Gastric Cancer最新文献

{"title":"Investigating the role of inflammatory cytokines in mediating the effect of gut microbiota on gastrointestinal cancers: a mendelian randomization study.","authors":"Wen-Tao Liu, Xin-Wen Hu, Yan-Ni Choy, Wei Lai, He-Yang Xu, Yu-Jie Zeng, Qiu-Sheng Lan, Lu Liu, Rong-Bin Yue, Zhong-Hua Chu","doi":"10.1007/s10120-025-01587-w","DOIUrl":"https://doi.org/10.1007/s10120-025-01587-w","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study is to explore the causal relationship between gut microbiota and gastrointestinal (GI) cancers and to investigate the potential mediating factors influencing the development of GI cancers.</p><p><strong>Methods: </strong>Using data from genome-wide association studies (GWAS), we employed two-sample Mendelian randomization (TSMR) to explore the relationship among gut microbiota, inflammatory cytokines and GI cancers. Subsequently, a multivariable Mendelian randomization (MVMR) analysis was meticulously conducted to perform a mediation analysis, thereby estimating the proportion of mediation effects conferred by inflammatory cytokines.</p><p><strong>Results: </strong>TSMR analysis established a causal relationship between 23 gut microbiota taxa and 11 inflammatory cytokines with GI cancers. Specifically, 7 gut microbiota taxa were associated with an increased risk of gastric cancer (GC), 6 with small intestine cancer, and 10 with colorectal cancer (CRC). Among the inflammatory cytokines, 4 were linked to GC risk, 3 to small intestine cancer, and to CRC. Mediation analysis further indicatedthat tumor necrosis factor ligand superfamily member 12 (TNFSF12) mediated 9.703% (95% CI 0.108%~15.891%) of the total effect of genus Ruminiclostridium9 on GC.</p><p><strong>Conclusion: </strong>Our findings support a causal relationship between gut microbiota, inflammatory cytokines, and GI cancers. These biomarkers provide new insights into the mechanisms underlying GI cancers and have the potential to improve strategies forprevention, diagnosis, and treatment.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinicopathological significance of JAK2, STAT3, and STAT4 expression in patients with gastric solid-type poorly differentiated adenocarcinoma: a retrospective study.","authors":"Shinya Umekita, Daisuke Kiyozawa, Hitoshi Honma, Kenichi Kohashi, Yoshiaki Taniguchi, Shinichiro Kawatoko, Taisuke Sasaki, Eikichi Ihara, Eiji Oki, Masafumi Nakamura, Yoshihiro Ogawa, Yoshinao Oda","doi":"10.1007/s10120-025-01589-8","DOIUrl":"https://doi.org/10.1007/s10120-025-01589-8","url":null,"abstract":"<p><strong>Background: </strong>The role of janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling remains unclear in gastric solid-type poorly differentiated adenocarcinoma. The present study investigates the clinicopathological significance of JAK2, STAT3, and STAT4 expression in solid-type poorly differentiated adenocarcinoma.</p><p><strong>Methods: </strong>We retrospectively enrolled 102 participants with primary solid-type poorly differentiated adenocarcinoma. We categorized participants according to deficient or proficient mismatch repair status (46 and 56 participants, respectively). Expression of phosphorylated JAK2 (pJAK2), phosphorylated STAT3 (pSTAT3), and STAT4 were analyzed via immunohistochemistry. We analyzed differences in protein expression in relation to mismatch repair status, and associations of high/low protein expression with clinicopathological characteristics and prognoses.</p><p><strong>Results: </strong>Deficient mismatch repair was found to be associated with high pJAK2 (p = 0.038) and STAT4 (p = 0.023) expression in contrast to proficient mismatch repair. Log-rank analysis revealed high pSTAT3 and low STAT4 expression to be significantly correlated with reduced overall survival (p = 0.001). Multivariate analysis revealed high pSTAT3 and low STAT4 expression to be independent indicators of unfavorable prognosis (hazard ratio = 2.751, p = 0.030), as was proficient mismatch repair status (hazard ratio = 3.819, p = 0.012).</p><p><strong>Conclusions: </strong>High expression of pJAK2 and STAT4 is more frequent in deficient compared with proficient mismatch repair in solid-type poorly differentiated adenocarcinoma. High pSTAT3 and low STAT4 expression could be a useful prognostic indicator in solid-type poorly differentiated adenocarcinoma.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The relationship between the gastric cancer microbiome and clinicopathological factors: a metagenomic investigation from the 100,000 genomes project and The Cancer Genome Atlas.","authors":"Mary E Booth, Henry M Wood, Mark A Travis, Phil Quirke, Heike I Grabsch","doi":"10.1007/s10120-025-01588-9","DOIUrl":"https://doi.org/10.1007/s10120-025-01588-9","url":null,"abstract":"<p><strong>Background: </strong>Findings from previous gastric cancer microbiome studies have been conflicting, potentially due to patient and/or tumor heterogeneity. The intratumoral gastric cancer microbiome and its relationship with clinicopathological variables have not yet been characterized in detail. We hypothesized that variation in gastric cancer microbial abundance, alpha diversity, and composition is related to clinicopathological characteristics.</p><p><strong>Methods: </strong>Metagenomic analysis of 529 GC samples was performed, including whole exome sequencing data from The Cancer Genome Atlas (TCGA) and whole genome sequencing data from the 100,000 Genomes Project. Microbial abundance, alpha diversity, and composition were compared across patient age, sex, tumor location, geographic origin, pathological depth of invasion, pathological lymph node status, histological phenotype, microsatellite instability status, and TCGA molecular subtype.</p><p><strong>Results: </strong>Gastric cancer microbiomes resembled previous results, with Prevotella, Selenomonas, Stomatobaculum, Streptococcus, Lactobacillus, and Lachnospiraceae commonly seen across both cohorts. Within the TCGA cohort, microbial abundance and alpha diversity were greater in gastric cancers with microsatellite instability, lower pathological depth of invasion, intestinal-type histology, and those originating from Asia. Microsatellite instability status was associated with microbiome composition in both cohorts. Sex and pathological depth of invasion were associated with microbiome composition in the TCGA cohort.</p><p><strong>Conclusion: </strong>The intratumoral gastric cancer microbiome appears to differ according to clinicopathological factors. Certain clinicopathological factors associated with favourable outcomes in gastric cancer were observed to be associated with greater microbial abundance and diversity. This highlights the need for further work to understand the underlying biological mechanisms behind the observed microbiome differences and their potential clinical and therapeutic impact.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lenvatinib suppress FGF19-FGFR4 signaling to enhance antitumor immune response in gastric cancer.","authors":"Yuya Maruyama, Motonobu Saito, Shotaro Nakajima, Katsuharu Saito, Hiroya Suzuki, Ryo Kanoda, Hirokazu Okayama, Hiroyuki Hanayama, Wataru Sakamoto, Zenichiro Saze, Tomoyuki Momma, Kosaku Mimura, Akiteru Goto, Koji Kono","doi":"10.1007/s10120-025-01596-9","DOIUrl":"https://doi.org/10.1007/s10120-025-01596-9","url":null,"abstract":"<p><strong>Background: </strong>Fibroblast growth factor receptor (FGFR) 4 is overexpressed in gastric cancer (GC) and is a potential therapeutic target for GC. Since the FGF/FGFR signaling is involved in tumor microenvironment inducing the formation of an immunosuppression, lenvatinib is expected to inhibit FGFR4 leading to reduced tumor PD-L1 levels and regulatory T cell (Treg) infiltration, improving pembrolizumab efficacy. This study explored the background of the molecular mechanisms underlying the therapeutic efficacy of lenvatinib plus pembrolizumab.</p><p><strong>Methods: </strong>Expression of FGFR4 and its specific ligand FGF19 was assessed by immunohistochemical staining and clinicopathological relevance was also examined. The effect of lenvatinib on FGF19-FGFR4 signaling was evaluated using cellular experiments. Lastly, the expression of FGFR4 on Treg cells was evaluated by immunostaining and flow cytometry. The Cancer Genome Atlas cBioPortal and Gene Expression Omnibus microarray databases were accessed to support these results.</p><p><strong>Results: </strong>High FGFR4 expression was associated with histological type and venous invasion and predominantly detected in human epidermal growth factor receptor 2 and Epstein-Barr virus-positive GC. Bioinformatics data suggested that FGF19-FGFR4 signaling was activated in GC, and cellular experiments showed that lenvatinib reduced FGFR4 and PD-L1 expression in GC cells. Results of integrating various analyses suggested that FGFR4 did not seem to be enough expressed on Treg cells in GC.</p><p><strong>Conclusions: </strong>The FGF19-FGFR4 signaling has a pivotal role in gastric tumorigenesis and may be involved in immunosuppression through PD-L1 modification. But, lenvatinib may not regulate immune editing by directly inhibiting FGFR4 on Treg cells.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple metachronous foveolar-type gastric adenomas in a Helicobacter pylori-naïve patient with long-term use of a proton pump inhibitor: a case report.","authors":"Yoichi Miyaoka, Kotaro Shibagaki, Ryoji Kushima, Taisuke Omachi, Takanobu Hino, Aya Fujiwara, Kousuke Tsukano, Sayaka Ogawa, Satoshi Yamanouchi, Masaki Tanaka, Tatsuya Miyake, Hirofumi Fujishiro, Naruaki Kohge, Hideyuki Ohnuma, Norihisa Ishimura, Tsuyoshi Mishiro, Shunji Ishihara","doi":"10.1007/s10120-025-01595-w","DOIUrl":"https://doi.org/10.1007/s10120-025-01595-w","url":null,"abstract":"<p><p>A 69-year-old man undergoing long-term administration of a proton-pump inhibitor (PPI) underwent upper endoscopy, which found a small, whitish, flat lesion in the fundic gland (oxyntic) mucosa. The patient had never received treatment for Helicobacter pylori (Hp) infection, and diagnostic testing for Hp was negative, suggesting an Hp-naïve status. Two years later, the lesion appeared markedly enlarged and was endoscopically resected. Histological examination revealed a low-grade foveolar-type gastric adenoma (FGA), predominantly expressing MUC5AC by immunohistochemistry. Two years later, while PPI therapy was continued, three new flat lesions were found. These were endoscopically resected and histologically diagnosed as low-grade FGAs as before, suggesting that multiple metachronous tumors had developed in a short period of time during long-term PPI administration. A KRAS mutation and a CTNNB1 mutation were identified in the tumor. To our best knowledge, this is the first report of potentially PPI-associated multiple metachronous FGAs in an Hp-naïve patient. Here we report a case of multiple foveolar-type gastric adenomas with rapid metachronous recurrences during long-term use of a proton pump inhibitor in Helicobacter pylori-naïve patient.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143407085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: A nonrandomized, single-arm confirmatory trial of expanded endoscopic submucosal dissection indication for undifferentiated early gastric cancer: Japan Clinical Oncology Group study (JCOG1009/1010).","authors":"Kohei Takizawa, Hiroyuki Ono, Noriaki Hasuike, Atsuo Takashima, Keiko Minashi, Narikazu Boku, Ryoji Kushima, Hiroshi Katayama, Gakuto Ogawa, Haruhiko Fukuda, Junko Fujisaki, Ichiro Oda, Tomonori Yano, Shinichiro Hori, Hisashi Doyama, Kingo Hirasawa, Yoshinobu Yamamoto, Ryu Ishihara, Satoshi Tanabe, Yasumasa Niwa, Masahiro Nakagawa, Masanori Terashima, Manabu Muto","doi":"10.1007/s10120-025-01591-0","DOIUrl":"https://doi.org/10.1007/s10120-025-01591-0","url":null,"abstract":"","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143407083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic landscape and potential therapeutic targets in alpha-fetoprotein-producing gastric cancer.","authors":"Likun Zan, Xin Zhang, Lulu Shen, Qi Zhao, Dongfeng Tan, Xiao Peng, Yi Jia, Jiawen Li, Jing Liu, Jiaqi Zhao, Ning Gao, Peng Bu, Yanfeng Xi","doi":"10.1007/s10120-025-01594-x","DOIUrl":"https://doi.org/10.1007/s10120-025-01594-x","url":null,"abstract":"<p><p>Alpha-fetoprotein-producing gastric carcinoma (AFPGC) is a rare and aggressive subtype of gastric cancer (GC). A comprehensive analysis of clinicopathological features, immunophenotypes, molecular characteristics, and survival in AFPGC contributes to identifying potential therapeutic targets and developing new strategies to manage this disease. A retrospective cohort study was conducted at Shanxi Cancer Hospital from January 2018 to December 2020, involving patients diagnosed with GC and elevated AFP serum levels. Among these, 91 patients underwent immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS) to reveal the immunophenotypic and molecular characteristics of AFPGC. We found that AFPGC is more common in males and primarily occurs in the cardia and antrum of the stomach. A panel of IHC markers including AFP, GPC3, SALL4, CD10, CDX-2, and ATBF1 can be used for the diagnosis and differentiating AFPGC. NGS analysis revealed that TP53 hypermutation was the most frequent molecular event associated with AFPGC. The altered signaling pathways included disease signal transduction, receptor tyrosine kinase signaling and intracellular second messenger signaling pathways. The cumulative incidence of 21 genes, based on the evidence of clinical actionability in the OncoKB, was found to be 59.34%. Among these genes, CCNE1, ERBB2, and EGFR were the most frequently observed. This underscores the potential benefit of targeted therapy for patients with AFPGC. Furthermore, LRP1B and ARID1A have been identified as prognostic factors associated with overall survival (OS) and disease-free survival (DFS), respectively. Our results aim to improve AFPGC diagnosis by identifying potential therapeutic targets and prognostic factors, which could help facilitate the development of new treatment strategies.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of CD66c as a potential target in gastroesophageal junction cancer for antibody-drug conjugate development.","authors":"Peng Zhang, Changjuan Tao, Hanfei Xie, Liu Yang, Ye Lu, Yun Xi, Shili Yao, Li Yuan, Peng Guo, Xiangdong Cheng","doi":"10.1007/s10120-025-01584-z","DOIUrl":"https://doi.org/10.1007/s10120-025-01584-z","url":null,"abstract":"<p><strong>Background: </strong>Gastroesophageal junction (GEJ) cancer exhibits unique biological characteristics and currently lacks specific targeted therapies. Given the clinical efficacy of antibody-drug conjugates (ADCs) in solid tumor treatment, we aimed to identify a novel ADC target and suitable payload for GEJ-targeted therapy.</p><p><strong>Methods: </strong>In this study, we conducted bioinformatic analyses of multi-omics data, including transcriptomics, proteomics, and phosphoproteomics, to identify CD66c as a promising ADC target for GEJ cancer. We then engineered a CD66c-directed antibody-drug conjugate (CD66c-DXd) incorporating a GGFG linker. The preclinical efficacy of CD66c-DXd was determined in multi GEJ xenograft models.</p><p><strong>Results: </strong>Proteomic analyses of 103 cases of GEJ cancer revealed that CD66c expression was significantly higher in tumoral tissues compared to normal tissues. Proteomic and phosphoproteomic analyses identified deruxtecan (DXd) as a potentially potent payload for ADCs targeting GEJ cancer. Furthermore, high CD66c expression in GEJ was associated with a significantly lower proportion of plasma cells. The drug-to-antibody ratio (DAR) of CD66c-DXd was determined to be 3.6. CD66c-DXd effectively and selectively ablated multiple human GEJ cell lines (OE-19, OE33 and SK-GT-4) without affecting non-malignant cells (GES-1) in vitro. Eventually, CD66c-DXd mediated potent and durable tumor regression in vivo with excellent safety profiles.</p><p><strong>Conclusions: </strong>This preclinical study provides a strong rationale for the further development of CD66c-DXd as promising therapeutic candidates to treat advanced GEJ cancer. Additionally, the study demonstrates the robustness of the multi-omics data in identifying novel potential ADC targets and payloads.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel ypN-TRG staging system for gastric cancer patients after neoadjuvant therapy based on the metro-ticket paradigm: a multicenter and large sample retrospective analysis.","authors":"Cai-Ming Weng, Qing Zhong, Yu-Qin Sun, Zhi-Yu Liu, Yu-Bin Ma, Zhi-Quan Zhang, Hao-Xiang Zhang, Ji-Yun Zhu, Wen Ye, Ju Wu, He Du, Chao-Hui Zheng, Ping Li, Qi-Yue Chen, Chang-Ming Huang, Jian-Wei Xie","doi":"10.1007/s10120-025-01586-x","DOIUrl":"https://doi.org/10.1007/s10120-025-01586-x","url":null,"abstract":"<p><strong>Background: </strong>Conventional ypT category evaluates the depth of invasion after neoadjuvant therapy (NAT) for gastric cancer (GC) and has limited prognostic value. Tumor regression grade (TRG) measures the extent of tumor response to treatment, and when combined with the ypN category, it may enhance the prediction of patient outcomes. This study aims to develop a new staging system by integrating TRG and ypN category to better evaluate the prognosis of GC patients receiving NAT.</p><p><strong>Methods: </strong>This retrospective analysis included 962 patients who underwent radical gastrectomy after NAT, with 513 in the development cohort (from one center) and 449 in the external validation cohort (from five centers). The ypN-TRG staging system was established by calculating the distance from the origin on a cartesian plane incorporating the ypN (x-axis) stage and TRG (y-axis) grade, and five sub-stages were delineated.</p><p><strong>Results: </strong>In the development cohort, 3-year overall survival rates according to ypN-TRG stage I, IIA, IIB, IIIA, IIB were 87.6%, 80.2%, 70.7%, 47.3%, 21.5%, p < 0.01. Compared with ypTNM, the ypN-TRG staging system performed better in terms of the prognostic discrimination power (C-index), goodness-of-fit (AIC, BIC), model improvement (NRI, IDI), and model stability (time-AUC). Multivariate Cox regression analysis confirmed the superiority of ypN-TRG over ypTNM staging. In the external validation cohort, ypN-TRG staging was a better predictor of OS and DFS in patients with GC.</p><p><strong>Conclusions: </strong>The ypN-TRG staging system is superior to the AJCC eighth edition ypTNM staging system in accurately assessing the prognosis of patients with GC after NAT.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics sequencing of gastroesophageal junction adenocarcinoma reveals prognosis-relevant key factors and a novel immunogenomic classification.","authors":"Zhao Ma, Mengting Li, Fuqiang Li, Kui Wu, Xianxian Wu, Tian Luo, Na Gao, Huijuan Luo, Zhilin Sui, Zhentao Yu, Hongjing Jiang, Xiaobin Shang, Chuangui Chen, Jie Yue, Fianbiao Meng, Xiaofeng Duan, Bo Xu","doi":"10.1007/s10120-025-01585-y","DOIUrl":"https://doi.org/10.1007/s10120-025-01585-y","url":null,"abstract":"<p><strong>Background: </strong>Gastroesophageal junction adenocarcinoma (GEJAC) exhibits distinct molecular characteristics due to its unique anatomical location. We sought to investigate effective and reliable molecular classification of GEJAC to guide personalized treatment.</p><p><strong>Methods: </strong>We analyzed the whole genomic, transcriptomic, T-cell receptor repertoires, and immunohistochemical data in 92 GEJAC patients and delineated the landscape of genetic and immune alterations. In addition to COSMIC nomenclature, the de novo nomenclature was also utilized to define signatures and investigate their correlation with survival. A novel molecular subtype was developed and validated in other cohorts.</p><p><strong>Results: </strong>We found 30 mutated driver genes, 7 novel genomic signatures, 3 copy-number variations, and 2 V-J gene usages related to prognosis that were not identified in previous study. A high frequency of COSMIC-SBS-384-1 and De novo-SV-32-A was associated with more neoantigen generation and a better survival. Using 19 molecular features, we identified three immune-related subtypes (immune inflamed, intermediate, and deserted) with discrete profiles of genomic signatures, immune status, and clinical outcome. The immune deserted subtype (27.2%) was characterized by an earlier KRAS mutation, worse immune reaction, and prognosis than the other two subtypes. The immune inflamed subtypes exhibited the highest levels of neoantigens, TCR/pMHC-binding strength, CD8 + T-cell infiltration, IFN-α/γ response pathways, and survival rate.</p><p><strong>Conclusions: </strong>These results emphasize the immune reaction and prognostic value of novel molecular classifications based on multi-omics data and provide a solid basis for better management of GEJAC.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}