Cancer Science最新文献

{"title":"Multi-Omics Integration Reveals Metabolic Reprogramming and EMT-Driven Metastasis in Triple-Negative Breast Cancer.","authors":"Yuheng Pang, Yuefeng Shang, Wenjing Wang, Tong Liu, Xiaolong Zou","doi":"10.1111/cas.70559","DOIUrl":"10.1111/cas.70559","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive subtype with high metastatic potential and poor prognosis, yet the molecular mechanisms driving metastasis remain incompletely understood. Here, we performed integrated transcriptomic, metabolomic, and imaging mass cytometry (IMC) analyses on tumor tissues from 52 TNBC patients stratified into NonMeta (long-term survival without metastasis, n = 39) and MetaPoor (metastasis-related death within 36 months after metastatic diagnosis, n = 13) groups. Transcriptomic analysis revealed significant enrichment of epithelial-mesenchymal transition (EMT), WNT signaling pathway, and angiogenesis pathways in MetaPoor tumors, with EMT identified as the top enriched hallmark by GSEA. Metabolomic profiling showed decreased branched-chain amino acids (BCAAs) and arginine derivatives, alongside elevated glycerophosphorylcholine (GPC), indicating enhanced metabolic demand and membrane remodeling. IMC-based spatial proteomics identified distinct tumor cell subpopulations, with MetaPoor tumors harboring higher proportions of stem-like and EMT-like cells characterized by upregulated HADHA (BCAA oxidation) and P38, and downregulated ATP5A (oxidative phosphorylation). Multi-omics integration revealed strong correlations between GPC and EMT markers, and between BCAA depletion and HADHA expression. Collectively, our multi-omics study demonstrates that metastatic TNBC is characterized by EMT activation, metabolic reprogramming toward altered BCAA metabolism and oxidative phosphorylation-related protein expression, and remodeling of the tumor immune microenvironment, suggesting candidate molecules that warrant independent validation and further mechanistic investigation.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial Atlas of Small Cell Lung Carcinoma Reveals Intratumoral Tumor-State Heterogeneity and an MMP12⁺ Macrophage Niche.","authors":"Naozane Nomura, Naoe Jimbo, Takaaki Nakanishi, Yukinobu Ito, Maki Sakaguchi, Daichi Maeda, Hiroko Ikeda, Tsukasa Ueda, Hayato Koba, Seiji Yano, Isao Matsumoto, Patrick Micke, Takayuki Kodama, Manabu Shigeoka, Yu-Ichiro Koma, Masafumi Horie","doi":"10.1111/cas.70555","DOIUrl":"10.1111/cas.70555","url":null,"abstract":"<p><p>Small-cell lung carcinoma (SCLC) is a highly aggressive tumor with a dismal prognosis among lung cancers. Treatment is failing because of primary or rapidly developing secondary resistance. Recent molecular studies have suggested four SCLC subtypes with unique therapeutic vulnerabilities-ASCL1, NEUROD1, POU2F3, and YAP. These subtypes still distinguish themselves by considerable intra-tumoral heterogeneity and the influence of the microenvironmental context, which are both considered to be responsible for treatment resistance. We integrated in situ hybridization-based spatial transcriptomics with histological and protein-expression analyses of 18 specimens, comprising 16 SCLCs, one atypical carcinoid, and one normal lung specimen. Systematic case-by-case analysis revealed multiple coexisting tumor states, including neuroendocrine and non-neuroendocrine components, regional hypoxic states, and case-specific FABP7-positive and loss-of-chromosome-Y-associated populations. Integrative transcriptome clustering, copy number estimation, and exploratory trajectory analysis revealed transcriptional relationships among spatially coexisting tumor states, including phenotypically distinct tumor components with molecular features consistent with close clonal relationships in selected heterogeneous tumors. Furthermore, we identified immune signatures and uncovered a previously unrecognized MMP12-positive tumor-associated macrophage population, enriched at the tumor interface and spatially associated with necrotic and hypoxic regions. In vitro co-culture experiments further showed that direct contact with SCLC cells increased MMP12 expression in macrophages, with hypoxia further enhancing its expression under specific conditions. Together, our study delineates the complex spatial architecture of SCLC by defining specific cellular programs and adjacent immune phenotypes that provide an organizational framework for understanding its marked intratumoral heterogeneity.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167736","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":"A20 Inhibits IFN-γ Signaling in Hepatocellular Carcinoma Cells by Binding to STAT1, Compromising Anti-Tumor Immunity.","authors":"Yanlei Dong, Jing Yi, Ruoxuan Yang, Yingyue Wang, Zelong Ma, Hong Yuan, Meichen Song, Ying Xiao, Chun Guo, Jianing Wang, Xiaoyan Wang, Faliang Zhu, Lining Zhang, Yuchen Fan, Yongyu Shi","doi":"10.1111/cas.70556","DOIUrl":"10.1111/cas.70556","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) has demonstrated efficacy in clinical cancer therapy; however, a significant proportion of cancer patients do not respond to ICB. One contributing factor to this lack of response is the impairment of IFN-γ signaling within cancer cells. A20 acts as a negative regulator of IFN-γ signaling. Our study aimed to investigate the mechanism by which A20 exerts its negative regulatory effect on IFN-γ signaling in hepatocellular carcinoma (HCC) cells. Bioinformatic analysis revealed that A20 expression in HCC cell lines is inversely associated with the activation of IFN-γ signaling. Functional loss and gain experiments demonstrated that A20 inhibits IFN-γ signaling in HCC cells. The interaction between A20 and STAT1 was assessed using Co-Immunoprecipitation (Co-IP) assays and bimolecular fluorescence complementation (BioFC) assays. Our results also indicated that A20 suppresses the expression of downstream molecules involved in IFN-γ signaling, such as CXCL9, CXCL10, and HLA-ABC, in HCC cells. Additionally, enforced expression of A20 in HCC cells inhibited anti-tumor immunity in a mouse model of HCC. Bioinformatic analysis suggests that A20 may negatively regulate IFN-γ signaling in HCC cells from human HCC cohorts. Collectively, our study uncovers a novel mechanism whereby A20 inhibits IFN-γ signaling in HCC cells through direct binding with STAT1. These findings enhance our understanding of the regulatory mechanisms of IFN-γ signaling in cancer cells and provide insights for designing strategies to enhance the effectiveness of ICB therapy.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13646509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149129019","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":"Mapping the Tissue Architecture and Endothelial-PEC Network in HAML Using Single-Cell and Spatial Transcriptomics.","authors":"Xinyang Liu, Yang Guo, Xuehong Tie, Yu Liu, Fuyu Li, Jingkai Liu, Xiaohang Sun, Jiajun Zhao, Feng Geng, Yingjian Liang","doi":"10.1111/cas.70550","DOIUrl":"10.1111/cas.70550","url":null,"abstract":"<p><p>Hepatic angiomyolipoma (HAML) is a rare variant of perivascular epithelioid cell neoplasms (PEComas). Unlike its more common renal angiomyolipoma (RAML), the unique spatial microenvironment of HAML and its specific progression mechanisms remain poorly characterized. Here, we integrated single-nucleus RNA-sequencing and spatial transcriptomics from three sporadic HAML cases. We mapped functionally heterogeneous PEComas subpopulations and their localized tissue niches. Transcriptomic alignment and spatial colocalization demonstrated a high similarity between endothelial cells and a subset of PEComas, supporting a potential transition trajectory. Furthermore, spatial intercellular communication analysis identified an endothelial-derived PDGFD-PDGFRB axis. We propose that this paracrine signaling engages downstream Ras cascades to sustain localized autophagic flux in adjacent PEComas, potentially acting as a compensatory survival mechanism parallel to intrinsic TSC-mTOR defects. While definitive in vivo functional fate-mapping and perturbation studies are requisite, this multi-omics atlas provides a novel spatial framework for HAML pathogenesis and highlights the endothelial-PEComa signaling network as a potential therapeutic vulnerability.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128986","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":"Assessment of MRD and Longitudinal Monitoring of Post-Surgery Biliary Tract Cancer With a Customized ctDNA Panel.","authors":"Yoshihito Shinohara, Toru Nakamura, Yasutoshi Kimura, Takeshi Murakami, Shigeyuki Kojima, Toshikazu Yamaguchi, Kanako C Hatanaka, Ryo Okazaki, Yosuke Kitayama, Keita Fukuda, Fabio Pittella-Silva, Yusuke Nakamura, Satoshi Hirano, Siew-Kee Low","doi":"10.1111/cas.70552","DOIUrl":"https://doi.org/10.1111/cas.70552","url":null,"abstract":"<p><p>Biliary tract cancer (BTC) is a rare abdominal cancer with poor prognosis. Circulating tumor DNA (ctDNA) analysis with liquid biopsy offers a minimally invasive approach for cancer detection and disease monitoring. Given limited reports, this study aims to evaluate minimal residual disease (MRD) and longitudinal ctDNA monitoring in BTC patients. A total of 124 BTC patients were enrolled, with 111 evaluable for ctDNA analysis using a tumor-informed approach. Baseline tumor tissue and plasma samples were collected for comprehensive genomic profiling (CGP). A customized ctDNA panel was developed based on CGP of resectable BTC tumors and public genomic databases for MRD assessment and longitudinal monitoring. ctDNA sequencing was performed using ultradeep targeted next-generation sequencing. Associations between ctDNA detection and outcomes were analyzed. Preoperative ctDNA detection was associated with advanced pathological stage and significantly worse relapse-free survival (RFS) and overall survival. Using this ctDNA panel, preoperative ctDNA was detected in 51.4% of cases, with TP53, KRAS, ARID1A, and SMAD4 being the most frequently mutated genes. During longitudinal monitoring, 57.8% of patients showed persistent ctDNA positivity or subsequent ctDNA detection before radiological recurrence. RFS was significantly shorter among patients with ctDNA positivity during longitudinal monitoring than among those with undetectable ctDNA (HR = 9.04; 95% CI, 3.56-23.97; p < 0.001). Our customized panel detected BTC-specific mutations in plasma using liquid biopsy, and ctDNA positivity was strongly associated with recurrence and survival outcomes. This panel has the potential to improve MRD assessment and longitudinal monitoring in BTC, enabling earlier intervention and improved patient stratification.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13636022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149117181","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":"Genetic Evolution in BRCA1-Associated Breast Cancer Reveals Early Driver Mutations Shaping Tumor Features and Prognosis.","authors":"Li Hu, Zhongwu Li, Qiting Wan, Xingyu Liao, Yaxin Zhang, Qian Liu, Xinyun Ding, Hua Meng, Yifan Wu, Jie Sun, Juan Zhang, Lu Yao, Ye Xu, Yuntao Xie","doi":"10.1111/cas.70460","DOIUrl":"10.1111/cas.70460","url":null,"abstract":"<p><p>Pathogenic germline variants in the BRCA1 gene significantly increase the lifetime risk of breast cancer and are frequently associated with early-onset and triple-negative disease. However, the chronology of genetic events during breast tumor evolution in BRCA1 carriers remains unclear. In this study, 57 primary breast tumors from 57 BRCA1 carriers were analyzed, including formalin-fixed paraffin-embedded specimens and fresh-frozen specimens. Formalin-fixed paraffin-embedded tumors were microdissected into normal mammary tissue, carcinoma in situ, and invasive carcinoma components for deep target-region sequencing, whereas fresh-frozen tumors underwent whole-exome sequencing and bulk transcriptome sequencing. Compared with non-carriers from The Cancer Genome Atlas, breast cancers from BRCA1 carriers showed a distinct mutational landscape characterized by a high prevalence of TP53 mutations and a reduced frequency of PIK3CA and GATA3 alterations. Based on the initiating driver event, BRCA1-associated tumors were classified into three subgroups: TP53, PI(3)K-AKT pathway, and unclassified. The TP53-driven subgroup was strongly associated with the triple-negative phenotype, loss of heterozygosity at the BRCA1 locus, and elevated genomic instability. TP53 truncating mutations were enriched in BRCA1 carriers compared with non-carriers and showed a trend toward worse outcomes, potentially related to lower homologous recombination deficiency scores and activation of epithelial-mesenchymal transition pathways. These findings highlight the distinct mutational architecture of breast cancers from BRCA1 carriers and suggest that TP53 truncating mutations may define a particularly aggressive subtype that warrants further investigation.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":"2863-2876"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148383033","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":"Immunological Heterogeneity in Gastric Cancer: Context-Dependent Role of CD8⁺ T Cells.","authors":"Xiaofei Sun, Zihao Yang, Hongtao Qu, Jinhui Wu","doi":"10.1111/cas.70469","DOIUrl":"10.1111/cas.70469","url":null,"abstract":"<p><p>CD8⁺ T cell infiltration in gastric cancer shows subtype-dependent prognostic and predictive significance across TCGA molecular subtypes. Its clinical value is context-dependent and requires integrated immune profiling to guide modern chemoimmunotherapy strategies.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":"2891-2893"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13395059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148431010","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":"Protein Profile of Multiple Myeloma-Derived Extracellular Vesicles for the Discovery of Novel Myeloma-Related Biomarkers.","authors":"Natalia Platonova, Gilda Aiello, Domenica Ronchetti, Valentina Citro, Rosanna Asselta, Lavinia Casati, Domenica Giannandrea, Elisa Taiana, Antonino Neri, Gloria Sini, Elisabetta Calzavara, Mauro Turrini, Alfonsina D'Amato, Raffaella Chiaramonte","doi":"10.1111/cas.70473","DOIUrl":"10.1111/cas.70473","url":null,"abstract":"<p><p>Despite therapeutic advances, multiple myeloma (MM) remains characterized by progression and relapse, underscoring the need for reliable biomarkers for early detection and monitoring. Extracellular vesicles (EV) are cell-derived, lipid bilayer-enclosed particles that mediate intercellular communication and circulate in body fluids, making them promising biomarkers. This study compares the proteome of MM-derived EV with parental cells and evaluates whether EV represent a superior source of MM-specific biomarkers. We used high-resolution mass spectrometry to analyze MM cell lines and their EV. Cell line-derived EV offer a cleaner, tumor-specific protein profile, minimizing background from nonmalignant cells and improving biomarker accuracy. MS datasets were subjected to bioinformatic analysis, followed by functional enrichment using gene set libraries such as Gene Ontology, Jensen Compartments, TRRUST and DisGeNET, to extend interpretation beyond limited protein databases. Compared to cellular proteins, the EV proteome was enriched in functions related to oncogenic signaling, transcriptional regulation and MM pathophysiology, strengthening its potential as a cancer-related biomarker source. DisGeNET identified cancer-related proteins that were further evaluated to identify MM-specific candidates analyzing MM patients' gene expression databases containing clinical data. This led to the identification of macrophage migration inhibitory factor (MIF) and prohibitin. ELISA on plasma from MM patients detected significantly increased MIF levels in smoldering and active MM compared with healthy donors. Approximately half of circulating MIF was EV-associated in MM patients, indicating that MIF is distributed between vesicular and soluble plasma fractions and underscoring its potential as a noninvasive biomarker for MM early detection and patient monitoring.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":"2877-2890"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148457378","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":"Phase II Study of Cisplatin/Gemcitabine Plus Necitumumab for Squamous NSCLC After ICI-Platinum Therapy (WJOG14120L).","authors":"Hiroshige Yoshioka, Keita Mori, Nobuhisa Ishikawa, Hiroaki Kanemura, Koichi Azuma, Yukihiro Toi, Hiroshi Handa, Yosuke Tamura, Hiroaki Akamatsu, Haruko Daga, Masafumi Yamaguchi, Teppei Yamaguchi, Yuki Sato, Nobuyuki Yamamoto, Kazuhiko Nakagawa, Takayasu Kurata","doi":"10.1111/cas.70553","DOIUrl":"https://doi.org/10.1111/cas.70553","url":null,"abstract":"<p><p>Treatment options remain limited for unresectable or advanced lung squamous cell carcinoma (LSqCC) that progresses after immune checkpoint inhibitor (ICI)-based therapy. Although combination therapy with cisplatin, gemcitabine, and necitumumab (CGN) represents a potential second-line regimen, no prospective data in a post-ICI setting have been reported. This open-label, multicenter single-arm Phase II study enrolled patients with LSqCC after platinum-based chemotherapy plus ICI, including concurrent chemoradiotherapy. The primary endpoint was objective response rate (ORR), with the null and alternative hypotheses set at 23% and 40%, respectively. Secondary endpoints included the disease-control rate (DCR), progression-free survival (PFS), overall survival (OS), the impact of platinum-free interval (PFI), eligibility for anti-angiogenic therapies, and safety. Forty-six patients were evaluable for efficacy. ORR was 26.1% (80% CI, 17.7-36.2) and DCR was 87.0% (95% CI, 73.7-95.1). Median PFS and OS were 4.4 months (95% CI, 4.1-5.5) and 12.2 months (95% CI, 9.4-15.2), respectively. Common adverse events included hematological toxicities, acneiform rash, and hypomagnesemia. No pneumonitis or treatment-related deaths were observed. The safety profile was consistent across prior treatment types and anti-angiogenic therapies eligibility. PFI analysis showed that longer PFI durations were associated with improvements in PFS and OS, and the optimal PFI cutoff value was approximately 4 months. Although the predefined response threshold was not met, CGN demonstrated modest antitumor activity with a high DCR and a manageable toxicity after ICI-based therapy. CGN may be a feasible treatment option for second-line after ICI-based therapy, including for patients unsuitable for anti-angiogenic therapies, although further validation is warranted. Trial Registration: jRCTs051200138.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149117173","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":"Dynamic Changes of ctDNA-Based MRD and Genomic Mutations Predict Prognosis in ESCC Treated With Definitive Radiotherapy.","authors":"Shutang Liu, Qi Wang, Chun Han, Xiaoning Li, Rutian Cheng, Lihong Liu, Hua Dong, Xuejiao Ren, Shuman Zhen, Lan Wang","doi":"10.1111/cas.70544","DOIUrl":"10.1111/cas.70544","url":null,"abstract":"<p><p>This study characterized the genomic profile of esophageal squamous cell carcinoma (ESCC) via circulating tumor DNA (ctDNA) to identify predictive biomarkers for efficacy of definitive radiotherapy combined with systemic therapy. In this prospective cohort of 40 ESCC patients, 7 tumor tissues and 71 serial plasma samples were analyzed using a 340-gene panel. TP53 (45%) and PIK3CA (12.5%) were the most frequent SNVs, followed by NOTCH1/2 (7.5%). The 11q13.2-13.4 amplification (including CCND1/FGF19) occurred in 12.5% of cases. TP53 mutation rate was significantly higher in cT4 than cT2-3 stages (60% vs. 20%, p = 0.010). Notably, patients with persistent TP53 positivity posttreatment had significantly shorter PFS than those converting to negativity (HR = 5.090, p = 0.035); the 2-year PFS rates were 33.3% vs. 75%, respectively, with OS showing a borderline difference (p = 0.053). Posttreatment ctDNA-based minimal residual disease (MRD) positivity was 18.8%, correlating with a trend toward worse PFS (HR = 3.027, p = 0.067). Among the 31 patients with paired pre- and post-treatment plasma samples, the positive detection rate of nucleosome-positioning (left-shifted profile) decreased from 67.9% at baseline to 35.7% after treatment (χ² = 5.793, p = 0.016). This work based on plasma ctDNA profiling demonstrated that posttreatment clearance of TP53 mutations may represent a favorable prognostic biomarker in ESCC treated with definitive radiotherapy and systemic therapy. ctDNA-derived MRD status and nucleosome positioning constitute promising non-invasive biomarkers for treatment response monitoring and risk stratification for ESCC. Trial Registration:This study was registered with the Chinese Clinical Trial Registry (ChiCTR) on December 6, 2019 (Registration No. ChiCTR1900027936).</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082597","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}