Homologous recombination deficiency (HRD) is a key determinant of sensitivity to DNA-damaging agents; however, its genomic characterization in colorectal cancer (CRC) remains limited. This study investigated whether low RNA expression of homologous recombination (HR) genes identifies patients with metastatic CRC who derive survival benefit from oxaliplatin- or irinotecan-based therapy.

Tumor-agnostic therapies represent a transformative shift in oncology, targeting molecular alterations irrespective of cancer histology. These therapies offer new hope for patients with rare and difficult-to-treat malignancies, yet their integration into clinical practice remains inconsistent because of the absence of guidelines. Traditional organ-based classifications hinder timely access to precision treatments, despite evidence supporting molecular-driven approaches. Living guidelines, continuously updated frameworks based on emerging data, are essential to bridge this gap. They enable just-in-time incorporation of new therapies, streamline biomarker-driven care, and address the unique needs of rare and ultrarare cancers. Regulatory approvals for tumor-agnostic agents, such as NTRK inhibitors and immunotherapies for microsatellite instability-high/mismatch repair-deficient tumors, underscore the urgency for unified guidance. Trials like TAPUR, TRACK, and NCI-MATCH demonstrate the feasibility and benefit of molecular profiling across diverse cancer types. Tools like ESMO's ETAC-S provide structured criteria for evaluating tumor-agnostic potential, yet real-world implementation lags. Living guidelines can harmonize testing practices, improve access, and educate clinicians on cross-tumor applicability. They also facilitate proactive biomarker testing, reduce treatment delays, and enhance patient safety through tailored toxicity management. As oncology evolves toward molecular precision, living tumor-agnostic guidelines are critical for ensuring equitable, evidence-informed care for all patients, particularly those with rare cancers. National organizations must prioritize their development to fully realize the promise of precision medicine.

The development of colorectal cancer (CRC) results from the progressive accumulation of genetic and epigenetic alterations, leading to the inactivation of tumor suppressor genes and activation of oncogenes. Aquaporin 1 (AQP1) has been shown to promote tumor angiogenesis; however, its specific role in CRC proliferation and migration remains unclear. This study aims to investigate the functions of miR-210-5p and AQP1 in CRC cell proliferation and migration. Using online datasets from the Cancer Genome Atlas (TCGA) and ten clinical samples, we examined AQP1 expression in CRC. Bioinformatic analysis was conducted to identify miRNAs potentially regulating AQP1. The effects of miR-210-5p and AQP1 on invasion and migration were further assessed in vivo in xenograft Balb/c nu/nu mice. Results showed that dysregulated AQP1 expression in CRC was correlated with advanced clinical stage and venous invasion. miR-210-5p was predicted to bind AQP1 and may target its expression. In vitro experiments revealed that miR-210-5p inhibits CRC proliferation and invasion by downregulating AQP1, which subsequently reduces the expression of vascular endothelial growth factor (VEGR), Wnt-7a, Matrix metallopeptidase 2 (MMP2), MMP9, and β-catenin. Targeting AQP1 led to suppressed proliferation and migration of CRC cells. In summary, AQP1 is upregulated in CRC and regulated by miR-210-5p. Downregulation of AQP1 by miR-210-5p attenuates CRC proliferation and migration through decreasing VEGR, Wnt-7a, MMP2, MMP9, and β-catenin expression.

Tyrosine kinase inhibitors are available in the Brazilian public health care system. However, reimbursement challenges limit access to molecular testing of BCR::ABL-1, which is essential for diagnosing and monitoring measurable residual disease in chronic myeloid leukemia (CML). This study estimated the costs associated with delivering the BCR::ABL-1 test in a tertiary academic reference care center in Brazil and simulated alternatives to increase patient access to the test.

Metabolic dysfunction-associated steatohepatitis (MASH) and its progression to hepatocellular carcinoma remain major clinical challenges. Chronic endoplasmic reticulum (ER) stress, induced by sustained high-fat diet (HFD) intake, promotes hepatic inflammation, lipid accumulation, and hepatocellular dysfunction during MASH pathogenesis. While transcriptional responses are well characterized, the posttranscriptional mechanisms underlying hepatocyte adaptation to chronic ER stress remain poorly understood. Using an integrative approach combining transcriptomics, ribosome profiling, cytoplasmic polyadenylation analysis, and cis-regulatory mapping, we define the posttranscriptional landscape induced by chronic HFD exposure. To delineate the specific role of chronic ER stress, we use a hepatocyte-specific knockout of a key regulator of translational control under prolonged ER stress. We show that ~70% of HFD-induced gene expression changes are modulated at the translational level. A distinct subset of mRNAs, enriched in suboptimal codons and bearing short poly(A) tails under normal diet, becomes selectively activated upon HFD-induced poly(A) tail elongation. These transcripts, associated with cell cycle, immune response, fibrosis, and tissue remodeling, correlate with MASH severity in both murine models and human samples. Their regulation is mediated by cis-elements in the 3' UTR that coordinate polyadenylation and deadenylation. Loss of this adaptive response exacerbates liver damage and tumor burden in HFD-fed mice.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a dense desmoplastic stroma and an immunosuppressive tumor microenvironment that contribute to therapeutic resistance. Here, we identify plasminogen activator inhibitor 1 (PAI1) as a stroma-derived mediator of immune evasion and tumor progression in PDAC. PAI1 is predominantly produced and secreted by cancer-associated fibroblasts, and its genetic ablation in the stromal compartment impairs tumor growth. Mechanistically, hypoxia induces PAI1 expression in fibroblasts, which in turn shifts macrophages toward immunosuppressive phenotypes and suppresses CD8+ T cell infiltration and function. We further show that tissue plasminogen activator (tPA), a direct PAI1 target, is also secreted by fibroblasts and supports antitumor CD8+ T cell responses. Notably, elimination of stromal tPA promotes immunosuppressive macrophage phenotypes, reduces CD8+ T cell infiltration, and accelerates PDAC progression. These findings define a previously unrecognized PAI1-tPA regulatory axis within the tumor stroma that modulates antitumor immunity. Targeting this pathway may provide a therapeutic opportunity to overcome stroma-driven immune suppression in PDAC.

Systemic neoadjuvant chemotherapy, often combined with immunotherapy, is the standard of care for early-stage, non-breast cancer susceptibility gene (BRCA)-mutant triple negative breast cancer (TNBC). However, up to 70% of patients retain residual disease after treatment, which is linked to recurrence and mortality within 5 years. To define mechanisms of resistance, we performed single-cell RNA sequencing on orthotopic TNBC patient-derived xenografts during a cycle of treatment with doxorubicin and cyclophosphamide (AC). Clustering identified four tumor epithelial cell populations, with basal cells enriched in residual tumors. These basal cells up-regulated C15ORF48, a paralog of the mitochondrial cytochrome c oxidase associated subunit FA4 (NDUFA4), while exhibiting reciprocal down-regulation of NDUFA4. Functionally, C15ORF48 knockdown sensitized breast cancer cells to AC, increasing reactive oxygen species (ROS) and apoptosis. Thus, the up-regulation of C15ORF48 blunts ROS accumulation and induces resistance to chemotherapy in the basal cell subpopulations. Our findings identify C15ORF48 as a potential therapeutic target for overcoming AC resistance in TNBC.

Cancer remains a leading cause of mortality worldwide and a significant barrier to improving quality of life across all populations. The protein kinase D family, including PRKD3, has been demonstrated to play a crucial role in cancer development through its involvement in regulating key cellular processes. Although growing evidence highlights the role of PRKD3 in the tumorigenesis of certain cancers, a comprehensive pan-cancer analysis of PRKD3 remains unavailable. To address this, we performed an integrative pan-cancer analysis of PRKD3 using multi-omics datasets from The Cancer Genome Atlas, the Genotype-Tissue Expression project, and cBioPortal. We examined PRKD3 expression, copy number variation, mutation, and DNA methylation, and evaluated their associations with clinicopathological features, patient survival, and diagnostic potential across 33 cancer types. Immune relevance was further assessed through correlations with immune infiltration, checkpoint gene expression, and immunotherapy response-related genomic biomarkers. Our results revealed that PRKD3 expression was highly heterogeneous, showing significant upregulation in liver cancer, gastric cancer, and adrenocortical carcinoma, and downregulation in others. Elevated expression was consistently associated with poor prognosis and increased stromal, neutrophil, and cancer-associated fibroblast infiltration in adrenocortical carcinoma, liver cancer, and stomach cancer, whereas paradoxical associations with favorable outcomes were observed in kidney clear cell carcinoma. PRKD3 expression also correlated with immune checkpoint molecules including PD-1, PD-L1, and CTLA-4, supporting an immunosuppressive role, while context-dependent associations with TMB and MSI highlighted its potential influence on tumor immunogenicity and responsiveness to immune checkpoint blockade. Collectively, these findings identify PRKD3 as a potential context-dependent modulator of tumor biology, prognosis, and immune interactions, underscoring its potential as a biomarker of diagnostic, prognostic, and therapeutic relevance in precision oncology.

Microcephalin-1 (MCPH1) is a tumour suppressor protein that regulates homologous recombination repair (HRR) and is down-regulated in several tumour types. Given that HRR-defective cancer cells can be killed via synthetic lethal approaches, MCPH1 thus represents an attractive target in cancer therapy. Functionally, cells lacking MCPH1 have reported defects in the recruitment and retention of BRCA2 and RAD51 to DNA double strand breaks (DSBs) during HRR, though the magnitude of this defect in human cells is not entirely clear. Multiple studies have demonstrated that HRR-defective cells, particularly those lacking BRCA1 and BRCA2, can be specifically killed by inhibitors of the base excision repair enzyme, poly(ADP-ribose) polymerase-1 (PARP-1). Mechanistically, PARP-1 inhibition can cause (i) elevated DNA single strand breaks (SSBs) and (ii) 'PARP-1 trapping' on damaged DNA, both of which can lead to the formation of DSBs during DNA replication, which would normally be repaired by HRR. Given the functional link between MCPH1 and BRCA2, this study aimed to compare HRR-deficiency in cells lacking either protein and correlate this with PARP-1 inhibitor sensitivity. Our data shows that MCPH1-deficient cells are defective in HRR but still retain ~50% activity and this results in little to no sensitivity to two clinically-relevant PARP-1 inhibitors. In contrast, BRCA2-deficient cells showed a far greater defect in HRR and consistent sensitivity to both PARP-1 inhibitors, which was not enhanced by co-depletion of MCPH1. These data suggest that the magnitude of HRR defect in cancer cells influences PARP-1 inhibitor sensitivity and BRCA2 retains significant functionality in the absence of MCPH1.

Programmed death-ligand 1 (PD-L1) positivity is associated with a favorable response to immune checkpoint blockade (ICB) in urothelial bladder cancer (BLCA). However, the efficacy of ICB in BLCA exhibits considerable heterogeneity, leading to the need for complementary predictive biomarkers. Recent studies suggest that a high degree of plasma cell infiltration is correlated with improved benefit from ICB, but a specific plasma cell marker in BLCA has not been identified. The aim of this study was to evaluate tumor necrosis factor receptor superfamily member 17 (TNFRSF17) as a plasma cell-specific marker in BLCA and test its utility, combined with PD-L1, for patient stratification receiving ICB therapy.

Growing scientific evidence suggested that hepatocyte growth factor (HGF) might play a crucial role in the development of lung cancer, which might be influenced by the epidermal growth factor (EGF)/EGF receptor. However, the specific causality behind the association has not been clarified due to potential bias. Thus, a Mendelian randomization (MR) study was conducted to investigate the effects of gene-determined elevated plasma HGF on the risk of lung cancer and its subtypes, as well as the mediating effects of EGF. Thirteen instrumental variants for plasma HGF were derived from a genome-wide association study (GWAS) with 21,758 European participants, presented in SCALLOP consortium. Datasets of lung cancer and its subtypes (lung adenocarcinoma [LUAD], lung squamous cell cancer [LUSC], and small cell lung cancer [SCLC]) were based on a GWAS conducted by the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium (TRICL-ILCCO) with 29,266 lung cancer cases and 56,450 controls of European descent. We employed the inverse-variance weighted (IVW) MR analysis followed by a series of sensitive analyses to evaluate the associations between genetically determined plasma HGF and the risk of lung cancer and its subtypes. The primary IVW analysis showed that genetically determined HGF was associated with an increased risk of total lung cancer (odds ratio: 1.11, 95% confidence interval [CI]: 1.05-1.17, P = 2.27E-04) and LUAD (odds ratio: 1.18, 95% CI: 1.09-1.27, P = 1.47E-05) but not with LUSC and SCLC, by the sensitivity analyses with different MR methods further confirming these findings. Additionally, mediated analysis demonstrated that EGF mediated the causal associations of HGF with lung cancer and LUAD, with mediating effects of 28.56% and 21.2% on them. Besides, reverse-MR studies further confirmed no reverse causality between lung cancer and plasma HGF. The intercept of MR-Egger regression showed no directional pleiotropy for all associations (P > .05). Upregulated genetically determined plasma HGF levels were associated with an increasing risk of lung cancer, especially for LUAD. Mediated regulation of EGF on these associations indicated a potential pathogenesis pathway in lung cancer, which provides important implications for the prevention and management of lung cancer.

Long-term follow-up studies regarding the safety of risk-reducing mastectomy (RRM) in terms of cancer risk and surgical complications among women with germline pathogenic variants (gPVs) in BRCA1 or BRCA2 (BRCA1/2) are scarce.

Colorectal cancer (CRC) is a prevalent and increasingly common malignancy that poses significant threats to patient survival and quality of life. This study investigates the role of ubiquitously expressed prefoldin-like chaperone (UXT) in regulating polyamine metabolism, particularly putrescine, and its impact on CRC progression. Through comprehensive bioinformatics analysis, UXT was identified as a key factor positively correlated with putrescine abundance in CRC cell lines. Clinical samples confirmed upregulation of UXT and its positive correlation with putrescine levels. Functional assays revealed that UXT knockdown reduced cell viability, migration, and invasion, while overexpression enhanced these phenotypes. Additionally, UXT knockdown decreased putrescine levels and increased the expression of ornithine decarboxylase antizymes (OAZ1, OAZ2, OAZ3), which negatively regulate polyamine synthesis. Conversely, UXT overexpression exhibited the opposite effects. In vivo experiments using a subcutaneous xenograft tumor model in nude mice showed that UXT overexpression enhanced tumor growth and putrescine levels, and UXT overexpression is associated with an increase in M2 macrophage markers, along with reduced M1-associated markers, while UXT knockdown inhibited these effects. These findings suggest that UXT contributes to CRC progression by regulating polyamine metabolism and macrophage polarization, demonstrating its potential as a therapeutic target to disrupt metabolic pathways essential for cancer cell survival and proliferation.

To evaluate the prognostic utility of the FIGO 2023 staging system with/without molecular classification vs. FIGO 2009 in endometrial cancer.

Thyroid carcinoma is characterized by significant heterogeneity and immune evasion, in which myeloid cells play a pivotal role in tumor microenvironment (TME) remodeling. However, the key regulatory genes and their underlying mechanisms are not yet fully elucidated.

BackgroundSERPINE1 has attracted considerable attention in tumor biology, but its clinical importance in head and neck squamous cell carcinoma (HNSCC) is not yet clear. We therefore examined whether SERPINE1 expression is related to survival in patients with HNSCC.MethodsWe searched three major databases (PubMed, EMBASE, and the Cochrane Library) and identified observational studies reporting survival outcomes in relation to SERPINE1 expression through November 11, 2024. From eligible reports we extracted data on progression-free survival (PFS), overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS), and calculated pooled hazard ratios (HRs) using random-effects models.ResultsEleven studies including 733 individuals with HNSCC met the inclusion criteria. Across these cohorts, higher SERPINE1 expression was consistently linked with shorter OS (HR 2.81, P = 0.003) and shorter DFS (HR 1.57, P = 0.004). In contrast, no clear associations were observed for PFS or DSS (P ≥ 0.05).ConclusionCurrent evidence suggests that increased SERPINE1 expression is associated with an unfavorable prognosis in HNSCC, particularly for OS and DFS. Larger prospective studies are needed to confirm these findings and to determine how SERPINE1 assessment might be incorporated into risk stratification and treatment planning for patients with HNSCC.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that, regarding the immunohistochemical images shown in Fig. 1A on p. 1377, the 'DNMT3A' and 'DNMT3B' images for the 'BN' row of data contained an overlapping section, such that date which were intended to show the results from differently performed experiments had apparently been derived from the same original source. In addition, upon performing an independent analysis of the data in this paper in the Editorial Office, it came to light that the same data had been included for the Petri dish images in Fig. 3B on p. 1382 for the DMSO experiments with the T24 and EJ cell lines, albeit the EJ image had been rotated through 90°. The authors were contacted by the Editorial Office to offer an explanation for this apparent duplication of data within these figures; however, up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [Oncology Reports 35: 1375‑1384, 2016; DOI: 10.3892/or.2015.4492].

High mobility group box 3 (HMGB3) acts as an essential participator in fundamental biological processes, including transcriptional regulation, chromatin remodeling and DNA repair. HMGB3 is highly expressed and functionally essential during embryonic development, particularly in the hematopoietic and nervous systems, but it is significantly downregulated or silenced in most normal adult tissues. Its aberrant upregulation has been revealed in numerous human malignancies, such as leukemia, as well as breast, bladder, colorectal and gastric cancer, and its expression levels have been established to be closely associated with poor prognosis of specific patients. Accordingly, the present review systematically explores the central roles of HMGB3 in mediating resistance to cancer therapy. This review focuses on its multifaceted mechanisms of maintaining cancer stemness, enhancing DNA damage repair, modulating cell death pathways and remodeling the tumor microenvironment, thereby contributing to the resistance to chemotherapy, radiotherapy, targeted therapy and immunotherapy collectively. HMGB3 can be accepted as a key target in the development of highly promising therapeutic strategies, given its pivotal involvement in multidrug resistance, which may offer novel avenues for overcoming clinical treatment resistance and improving patient outcomes.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that, regarding the paraffin‑embedded glioma tissue sections shown in Fig. 2A on p. 494, the Ki‑67/Grade III and DTX3L/Grade IV data panels contained an overlapping section, suggesting that these data panels were derived from the same original source where different experimental groups were reported. In addition, GAPDH control western blots featured in Figs. 1C and 4E were found to be strikingly similar, even though the experimental conditions reported for these figure parts were different. The authors have been contacted by the Editorial Office to offer an explanation for these apparent anomalies in the presentation of the data in their paper, and we are awaiting their response. Due to the fact that we have been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of these potential problems while the Editorial Office continues to investigate this matter further. [International Journal of Molecular Medicine 40: 491‑498, 2017; DOI: 10.3892/ijmm.2017.3023].

Chromodomain helicase DNA‑binding protein 4 (CHD4) is a core adenosine triphosphate (ATP)‑dependent chromatin‑remodeling factor of the nucleosome‑remodeling and deacetylase (NuRD) complex. It plays a crucial role in chromatin structure regulation, gene expression regulation, and DNA damage response. It has been demonstrated that CHD4 has context‑dependent functions in tumor development and progression. It can influence tumor progression via such mechanisms as regulating tumor‑related signaling pathways, maintaining the silencing of tumor suppressor genes, and promoting metabolic adaptation; it can also exert tumor‑suppressive effects in specific transcriptional regulatory environments. Additionally, during DNA damage response, CHD4 participates in chromatin remodeling at damage sites, in cell cycle recovery, and in repair pathway selection. It is also involved in the development of tumor treatment resistance through mechanisms that include regulation of DNA repair, cell cycle progression, drug efflux, the tumor immune microenvironment, and replication fork stability. It has also been shown that various non‑coding RNAs participate in the functional regulation of CHD4 by modulating its expression, localization, and protein stability. In summary, as a key node connecting chromatin regulation, genome stability, and tumor treatment response, CHD4 holds significant importance in tumor progression and treatment.