Serous tubal intraepithelial carcinomas (STIC) are precursors of high-grade serous carcinoma (HGSC), the deadliest subtype of ovarian carcinoma. To establish clinically actionable strategies against these lesions, a better understanding of the mutational, transcriptional, and genetic/epigenetic alterations, as well as interactions among epithelial, immune, and stromal cells, is essential. In this issue of Cancer Research, Shih and colleagues conducted the first integrated spatial multiomics analysis of ovarian precancerous lesions, revealing substantial heterogeneity within the fallopian tube epithelium that may influence cancer susceptibility. They described four molecular subclasses of STICs according to their epithelial transcriptomic profiles: proliferative, immunoreactive, mixed, and dormant (PIMD) subtypes. Molecular links of this "PIMD" STIC subclassification to tumor progression were proposed, uncovering early events in ovarian tumorigenesis and potential genetic drivers of STIC heterogeneity. Furthermore, the STIC subtypes showed distinct histologic and molecular characteristics that warrant further investigation to develop a deeper understanding of the molecular and cellular processes driving the evolution of STIC heterogeneity, which may facilitate the development of early diagnostic approaches for HGSC. Collectively, the findings that not all STICs are equal open new avenues for further clinicopathologic, translational, and basic research to improve risk classification and early intervention in HGSC. See related article by Chang et al., p. 1739.

Despite extensive global efforts to eradicate cervical cancer through improved screening and widespread HPV vaccination, the disease continues to claim over 350 000 lives annually. Persistent infection with high-risk HPV genotypes, primarily HPV-16 and HPV-18, is the principal etiological driver, with viral DNA integration into the host genome representing a critical event in malignant progression. In this study, HPV integration was investigated using 25 RNA-seq datasets from HPV-positive cervical cancer cell lines and 2 datasets from the HPV-negative C-33A cell line. Analysis revealed a recurrent HPV-16 integration hotspot on Chromosome 6 within the CLIC5 gene. This integration was validated by qRT-PCR and Sanger sequencing. Subsequent gene expression analysis demonstrated significant CLIC5 upregulation in HPV-16-positive cell lines, with a 21-fold increase in CaSki and a 4-fold increase in SiHa compared to HPV-negative and HPV-18-positive controls. These findings delineate a distinct HPV-16 integration pattern and its associated transcriptional impact. The identification and validation of this strain-specific integration site nominates HPV-16 integration at the CLIC5 locus as a potential biomarker for HPV-driven cervical cancer.

Tensins are a family of adhesion proteins that play a role in constructing the cytoskeleton, as well as in intracellular and extracellular communication. Their expression was evaluated in 22 pancreatic cancer patients using the immunohistochemistry method. TNS1 expression occurred more frequently among patients with tumor diameter ≥ 2 cm, which may suggest an association with the development of pancreatic cancer. Intraductal TNS1 was observed less often with presence of necrosis and hemorrhages in tumor. The fact that cancer cells secrete TNS1 suggests that it could be investigated as a potential target for liquid biopsies. TNS4 expression occurred more frequently among females and was observed when necrosis in tumor was strong. TNS2 and TNS3 are not involved in the development of ductal pancreatic adenocarcinoma.

T helper 17 cells play essential roles in mucosal immunity and autoimmunity, yet the mechanisms that protect these cells from oxidative DNA damage remain poorly defined. Here we show, in a murine model, that the nucleotide excision repair sensor Xeroderma Pigmentosum Complementation Group C preserves genomic stability and metabolic fitness during T helper 17 cell differentiation. Loss of this factor reduces interleukin 17 production and increases mitochondrial reactive oxygen species and oxidative DNA damage, resulting in altered metabolic programs. Mechanistically, Xeroderma Pigmentosum Complementation Group C interacts with the base excision repair enzyme 8-oxoguanine DNA glycosylase, and its absence enhances oxidative lesion incision activity, indicating defective coordination between DNA repair pathways. Restoring antioxidant capacity rescues cytokine production and limits DNA damage in deficient cells. Together, these findings identify Xeroderma Pigmentosum Complementation Group C as a key coordinator of DNA repair and redox control required for T helper 17 cell function in inflammatory settings.

Approximately 70% of clear cell renal cell carcinoma (ccRCC) patients harbor von Hippel‒Lindau (VHL) deficiency, which drives pseudohypoxia and metabolic reprogramming. Here, we report a histone H4 lysine 12 lactylation (H4K12la)-fueled phosphoglycerate kinase 1 (PGK1)-lactate positive feedback loop that sustains glycolytic flux in VHL-deficient ccRCC and is pharmacologically disruptable by glucocorticoids. H4K12la is markedly elevated in ccRCC tissues and is associated with advanced pathological stage and unfavorable patient outcome. Integrative transcriptomic and epigenomic profiling revealed that VHL deficiency amplifies H4K12la deposition at accessible promoters, coupled to transcriptional activation of glycolytic and tumor-promoting programs, exemplified by PGK1. Through high-content drug screening, we identify glucocorticoids as effective suppressors of H4K12la, which act via glucocorticoid receptor-mediated transcriptional repression of glycolytic genes and consequent attenuation of lactate production. Strikingly, VHL-deficient ccRCC exhibits greater on-target pathway sensitivity to dexamethasone at the H4K12la-glycolysis axis, and glucocorticoid dexamethasone potentiated the antitumor efficacy of the HIF-2α inhibitor belzutifan in both orthotopic cell line-derived and patient-derived xenograft models. Collectively, our findings establish H4K12la as a metabolic‒epigenetic amplifier in VHL-deficient ccRCC, reposition glucocorticoids as epigenetically active modulators that dampen lactate-driven chromatin activation and glycolytic output, and provide a mechanistically grounded combination strategy with HIF-2α blockade to target lactate-fueled transcriptional dependence in metabolically rigid tumors.

To clarify the karyotype evolution of multiple myeloma (MM), multiple karyotypes of 22 patients with MM were analyzed using G-banding, and their karyotype evolutions were depicted as phylogenetic trees. Eleven patients exhibited highly complex karyotype evolutions, combining branched evolution, linear evolution, parallel evolution and macroevolution. While chromosomal structural abnormalities involving 14q32 were detected at the roots of the phylogenetic trees of karyotype evolution, aneuploidies and the other structural abnormalities were identified in both the initial clones and karyotypically evolved subclones. The findings indicated that aneuploidies might be caused by unequal chromosomal segregation, loss of the chromosome with unbalanced whole-arm translocation, and whole-chromosome doubling in patients with near-tetraploidy. Four patients had karyotype abnormalities (three del(20)(q) and one del(5)(q)) associated with myelodysplastic syndrome independent of the karyotype evolution of MM. In conclusion, the phylogenetic trees depicted by G-banding present the karyotype evolution of MM.

Insufficient T-cell infiltration limits the effectiveness of immunotherapy in sarcoma, yet the tumor-intrinsic mechanisms that govern immune exclusion remain poorly defined.

Psychologically Informed Reminder Messages (PIRMs) may promote health-behavior change, but their impact on preventive genetic screening is unclear. Due to low adherence to a screening program, Clalit Health Services initiated an intervention to encourage BRCA1/2 carrier screening in July 2022. This observational study assesses the effectiveness of the intervention in encouraging screening and its spillover effect on related healthcare utilization, focusing on Ashkenazi Jewish females aged 25-50 with no relevant cancer history. Patients were randomly assigned to receive one of five PIRMs. Four PIRMs utilized different psychological strategies, while the fifth served as a control. The effectiveness of the intervention on screening adherence was assessed using a regression discontinuity analysis. A Cox regression assessed the effectiveness of the four PIRMs compared to the control. Spillover effects on healthcare utilization were evaluated using logistic regressions. The intervention showed a positive correlation with increased adherence to screening (β = 0.37, 95% CI: 0.01-0.72). The "Barrier Remover" PIRM emphasized ease (hazards ratio = 1.09, 95% CI: 1.02-1.16), while the "Health Control" PIRM focused on autonomy (hazards ratio = 1.07, 95% CI: 1.01-1.14), both indicating greater effectiveness than the control. The findings suggest a positive short-term spillover effect of the "Health Control" PIRM on healthcare utilization compared to the control (odds ratio = 1.16, 95% CI: 1.04-1.29). PIRMs effectively increased BRCA1/2 carrier screening adherence, demonstrating a scalable, low-cost intervention to improve preventive healthcare uptake. The effect varied by the psychological strategies, highlighting the potential of tailored behavioral interventions to enhance public health.

Cancer-associated fibroblasts (CAFs) represent a predominant cell population in the tumor microenvironment (TME) of hepatocellular carcinoma (HCC). How the spatial distribution of CAF subtypes relates to immune modulation within the TME remains incompletely understood. This study aimed to characterize the spatial organization of CAF subtypes in HCC and to explore their potential associations with immune contexture.

Mucosal melanoma (MM), an aggressive melanoma subtype arising in mucosal tissues, displays resistance to therapies effective in cutaneous melanoma. To understand how mucosal microenvironment contributes to treatment nonresponsiveness, we performed integrative analysis of single-cell and bulk messenger RNA sequencing data derived from oral mucosa-originated melanoma and revealed that mucosa-specific inflammation induces enrichment of low-pigmented neural crest-like cancer cell, mediated by COX2+ macrophages and their secretome. Maintenance of this inflammation-induced neural crest-like state in cancer cells depends on HER2 and HER3 activation. Inhibition of HER2/3 by pan-HER inhibitors blocks cell state plasticity and overcomes chemoresistance in primary MM cell lines and patient-derived xenograft (PDX) models. These findings provide insights into how the tissue of origin determines cancer aggressiveness, highlight the role of mucosal inflammation in driving melanoma stemness and chemoresistance, and advance the identification of effective treatment options currently lacking for patients with MM.

Inactivating mutations in BAP1 (BRCA1-associated protein 1) are prevalent in many aggressive cancers of high global concern, including cholangiocarcinoma, mesothelioma, uveal melanoma, and renal cell carcinoma. However, research on BAP1 has been predominantly focused on single cancer types, lacking comprehensive pancancer studies that could uncover universal molecular mechanisms and therapeutic vulnerabilities. Our pancancer study uses K-ε-GG ubiquitin remnant motif pulldown coupled with mass spectrometry to comprehensively map the landscape of proteins deubiquitinated by BAP1. Combined with transcriptomics and functional assays, we uncover previously unrecognized roles of BAP1 in enhancing global genome nucleotide excision repair (GG-NER) by modulating the deubiquitination dynamics of three GG-NER DNA damage recognition proteins, DDB1, RAD23B, and COPS7B. We also identify LSD1 (lysine-specific histone demethylase 1) and PARP1 [poly(ADP-ribose) polymerase 1] as synthetic lethal partners of BAP1 through high-throughput drug inhibitor screening. Integrative analysis using ChIP sequencing, ATAC sequencing, and transcriptomics demonstrates the colocalization of BAP1, LSD1, and PARP1 on chromatin loci, with LSD1 promoting chromatin relaxation to facilitate efficient transcription-coupled NER (TC-NER) in addition to GG-NER, whereas PARP1 facilitates lesion recognition of both TC-NER and GG-NER. Combined inhibition of LSD1 and PARP1, using SP2509/SP2577 and olaparib, respectively, synergistically hinders NER, induces apoptosis, reduces tumor burden, and prolongs the survival of multiple BAP1-deficient pancancer in vitro models and in vivo xenografts. In conclusion, our results provide a deubiquitination landscape of BAP1; elucidate the mechanisms of action of BAP1, LSD1, and PARP1 in pancancers; and describe a promising combination therapeutic strategy applicable across multiple cancers with BAP1 mutations.

Altered cell-surface glycans are established cancer biomarkers, yet no oncogenes have been identified within glycan biosynthesis machinery. This represents a critical gap, as defining a gene as a true oncogene, rather than merely a component of an oncogenic pathway, reveals targetable dependencies that can improve clinical decisions. To date, no gain-of-function mutations have been detected in glycogenes, and the search for such mutations is largely saturated. To address this gap, we developed a bioinformatic-experimental pipeline to identify copy number alteration (CNA)-based driver genes, overcoming noise from passenger genes. The approach recovered known oncogenes and tumor suppressors, while revealing novel candidates, including glyco-oncogenes. Focusing on the glycosphingolipid (GSL) biosynthetic pathway, we validated B4GALT5 as a bona fide glyco-oncogene whose genomic amplification drives proliferation, oncogene addiction, and poor prognosis, effects that can be reversed by targeted pathway inhibition. Mechanistic studies show that B4GALT5 promotes cancer cell survival via integrin-Src signaling under anchorage-independent conditions. Collectively, these findings establish glycosylation enzymes as a druggable oncogene class and provide a resource of high-confidence CNA-based cancer regulatory genes.

Targeted therapies have significantly transformed the management of chronic lymphocytic leukaemia (CLL), yet most recommendations continue to reflect Western practice patterns. Variations in disease biology, healthcare resources and treatment accessibility across the Asia-Pacific (APAC) necessitate region-specific guidance. The Asia-Pacific Leukaemia Consortium (APLC) therefore developed updated consensus statements to support standardised, context-appropriate care for patients with CLL.

This review outlines the molecular biology, diagnostic tools, screening strategies, and management options of Lynch syndrome (LS)-associated upper tract urothelial carcinoma (LS-UTUC).

Globally, breast cancer (BC) continues to be the primary cause of cancer-related death for women, underscoring the need for reliable biomarkers for early detection and improved patient outcomes. Because of their stability in biological fluids and their functions in controlling gene expression, microRNAs (miRNAs) have become attractive diagnostic tools.

Breast cancer remains the most prevalent malignancy among women worldwide, driven by complex interactions between tumor-intrinsic factors and the immune microenvironment. Understanding immune-related molecular regulators is essential to improve diagnostic and therapeutic strategies. Transcriptomic data from the TCGA-BRCA dataset (1109 tumor and 113 normal samples) were analyzed to identify differentially expressed immune-related genes by cross-referencing ImmPort and InnateDB gene sets. Protein-protein interaction networks were constructed using STRING and Cytoscape to identify hub genes. Validation analyses were conducted using GSCA, cBioPortal, and GEO datasets. miRNA-mRNA regulatory interactions were explored using TargetScan, miRDB, miRWalk, and miRTarBase databases, followed by dual-luciferase reporter assays. Functional characterization of CCL5 and CD74 was performed through siRNA-mediated knockdown in breast cancer cell lines, proliferation, colony formation, and wound healing assays, as well as xenograft mouse models. Four key immune-related hub genes, including CXCL9, CXCL13, CCL5, and CD74 were identified as significantly upregulated in breast cancer. Epigenetic and prognostic analyses revealed that these genes were influenced by promoter methylation and correlated with poor survival outcomes. miRNA-mRNA network analysis identified hsa-miR-146a-5p and hsa-miR-200c-3p as central regulators, validated by luciferase assays. Functional studies showed that silencing CCL5 and CD74 significantly reduced cell proliferation, migration, and tumor growth in vivo, confirming their oncogenic roles. This integrative multi-omics and experimental study identified CCL5 and CD74 as key immune-oncogenic drivers of breast cancer progression. Their modulation of the MIF-CD74 signaling axis highlights potential therapeutic targets for immunomodulatory interventions and combination therapy in breast cancer.

Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating malignancies worldwide, characterized by late diagnosis, rapid progression, and dismal survival rates. The discovery of reliable biomarkers for early detection and disease monitoring remains an urgent clinical need. Owing to its proximity to tumor cells and protein-rich composition, pancreatic juice represents a compelling reservoir for biomarker discovery.

Despite the remarkable success of immune checkpoint inhibitor (ICI) therapy in solid tumors, immune-related adverse events (irAEs) have posed great challenges in the whole-course management of ICI immunotherapy. Reliable biomarkers helping to predict irAEs are still limited and lacking.

The prognostic value of TP53 mutations in metastatic colorectal cancer remains unclear owing to inconsistent findings in the literature. Given its central role in tumor biology, clarifying the impact of TP53 status on survival outcomes is clinically relevant.

Clonorchis sinensis, a common food-borne liver fluke in East Asia, is a Group 1 carcinogen strongly linked to cholangiocarcinoma. In recent years, molecular biology and multi-omics studies have revealed that this parasite drives chronic inflammation of the bile duct epithelium, epigenetic abnormalities, and the formation of precancerous lesions. Concurrently, circulating miRNAs, DNA methylation patterns, differential protein expression, metabolite profiles, and parasite-specific antigens have been proposed as potential early molecular biomarkers, which offers new avenues for the non-invasive detection of precancerous conditions. However, current research mainly remains at the laboratory stage and studies have small-scale cohorts, lacking multi-center, large-sample prospective validation and standardized detection protocols, which limits their clinical applicability. Furthermore, traditional imaging and histological methods exhibit limited sensitivity for early identification. This review aims to systematically summarize the molecular carcinogenic mechanisms associated with C. sinensis infection, recent advances in molecular biomarker research, and strategies for identifying precancerous lesions. It will particularly focus on discussing the major obstacles in clinical translation and future directions, with the goal of providing insights for early screening and prevention strategies.