Cancer Science最新文献

BRAF V600E-mutant colorectal cancer (CRC) represents a distinct molecular subtype with considerable heterogeneity in tumor biology and therapeutic response. Although gene expression-based classifications (BM1/BM2 subtypes) provide valuable insights into underlying molecular and immune features, their clinical application is limited by the need for high-throughput sequencing. This study aims to establish an immunohistochemistry (IHC)-based classification system to enable practical subtype stratification and aid prognostic and therapeutic evaluation. Using two independent cohorts (public dataset, n = 218; institutional cohort, n = 122), we performed differential expression analysis, machine learning modeling, and clinical feasibility evaluation. Fourteen candidate markers were identified, and a decision tree algorithm selected CD8 and ARHGEF17 as optimal classifiers. Based on these markers, two IHC-based subtypes were established: iBM1 (CD8⁺/ARHGEF17⁻) and iBM2 (CD8⁻ with any ARHGEF17 expression or CD8⁺/ARHGEF17⁺). The IHC-based subtypes showed concordance with transcriptomic BM subtypes (training: 82.69%, κ = 0.55; validation: 72.22%, κ = 0.44; prospective: 83.33%, κ = 0.57). Transcriptomic profiling revealed enrichment of immune activation and epithelial–mesenchymal transition in iBM1, and cell cycle-related pathways in iBM2. In clinical validation, iBM1 was associated with poorer survival but greater sensitivity to immune checkpoint inhibitors. This IHC-based classification provides a practical and accessible approach for BM subtype stratification, reflecting underlying molecular and immune characteristics, and may support prognostic assessment and therapeutic decision-making in BRAF V600E-mutant CRC.

Investigating the phenotypic contribution of gene-spliced isoforms to tumor cellular heterogeneity can facilitate the development of innovative strategies for precision medicine. Serine protease 3 (PRSS3), a trypsin-like protease with four spliced variants (PRSS3-SVs: PRSS3-V1 to V4), plays diverse biological roles in cancer progression. Herein, we systematically analyzed the expression patterns and functional implications of PRSS3-SVs in gastric cancer (GC) using an integrative approach that combined bioinformatic analyses, CpG site-specific methylation detection, splice-specific qPCR, isoform-based methodologies, and multiple functional assays. Our findings revealed that differentially expressed PRSS3 isoforms, predominantly PRSS3-V1 and PRSS3-V2, are regulated by intragenic methylation and exert pleiotropic roles in GC. Overexpression of PRSS3 transcripts suppressed GC cell proliferation via the NF-κB signaling pathway, while exerting distinct effects on matrix metalloproteinase-associated cell migration and invasion. Clinically, patients with low PRSS3-V1 or high PRSS3-V2 expression exhibited poorer survival outcomes, and the expression difference between these two transcripts was identified as an independent prognostic indicator for GC patients. Epigenetically, differential methylation patterns within PRSS3 enabled stratification of GC patients into subgroups characterized by either high-methylation with low-expressed PRSS3-SVs or low-methylation with high-expressed PRSS3-SVs. The UHRF1/DNMT1 complex was found to mediate CpG site methylation and regulate PRSS3 transcripts, particularly silencing PRSS3-V1 through intragenic CpG methylation. This methylation pattern was associated with reduced survival rates and further validated its correlation with tumor metastasis in an independent cohort (n = 243). Our study elucidates that methylation-regulated alternative splicing contributes to phenotypic heterogeneity in GC, highlighting its potential advantage over differentially expressed genes in improving stratification strategies for precision oncology.

EXPRESSION OF CONCERN: M. Xue, H. Pang, X. Li, H. Li, J. Pan and W. Chen, “ Long Non-coding RNA Urothelial Cancer-associated 1 Promotes Bladder Cancer Cell Migration and Invasion by Way of the hsa-miR-145–ZEB1/2–FSCN1 Pathway,” Cancer Science 107, no. 1 (2016): 18–27, https://doi.org/10.1111/cas.12844.

This Expression of Concern is for the above article, published online on 06 November 2015 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editor-in-Chief, Masanori Hatakeyama; the Japanese Cancer Association; and John Wiley & Sons Australia Ltd. The Expression of Concern has been agreed upon due to several instances of image duplication identified between Figures 3b, 3f and 3 g of this article and images published in another paper by a different group of authors. These duplicated images were used to represent different scientific contexts. Although this article was published earlier, the authors did not respond to requests for comments or original data, therefore the authenticity of the images could not be verified. Furthermore, concerns were raised regarding Figures 2c, 2e, 4f and 5 g, where the western blot backgrounds appear unusually clean, deviating from typical experimental results. Due to the nature of these concerns and the absence of author response, the journal has decided to issue an Expression of Concern to inform and alert readers.

Obesity is a known risk factor for breast cancer, particularly in postmenopausal women. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with body mass index (BMI). We conducted a case–control study with 1273 breast cancer cases and 4816 controls to examine whether five BMI-associated SNPs (rs939584 [TMEM18], rs4409766 [BORCS7-ASMT], rs6265 [BDNF], rs1927790 [HS6ST3], rs1421085 [FTO]) influence breast cancer risk through BMI-dependent or -independent pathways using mediation analysis. For postmenopausal breast cancer, rs6265 (C > T) exhibited a carcinogenic direct effect (odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.04–1.34) along with a protective indirect effect through changes in BMI (OR = 0.98, 95% CI 0.96–0.99), while rs1421085 (T > C) showed a carcinogenic indirect effect (OR = 1.03, 95% CI 1.00–1.05). No significant associations were observed for any SNPs in premenopausal breast cancer. These findings suggest that two BMI-associated genetic variants, rs6265 and rs1421085, influence postmenopausal breast cancer risk through changes in BMI, and that rs6265 also exerts a direct effect through pathways independent of BMI, providing insight into a previously uncharacterized association between obesity-related genetic factors and breast cancer and highlighting the potential utility of genetic profiling in personalized risk assessment.

Disruptions in lipid metabolism can hasten disease progression and impose a heavier burden on patients with nasopharyngeal carcinoma (NPC). We previously observed a positive correlation between zinc finger and BTB domain-containing protein 7A (ZBTB7A) and the long non-coding RNA antisense non-coding RNA in the INK4 locus (ANRIL), indicating a potential link between NPC and lipid metabolism; however, the underlying mechanism remains unclear. This study investigated primary NPC tissues that had significantly lower ZBTB7A expression than that in normal nasopharyngeal epithelium. Subsequent results confirmed that ANRIL promoted ZBTB7A expression by sponging miR-339-5p. ZBTB7A directly promoted ANRIL expression but inhibited SREBP1 and FASN expression. Thus, the ANRIL/miR-339-5p/ZBTB7A axis creates a positive feedback loop that suppresses the lipid pathway. Combining stable ANRIL overexpression with ZBTB7A shRNA effectively reduced lipid metabolism and the migratory, invasive, and metastatic capacities of NPC cells in vitro and in vivo. Furthermore, the SREBP inhibitor, fatostatin, enhanced the suppression of NPC metastasis. Our results indicated that interventions targeting ANRIL-shZBTB7A and SREBP inhibitors can effectively disrupt lipid metabolism and impair the invasive and metastatic properties of NPC cells. These findings provide valuable insights into the potential experimental strategies for inhibiting NPC metastasis.

WJOG15221M is Japan's first fully remote, investigator-initiated oncology trial, successfully enrolling 28 patients—36% remotely—by integrating trial access into the national CGP program and leveraging existing healthcare infrastructure without new digital tools. Targeting rare ALK fusion-positive tumors, the trial demonstrated that decentralized models can improve equity, efficiency, and continuity of care, offering a scalable path for future precision oncology trials.

Next-generation sequencing-based comprehensive cancer genomic profiling is promising in cancer management; however, most studies rely on tumor-only DNA panels from single institutions. In 2023, Japan introduced an insurance-covered cancer genomic profiling test—the GenMine TOP Cancer Genome Profiling System—a dual DNA–RNA panel with matched tumor–normal testing. This study evaluated its utility compared to a conventional DNA-only test (FoundationOne CDx) in managing sarcoma patients using a nationwide genetic profiling database provided by the Center for Cancer Genomics and Advanced Therapeutics. This study included 1046 patients registered between August 2023 and October 2024. The dual DNA–RNA test identified significantly more fusion genes (20.3% vs. 7.4%, p < 0.001) and therapeutically targetable kinase fusions (3.5% vs. 1.2%, p = 0.019) than the DNA-only test. Among patients with translocation-related sarcomas, histology-specific fusion genes were identified in 77.5% using the dual panel, compared to 40.0% with the DNA-only panel (p < 0.001). In non-gastrointestinal stromal tumor sarcomas, the dual test showed a trend toward higher rates of genotype-matched therapy (4.3% vs. 2.6%, p = 0.25) and a significantly higher rate of molecular targeted therapy (4.3% vs. 1.5%, p = 0.03). Additionally, 5.7% of patients had pathogenic germline variants identified through tumor–normal matched analysis. These findings suggest that a dual DNA–RNA panel with matched tumor–normal testing may improve diagnostic accuracy and inform treatment decisions in the routine clinical management of sarcoma.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, highlighting the urgent need for improved therapeutic strategies. In this study, we identified zinc finger protein 282 (ZNF282), located on chromosome 7q, as a novel gene that contributes to CRC progression through comprehensive expression profiling using data from The Cancer Genome Atlas (TCGA) and single-cell RNA sequencing combined with spatial transcriptomics in clinical CRC datasets. ZNF282 was overexpressed in tumor cells. High ZNF282 mRNA expression was associated with distant metastasis and served as an independent poor prognostic factor in CRC. In vitro and in vivo experiments using CRISPR/Cas9-mediated ZNF282 knockout CRC cell lines demonstrated significantly reduced tumor growth and cell proliferation, which were reversed by reexpression of ZNF282. Mechanistically, ZNF282 knockout impaired the G1/S cell cycle transition and downregulated E2F1 and its downstream targets, CCNE1 and CCND1. These findings were supported by single-cell RNA sequencing analysis, which showed ZNF282 enrichment in malignant epithelial cells linked to cell cycle pathways. Motif scanning further identified a putative ZNF282 binding site upstream of the E2F1 transcription start site, suggesting that ZNF282 may enhance E2F1 expression by facilitating the activity of an upstream regulatory region. In conclusion, ZNF282 is a novel gene that promotes CRC progression in part by enhancing cell cycle progression possibly via E2F1 activation. Its high expression is associated with poor prognosis, supporting its potential as a prognostic biomarker and therapeutic target in CRC.

Tumor-associated neutrophils (TANs) play crucial roles in malignant tumors, and their polarization is considered a determining factor in cancer progression. However, knowledge concerning the molecular mechanisms that regulate the changes in the polarization phenotype of TANs and their impact on tumor biology is limited. Here, we demonstrate that tumor-derived prostaglandin E2 (PGE2) regulates the polarization of TANs toward the N2 phenotype within the tumor microenvironment, promoting tumor cell proliferation and migration. Mechanistically, PGE2 is released from the LDs of CRC cells into the TME, where the stimulation of ROS-mediated methylation increases through binding with the surface receptors prostaglandin E receptor 2 (EP2, PTGER2) and EP4 on TANs, resulting in a reduction in the expression of the transcriptional repressor FOXO3a and thereby eliminating its ability to bind to the promoter region of N2-associated molecules such as ARG1, MMP9, and BV8 in TANs and promote their production. In summary, PGE2-induced N2-type TAN polarization directly affects the malignant progression of tumors. Our research revealed that PGE2 could be a potential effective molecule for targeting TANs in antitumor immunotherapy for CRC.

Even after surgical resection, the prognosis is poor for patients with esophagogastric junction adenocarcinoma who develop upper mediastinal lymph node metastasis. Moreover, the current preoperative diagnostic accuracy for upper mediastinal lymph node metastasis remains inadequate, which complicates treatment planning. To enhance diagnostic precision and facilitate personalized therapeutic strategies, we aimed to develop a novel diagnostic model that integrates a DNA methylation panel with conventional clinical parameters. First, genome-wide methylation profiling of 69 tumors identified seven CpG sites significantly associated with upper mediastinal lymph node involvement. We then evaluated a methylation panel based on these markers in two independent cohorts comprising a total of 133 treatment-naïve patients. The methylation panel alone achieved moderate diagnostic performance (AUC 0.71, 95% CI 0.52–0.91), whereas its integration with clinical data substantially improved accuracy (training cohort: AUC 0.87, 95% CI 0.75–0.99). Applying the same model formula to an independent pretreatment validation cohort confirmed its robustness (AUC 0.85, 95% CI 0.70–1.00). Furthermore, the methylation panel was identified as an independent prognostic factor for overall survival (p < 0.01). Finally, to facilitate clinical implementation, the integrated model was formalized as a nomogram. In summary, this novel diagnostic model enables highly accurate detection of upper mediastinal lymph node metastasis in esophagogastric junction adenocarcinoma, with the potential to optimize treatment decisions and reduce the need for invasive procedures, thereby contributing to precision oncology.