To investigate the effect of long non-coding RNA (LncRNA) differentiation antagonizing non-protein coding RNA (DANCR) on the immune microenvironment of glioma cells by regulating the miR-656/bone morphogenetic protein receptor type 1A (BMPR1A) axis.

Biliary tract cancer (BTC) represents a heterogeneous disease with highly lethal malignancy and poor clinical outcomes. Here, we aimed to evaluate its genomic profiles to promote the development of precision medicine for BTC.

Endometrial cancer (EC) incidence continues to rise, underscoring the need for effective therapies beyond BRCA-mutant disease. Although PTEN loss, a frequent alteration in EC, has been implicated in impaired homologous recombination and increased sensitivity to PARP inhibitors, responses to PARP inhibitor monotherapy remain variable and are often limited by resistance mechanisms in PTEN-deficient tumours. Here, we show that the dual PARP/tankyrase (TNKS) inhibitor JPI-547 exerts potent antitumor activity, particularly in PTEN-deficient Ishikawa tumours. In vitro, JPI-547 and olaparib more effectively reduced cell survival in PTEN-deficient cells, and combined treatment with olaparib and the TNKS inhibitor XAV-939 induced synergistic cytotoxicity with elevated DNA double-strand breaks. Dual PARP/TNKS inhibition did not further suppress RAD51 but modulated non-homologous end joining and attenuated Wnt/β-catenin signalling in a PTEN-dependent manner. PTEN knockdown further showed enhanced vulnerability to combined targeting. These findings show that JPI-547 enhances antitumor efficacy in PTEN-deficient EC by disrupting DNA repair pathways and Wnt signalling, supporting dual PARP/TNKS inhibition as a potential therapeutic strategy and providing a rationale for further clinical evaluation.

The majority of intestinal tumors harbor mutations in canonical Wnt pathway genes such as APC, whereas the lack of such alterations in a subset of tumors implies alternative tumorigenic routes. Here we identify recurrent in-frame deletion in COPA, frequently co-occurring with USP9X-truncating mutation, in small intestinal adenoma and adenocarcinoma. Patient-derived and CRISPR-engineered small intestinal organoids carrying COPA in-frame deletions exhibit R-spondin-independent yet Wnt ligand-dependent growth, maintaining LGR5 expression without canonical Wnt drivers. Mechanistically, COPA mutation stabilizes the Frizzled coreceptor LRP6 irrespective of R-spondin, sustaining Wnt pathway activation under growth factor-restricted conditions. USP9X loss further potentiates this phenotype. Unlike canonical Wnt pathway members, COPA encodes the α-subunit of coatomer complex I, which engages in vesicle trafficking with little prior linkage to intestinal tumorigenesis. Our findings establish COPA mutation as a unique and atypical intestinal tumor driver and implicate USP9X loss as a cooperating lesion.

Constitutional epimutations arise early in development and are present across normal tissues, including peripheral blood. Constitutional BRCA1 promoter methylation has emerged as a risk factor for BRCA1-associated cancers, such as ovarian cancer (OC), and may serve as a biomarker for OC risk. This study retrospectively evaluated the clinical relevance of constitutional BRCA1 promoter methylation in 473 patients with OC enrolled in the observational AGO-TR1 study (ClinicalTrials.gov identifier: NCT02222883).

Dabrafenib plus trametinib is a standard first-line treatment for BRAF V600E-mutated non-small cell lung cancer (NSCLC). The LiBRA study aimed to explore the role of liquid biopsy in detecting and monitoring BRAF V600E mutation, assessing its potential to predict treatment response and emerging resistance.

The frequency of histologic subtypes in epithelial ovarian cancer (EOC) varies by geographic region. In Western countries, high-grade serous ovarian cancer (HGSOC) is the most common and well characterized, whereas non-HGSOC subtypes, particularly clear cell ovarian cancer (CCOV), are more prevalent in Asia. However, their clinicogenomic features remain poorly defined.

Inhibition of DNA polymerase theta (Polθ), an essential enzyme for repairing DNA double-strand breaks (DSBs) via microhomology-mediated end joining (MMEJ), has proven to be an exquisitely effective monotherapy in HR-deficient tumor models. In addition, Polθ inhibition (Polθi) can induce tumor-selective radiosensitization, but unlike its monotherapy use, no clinically actionable biomarkers have yet been identified to predict this effect. Here, we profiled 54 cancer cell lines and found that Polθi induces substantial radiosensitization in most models, although with marked variability not explained by indicators of Polθ activity. To pinpoint molecular determinants of radiosensitization by Polθi, we performed a CRISPR knockout screen which revealed loss of the TP53BP1/Shieldin pathway component SHLD2 (FAM35A) as a vulnerability to Polθi combined with RT. We found that SHLD2 is deleted in a subset of human prostate cancers, frequently alongside PTEN loss, an adverse prognostic factor. We demonstrated that SHLD2 loss not only increases sensitivity to RT alone, as reported previously, but also enhances the radiosensitizing effect of Polθi, independently of PTEN status and without requiring HR deficiency. Moreover, our findings support a model in which SHLD2 deficiency increases Polθ dependence following RT, with Polθ activity limiting DSB accumulation and chromosomal instability, via a compensatory mechanism independent of canonical MRE11/CtIP-mediated DNA end resection. In summary, we found that SHLD2 loss is a collateral vulnerability that can be exploited through combined treatment with Polθi and RT.

Cellular double-stranded RNA (dsRNA) can activate immune pathways similar to viral RNA. Adenosine deaminases acting on RNA 1 (ADAR1)-mediated adenosine-to-inosine (A-to-I) RNA editing has long been believed to destabilize endogenous dsRNA, thus preventing immune activation. We identified DEAD-box RNA helicase 6 (DDX6) as a potent editing repressor and an immune protector under normal conditions but as an immunosuppressor in cancer contexts. Through its interaction with ADAR1, DDX6 binds preferentially to cytoplasmic dsRNA, repressing editing of adenosines in A:C mismatches across the transcriptome, disrupting dsRNA structural stability, and suppressing interferon signaling and immune responses. Depleting DDX6 in tumor cells triggers dsRNA accumulation and activates both intrinsic and extrinsic immunity to hinder tumor growth. Our findings broaden our understanding of the paradigm that RNA editing not only destabilizes cellular dsRNAs but also can stabilize them through I-C pairing, a process preferentially suppressed by DDX6, to limit cytosolic dsRNA sensor recognition. Targeting DDX6 and harnessing RNA-associated tumor cell-intrinsic innate immune activation holds promise for cancer immunotherapy.

THSD7B (thrombospondin type-1 domain-containing 7B) has been implicated in several malignancies; however, its role in gastric adenocarcinoma remains unclear. This study aimed to investigate the expression pattern, clinical significance, and biological function of THSD7B in gastric adenocarcinoma. Public datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to evaluate THSD7B expression and its association with clinical outcomes. Functional enrichment analysis was performed to explore potential biological processes. In vitro assays, including cell proliferation, colony formation, wound healing, and Transwell invasion, were conducted following THSD7B knockdown or overexpression in gastric cancer cell lines. In addition, a xenograft model was established to assess tumor growth in vivo. THSD7B expression was significantly elevated in gastric adenocarcinoma tissues compared with normal controls and was associated with patient survival. Functional analyses suggested that THSD7B-related genes were mainly enriched in cell adhesion and cytoskeleton-associated processes. In vitro experiments showed that THSD7B knockdown suppressed cell proliferation, migration, and invasion, whereas overexpression produced the opposite effects. Consistent with these findings, THSD7B modulation was accompanied by alterations in adhesion-related signaling molecules and phenotype-associated protein expression. In vivo, THSD7B promoted tumor growth in xenograft models. In conclusion, THSD7B is associated with tumor progression and clinical outcomes in gastric adenocarcinoma and may be involved in the regulation of cell motility-related processes. These findings suggest that THSD7B may serve as a potential biomarker in gastric cancer.

Lung adenocarcinoma (LUAD) is a predominant subtype of lung cancer associated with an unfavorable prognosis. However, the roles of the tumor microenvironment (TME) and Kynureninase (KYNU) in LUAD remain largely unclear. This study aimed to investigate the potential role of KYNU in macrophages and LUAD.

Uterine corpus endometrial carcinoma (UCEC) ranks as the most frequently diagnosed gynecologic malignancy and the second leading cause of gynecologic cancer-related mortality. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of gene expression and tumor biology; however, their prognostic significance in UCEC remains largely unexplored. To systematically identify survival-associated lncRNA biomarkers, we integrated clinical and transcriptomic data from two independent cohorts: TCGA-UCEC (548 tumor, 35 normal) and CPTAC-Uterus (102 tumor, 15 normal). Following upper quartile normalization and ComBat-based batch effect correction, differentially expressed lncRNAs (FDR < 0.01, |log2FC| > 2) were identified using Student's t-test. The intersecting set of consistently dysregulated lncRNAs from both cohorts was subjected to Cox proportional hazards regression to identify survival-associated candidates. Functional inference was performed through Spearman correlation with protein-coding genes and Gene Set Enrichment Analysis (GSEA) of KEGG pathways. A total of 550 lncRNAs were consistently downregulated and 148 were upregulated in UCEC across both cohorts. Cox regression identified 30 survival-associated lncRNAs (FDR < 0.01), all with elevated expression correlating with worse overall survival. The top two candidates, AC025811.3 and AC012354.6, showed significant stage-dependent expression patterns across FIGO stages I-IV and were functionally enriched in immune regulation and carbohydrate metabolism pathways. In conclusions, AC025811.3 and AC012354.6 represent novel candidate prognostic lncRNA biomarkers in UCEC. Experimental validation, including FISH-based tissue localization and staged quantification, and functional assays, is warranted to confirm their biological roles.

Cervical cancer (CC) is characterized by tumor immune escape, which underlies suboptimal therapy responses and an increased recurrence risk. Despite the established role of LAT1 in cancer progression, its regulatory mechanism in the CC immune microenvironment remains elusive. LAT1 expression in cervical squamous cell carcinoma and its correlation with CD8+ T cell infiltration were assessed through the bioinformatic approach. LAT1 mRNA and protein expression were examined by qRT-PCR and Western blot, respectively. In a co-culture system with CC cells, CD8+ T cell antitumor activity was measured by lactate dehydrogenase release, ELISA, CCK-8, colony formation, and flow cytometry. The LAT1/TRIM67 interaction was identified through bioinformatics and validated by Co-IP and immunofluorescence. Potential ubiquitination substrates of TRIM67 were screened through bioinformatics. CHX chase assays combined with ubiquitination analysis were employed to verify the IRF3 degradation pathway. Finally, in vivo functional validation was conducted in a mouse xenograft model. LAT1 was overexpressed in CC tissues and cell lines. LAT1 expression negatively correlated with CD8+ T cell infiltration. LAT1 knockdown enhanced CD8+ T cell antitumor activity. Mechanistically, LAT1 suppressed CD8+ T cell antitumor function in CC by interacting with TRIM67 to promote ubiquitination and degradation of IRF3. LAT1 recruits TRIM67 to mediate IRF3 ubiquitination and degradation, ultimately suppressing CD8+ T cell function and promoting immune escape. These findings provide a theoretical basis for targeting the LAT1/TRIM67 axis to enhance immunotherapy in CC.

Biallelic germline variants in TP53 are exceedingly rare, and their clinical consequences remain poorly defined. Here, we report a female infant born to consanguineous parents who presented with early-onset, aggressive choroid plexus carcinoma causing death at age 4. Molecular analysis identified a homozygous synonymous variant in the last nucleotide of exon 4 in TP53 (NM_000546.6:c.375G > A, p.Thr125 =). This variant has been previously shown to cause aberrant splicing and partial loss of p53 function, and has been associated with variable penetrance in heterozygous carriers. Both parents, who were first cousins, were heterozygous carriers, and no malignancy history was present at the time of diagnosis. Following identification of carrier status, the couple underwent preimplantation genetic testing and subsequently had a child who did not inherit the familial TP53 variant. This report represents one of the very few documented cases of biallelic TP53 variants and underscores the phenotypic heterogeneity associated with TP53 homozygosity. The case highlights the importance of genetic evaluation in pediatric patients with rare aggressive tumors, particularly in consanguineous families, and demonstrates the critical role of genetic counseling and surveillance in affected relatives.

Breast cancer (BC) is the most prevalent cancer among women and the second leading cause of cancer-related deaths globally, after lung cancer. Despite advances in treatment, BC remains a major contributor to cancer mortality worldwide, underscoring the need for innovative therapeutic approaches. The TopBP1 (DNA Topoisomerase II Binding Protein 1) gene, involved in DNA damage response and cell cycle regulation, has been associated with cancer progression and resistance to chemotherapy. This study investigates the potential of using CRISPR/Cas9 technology to knockout the TopBP1 gene as a novel strategy in breast cancer research.

Conventional high - throughput sequencing data analysis methods, relying on large cohorts, are unsuitable for rare diseases with few cases and poor at explaining gene biological functions. This study proposes a biological-function-based method for mining core genes under limited-sample conditions. Using colorectal cancer (CRC) and its rare subtype signet-ring cell carcinoma (SRCC) as examples, differential expression analysis was performed separately for each SRCC sample against CRC samples. Shared genes obtained through progressive intersections were defined as the initial core gene set (List 1). Non-core genes were subjected to functional enrichment analysis, and pathway-associated genes were integrated to construct the non-core gene set. Two independent SRCC samples were subsequently used for secondary mining to obtain the final biologically significant core gene set (List 2). In addition, RankProd (RP), Robust Rank Aggregation (RRA), and an external mucinous adenocarcinoma dataset (GSE281917) were used for validation. First-round mining identified 246 core genes in SRCC, while secondary mining generated 66 and 65 biologically significant core genes from two validation samples with a high degree of overlap. RP identified 1,850 candidate genes and RRA identified 601 candidate genes, among which 64 genes overlapped with the 65 genes identified by this method. In the external mucinous adenocarcinoma dataset, first-round mining identified 144 core genes, while secondary mining generated 122 and 119 core genes with high overlap between validation samples. This method enables the identification of biologically significant core genes in rare diseases under limited-sample conditions, improves the biological interpretability of gene-mining results, demonstrates stable performance in both SRCC and external mucinous adenocarcinoma datasets, and provides a reliable experimental basis for the advancement of precision medicine in rare disease research.

Poly(ADP-ribose) polymerase (PARP) inhibitors have emerged as an important therapeutic option for patients with homologous recombination repair (HRR)-deficient cancers, especially those with BRCA1/2 mutations. Since the initial US Food Administration approval of olaparib in 2014, PARP inhibitors have shown efficacy across ovarian, breast, and prostate cancers, although differences in trial design and biomarker strategies have resulted in tumor-specific indications. Homologous recombination deficiency (HRD) arises from germline or somatic mutations in HRR genes or from epigenetic inactivation, and it can be assessed through genomic "scars" such as loss of heterozygosity and mutational signatures. Although BRCA1/2 alterations confer the strongest sensitivity to PARP inhibitors, non-BRCA HRR gene mutations demonstrate heterogeneous responses, highlighting the need for more precise HRD assessment, including the role of biallelic vs monoallelic inactivation. Despite initial success, both primary and acquired resistance-through reversion mutations, replication fork stabilization, and therapy-induced clonal hematopoiesis-limit the durability of the response to PARP inhibition. Ongoing studies are evaluating rational combinations targeting complementary DNA damage response pathways (ATR/CHK1/WEE1, PI3K/AKT) and integrating immunotherapy or hormonal agents to extend benefit. Moving forward, harmonizing HRD testing across tumor types, accounting for germline, somatic, and liquid biopsy-derived alterations, and refining patient selection will be essential to maximize therapeutic efficacy and safely expand PARP inhibitor use beyond canonical BRCA-mutated cancers.

Alterations involving RUNX1 are recurrent in hematologic malignancies and contribute to disease pathogenesis via dysregulation of transcriptional factors essential for hematopoiesis. Here, we report an acquired alteration in both alleles of RUNX1; one is a truncating mutation and the second is a novel RUNX1::ARID1B identified in acute myeloid leukemia.

Long noncoding RNAs (lncRNAs), widely regarded as nonprotein-coding transcripts longer than 200 nucleotides in length, play active roles in tumorigenesis, including in colorectal cancer (CRC). The abnormally elevated lncRNA small nucleolar RNA host gene 9 (SNHG9) in CRC samples was observed in The Cancer Genome Atlas (TCGA) database. However, the biological role and potential mechanism of SNHG9 in CRC development remain elusive. Herein, 49 paired CRC tissues and matched adjacent normal tissues were obtained to examine SNHG9 levels. Biological functions related to cell proliferation, migration and invasion were evaluated using CCK-8, colony formation, and Transwell assays and western blot analysis. RNA pull-down and RNA immunoprecipitation (RIP) assays were used to verify the SNHG9/PTBP1/PRMT7 regulatory axis. Interestingly, our data revealed that increasing levels of SNHG9 in CRC tissues and cells were positively correlated with poor prognosis and tumour metastasis, while depletion of SNHG9 caused the suppression of cell proliferation, migration, and invasion. Moreover, cytoplasmic SNHG9 enhanced the mRNA stability of PRMT7 by directly binding to PTBP1 through the "lncRNA‒RNA binding protein (RBP)" complex. The regulatory function of SNHG9 on PRMT7 was also validated via rescue functional assays. In summary, our data demonstrated that SNHG9 may play an oncogenic role in CRC tumorigenesis by stabilizing PRMT7 by recruiting PTBP1. This could be a prognostic biomarker and therapeutic target for CRC.

Structural variants (SVs) are major contributors to genome diversity and disease susceptibility, particularly in cancer. Although third-generation sequencing technologies have substantially improved SV detection sensitivity, accurate detection of complex SVs remains challenging due to fragmented and heterogeneous alignment signals, as well as the dependence of many existing methods on predefined variant models. In this paper, we propose gSV, a general SV detector that integrates alignment-based and assembly-based approaches with the maximum exact match strategy, with particular emphasis on resolving SVs with complex or atypical alignment signatures. Without predefined assumptions about SV types, gSV captures diverse variant signals, enabling the detection of SVs that are usually missed by conventional tools. Benchmarking using both simulated datasets and real long-read sequencing data demonstrates that gSV achieves improved sensitivity and overall detection performance compared with current state-of-the-art SV callers, particularly for simple and complex SV events with complex alignment patterns. Unique SV discoveries in four breast cancer cell lines, particularly in cancer-associated genes, demonstrate the potential biological relevance of gSV-enabled discoveries. Furthermore, analysis of a breast cancer cohort from the Chinese population highlights the utility of gSV for population-scale genomic studies. Collectively, gSV provides a unified framework for comprehensive SV discovery in both research and clinical genomics settings.