Magdalena Chottova Dvorakova , Petr Holý , Václav Liška , Pavel Skalický , Daniela Skanderová , Aleš Langer , Beatrice Mohelníková-Duchoňová , Pavel Souček","doi":"10.1016/j.labinv.2025.104205","DOIUrl":"10.1016/j.labinv.2025.104205","url":null,"abstract":"<div><div>Considering the lack of molecular background of the metastatic process in pancreatic ductal adenocarcinoma (PDAC) and the fact that the location of the metastasis may carry prognostic information and potential therapeutic opportunities, we aimed to explore genomic profiles of metastases from diverse loci and their value for the patients’ therapeutic management. DNA samples from paired primary and metastatic tissue of 20 patients were microdissected and sequenced using whole exome target enrichment. Somatic genetic variability, copy number variations (CNVs), and mutational signatures were assessed for associations with clinical data of patients. <em>KRAS</em> (78% in primary tumors, 74% in metastases)<em>, TP53</em> (67%-68%), <em>CDKN2A</em> (28%-37%), and <em>SMAD4</em> (22%-26%) were the most commonly mutated oncodrivers in primary tumors and metastases. Other frequently mutated genes were <em>CCDC187</em> (50%-58%), <em>MUC5AC</em> (50%-53%), <em>EPPK1</em> (39%-63%), <em>SYN2</em> (39%-26%), <em>MUC19</em> (33%-47%), <em>MUC3A</em> (33%-26%), <em>DNAH12</em> (28%-37%), <em>ZBED3</em> (22%-26%), <em>PKHD1L1</em> (28%-16%), and <em>GTPBP6</em> (11%-32%). Lung metastases differed from other metastatic sites (liver, stomach, and locoregional) in a higher frequency of nonsense mutations in the MH2 domain of <em>SMAD4</em>, oncodriver comutations, gains on chromosomes 2 and 20, CNV counts, and share of signature SBS5. Somatic alterations of <em>KRAS</em> in metastases (<em>P</em> = .041) and <em>MUC3A</em> in both loci (<em>P</em> = .041 and <em>P</em> = .011, respectively) and CNVs count and size in metastases (<em>P</em> = .024 and <em>P</em> = .011) associated with response to systemic chemotherapy. Patients with mutated <em>KRAS</em> (<em>P</em> = .045), high mutational load (<em>P</em> = .004), and frequent CNVs (<em>P</em> = .004) in metastatic loci had shortened survival after metastasis resection. Interestingly, the personalized treatment targetable alterations, such as microsatellite instability and mismatch repair or homologous recombination deficiencies did not differ between the primary tumors and paired metastases or between the metastases from different secondary sites and had no prognostic value. The results suggest a potential prognostic role of <em>KRAS</em> mutations, mutation load, and CNVs in PDAC patients after metastasectomy and encourage further molecular profiling for personalized treatment of PDAC patients with different metastasis localization.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 10","pages":"Article 104205"},"PeriodicalIF":5.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144368969","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}
Xianjie Xiu , Zhenwei Yu , Georgios Kravvas , Christopher B. Bunker , Liang Cheng , Guangyu Mao , Juan Tang , Ruihang Zhang , Tianzheng Hao , Lichun Yang , Zeyu Wang , Weidong Zhu , Wei Yuan , Zuojing Yin , Lujie Song
{"title":"Molecular Subtypes of Balanopreputial and Urethral Male Genital Lichen Sclerosus: Distinct Transcriptomic and Clinicopathological Profiles","authors":"Xianjie Xiu , Zhenwei Yu , Georgios Kravvas , Christopher B. Bunker , Liang Cheng , Guangyu Mao , Juan Tang , Ruihang Zhang , Tianzheng Hao , Lichun Yang , Zeyu Wang , Weidong Zhu , Wei Yuan , Zuojing Yin , Lujie Song","doi":"10.1016/j.labinv.2025.104206","DOIUrl":"10.1016/j.labinv.2025.104206","url":null,"abstract":"<div><div>Male genital lichen sclerosus (MGLSc) is a heterogeneous and aggressive disease characterized by varying severities of balanopreputial and urethral disease (MGLSc-US) and outcomes, including stricture. This study aims to elucidate the transcriptomic heterogeneity of MGLSc and explore its associations with histological and clinical features. We collected 40 preputial samples and 14 urethral tissue samples from patients with MGLSc-US, non-MGLSc urethral strictures, and redundant prepuce. Bulk RNA sequencing was performed to comprehensively profile the transcriptome. Molecular subtypes, functional features, and gene signatures were identified in MGLSc prepuce and urethral lesions. Additionally, we examined the histological and clinical features specific to each subtype. Two distinct transcriptomic subtypes in preputial lesions were identified. Subtype 1 was characterized by the upregulation of immune pathways and increased lymphocytic stromal infiltration. Subtype 2 showed an upregulation of epithelial cell proliferation and cellular stress response pathways. Both subtypes demonstrated features of hyperkeratosis; however, atrophy was specifically associated with subtype 1, whereas subtype 2 showed significant downregulation of extracellular matrix organization pathways and milder dermal sclerosis. <em>PLEK</em>, <em>PIK3AP1</em>, <em>NCF1</em>, <em>CTSS</em>, and <em>SELL</em> and <em>EVPL</em>, <em>RAPGEFL1</em>, and <em>TMEM79</em> were identified as 2 subtype gene signatures across preputial and urethral lesion cohorts. Clinically, subtype 2 was significantly associated with longer US segments compared with subtype 1. This study provides the first detailed transcriptomic characterization of MGLSc, identifying 2 distinct molecular subtypes with stratified markers. These findings offer a foundation for clinical and molecular classification of MGLSc and may guide management strategies and novel therapeutic developments for this challenging condition.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 10","pages":"Article 104206"},"PeriodicalIF":5.1,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340253","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}