Olaparib is approved for the treatment of germline BRCA mutant (gBRCAm) high-risk early breast cancer (eBC) following treatment with neoadjuvant or adjuvant chemotherapy. The potential long-term outcomes of widespread germline BRCA testing and treatment with olaparib in the US have not been quantified.

Protein disulfide isomerase family A member 4 (PDIA4), a member of the protein disulfide isomerase family, has been associated with the progression of cancer. Nevertheless, its specific function in oral squamous cell carcinoma (OSCC) is not yet well understood.

Extracranial metastasis of IDH-wildtype glioblastoma is very rare and poorly understood at the molecular level. We report a case of FGFR3::TACC3 fusion IDH-wildtype glioblastoma in a 61-year-old male, whose preoperative blood sample showed highly aberrant cfDNA fragmentation patterns, which could be suggestive of early systemic dissemination, undetected by standard-of-care imaging of his body. Eleven months post-resection and adjuvant therapy, he developed widespread extracranial metastases. Comprehensive molecular profiling of matched primary and metastatic tumors revealed broadly conserved genomic, transcriptomic, and copy number landscapes, with the metastasis harboring an additional ERCC6 deletion and enriched expression of receptor tyrosine kinase signaling genes. These findings provide rare insight into the genetic continuity and evolution underlying IDH-wildtype glioblastoma metastasis.

In many cancer patients, distant metastases develop after years of dormancy. Understanding how disseminated tumor cells (DTCs), which are often found in proximity to the microvasculature, remain dormant and what regulates their reactivation is one of the major challenges in tumor biology. In a screen for endothelial secreted and plasma membrane proteins able to regulate tumor cell dormancy, we identified the transmembrane protein platelet and endothelial aggregation receptor 1 (PEAR1). Human and murine endothelial cells lacking PEAR1 lost the ability to promote dormancy of different tumor cells, and the extracellular part of PEAR1 was able to rescue this effect. Similarly, in mice lacking PEAR1 in endothelial cells, tumor cell dormancy in the lung was reduced and tumor metastasis was increased. We found that PEAR1 induces tumor cell dormancy by binding lysyl oxidase like 2 (LOXL2) and cathepsin D (CTSD), which both inhibit tumor cell dormancy and promote tumor growth and metastasis. Tumor cells with suppressed CTSD expression showed increased dormancy and decreased metastatic potential in vivo. Our data identify a mechanism underlying tumor cell dormancy and suggest CTSD and LOXL2 as targets for approaches to promote dormancy.

This study aimed to investigate the potential prognostic role of nitrogen permease regulator-like 2 (NPRL2) gene expression in predicting biochemical recurrence (BCR) following robot-assisted radical prostatectomy (RARP).

Gastric cancer is a highly aggressive malignancy with poor prognosis and low survival rates. The Fragile X Mental Retardation 1 (FMR1) gene has been implicated in the development and progression of various tumors, but its role in gastric cancer remains unclear.

Abnormal one-carbon metabolism has been reported by observational studies to contribute to an increased risk of polycystic ovary syndrome (PCOS) and undesirable reproductive outcomes in women with PCOS. However, the underlying causal associations remain uninvestigated. This study aims to assess the independent causal links between essential substrates, enzymes and cofactors involved in one-carbon metabolism and PCOS, using bidirectional two-sample Mendelian randomization (MR) and Multivariable MR.

Metastasis is the most common cause of colorectal cancer (CRC)-related death. Neutrophil extracellular traps (NETs) promote tumor progression and distant metastasis. This study aimed to explore the role of NETs in CRC liver metastasis. Through analysis of publicly available single-cell transcriptome sequencing databases, in vitro experiments and nude mouse liver xenograft model experiments, we revealed that NETs promote CRC metastatic progression. Using scRNA-Seq technology, we showed that NETs marker expression was higher in metastatic lesions than in primary tumors. NET marker expression was high in colorectal cancer tissues and correlated with advanced tumor pathological grade. In addition, treatment with NETs enhanced the proliferation, migration and invasion of CRC cells in vitro by inducing EMT, as indicated by downregulation of E-cadherin and upregulation of N-cadherin and Vimentin. Cell-cell communication analysis revealed that NETs are related to the PI3K/AKT pathway and regulate the expression of LDHA, a key enzyme in glucose metabolism. In vitro, treatment with NETs promoted LDHA production and cell invasion and migration in CRC, while knockdown of LDHA suppressed EMT. Further, inhibition of LDHA expression or NET formation effectively inhibited NET-induced liver metastasis. In summary, this study elucidates the mechanism by which NETs regulate LDHA expression to promote CRC liver metastasis.

Lung adenocarcinoma (LUAD) is characterized by poor prognosis and limited treatment options. The homologous recombination factor with OB-fold (HROB) is reportedly associated with DNA repair, playing an essential role in a variety of cancers. However, the functional impact, clinical relevance, and underlying mechanisms of HROB in LUAD remain elusive, prompting this study to comprehensively characterize its expression profile and pathogenetic contributions.

To analyze the lipidomic profile of ESCC patients, link changes in cancer lipid metabolism to gene expression changes, and provide new insights into the diagnosis and treatment of ESCC patients in the Kazakh Xinjiang ethnic group.

The clinical heterogeneity observed in chronic lymphocytic leukemia (CLL) is largely attributed to diverse underlying genomic alterations. Fluorescence in situ hybridization (FISH) remains the standard cytogenetic technique but is limited to predefined loci. As a genome-wide approach, optical genome mapping (OGM) facilitates the identification of structural variants (SVs), such as copy number variations (CNVs), offering a broader genomic perspective. This study was designed to compare the findings of FISH and OGM in a cohort of CLL patients. By integrating these two cytogenetic approaches, we sought to evaluate the potential of OGM in detecting additional or cryptic genomic alterations that may impact prognosis and therapeutic decision-making.

Hepatocellular carcinoma (HCC) is a prevalent and deadly cancer worldwide, characterized by poor prognosis, multiple therapeutic challenges, and considerable heterogeneity among patients with diverse etiologies. This heterogeneity contributes to resistance to chemotherapies and molecularly targeted agents, posing a major therapeutic challenge. Therefore, there is an increasing need for treatment strategies targeting HCC across various biological processes. miR-192-5p has been reported to function as a tumor suppressor in HCC, but its target genes remain largely unknown. In this study, we aimed to identify novel target genes of miR-192-5p in HCC using RNA sequencing and 3'-untranslated region analysis. As a result, eight genes-EFEMP1, DLG5, PPP1CA, FAM234B, RPL4, SEC23B, ELOVL1, and CBFB-were identified as novel target genes of miR-192-5p, all of which were significantly upregulated in HCC tissues. Notably, three genes-CBFB, SEC23B, and RPL4-were also validated as novel targets of miR-194-5p, which clusters with miR-192-5p. These findings suggest that miR-192-5p exerts its tumor-suppressive function by inhibiting a novel gene network that may contribute to HCC progression. This study provides new insights into the molecular mechanisms underlying HCC heterogeneity and highlights miR-192-5p-regulated networks as potential therapeutic targets for HCC.

The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 14,106 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, MT-RNR1) and large (16S, MT-RNR2) mitochondrial RNA subunits of the mitochondrial ribosome encoded within mitochondrial DNA (mtDNA). Compared to non-hotspot positions, mitochondrial rRNA hotspots preferentially affected positions under purifying selection in the germline and demonstrated structural clustering within the mitoribosome at mRNA and tRNA interacting positions. Using precision mtDNA base editing, we engineered models of an exemplar MT-RNR1 hotspot mutation, m.1227G>A. Multimodal profiling revealed a heteroplasmy-dependent decrease in mitochondrial function and loss of respiratory chain subunits from a heteroplasmic dosage of ~10%. Mutation of conserved positions in ribosomal RNA that disrupt mitochondrial translation therefore represent a class of functionally dominant, pathogenic mtDNA mutations that are under positive selection in cancer genomes.

Due to a high rate of recurrence coupled with resistance towards modern therapies, colorectal cancer (CRC) is considered as the third cause of cancer-related death worldwide. Gemini curcumin (Gemini-Cur) is one of the last nanoformulation of curcumin with significant toxicity on colorectal cancer. Herein, we aimed to unravel the modulated lncRNAs, related mRNAs and downstream cellular pathways in Gemini-Cur treated HT-29 colorectal cancer cells. 9805 lncRNAs were found to be differentially expressed in nanocurcumin-treated cancer cells versus non treated group. The top 20 lncRNAs were selected for further studies and, 14,472 co-expression relationships between these RNAs and 70,711 mRNAs were identified. Among top 20 lncRNAs, tumor-suppressive C8orf31 and ARHGAP5-AS1, as well as oncogenic XIST, FTX, and NEAT1 were the most notable due to their involvements in cancer-related cellular pathways. Functional enrichment analyses demonstrated that the modulated lncRNAs and their targets are involved in cell cycle, p53 signaling, translation, and helicase activity pathways. In conclusion, our study elucidated new molecular mechanisms of nano-curcumin in the regulation of lncRNA expression and the discovery of potential targets in therapeutic interventions for CRC. More studies are needed to confirm the therapeutic implications of these findings.

Insulin-like growth factor-1 (IGF-1) is associated with prostate cancer (PCa) development and lethality and exhibits immunosuppressive properties in other models. We investigated IGF-1's tumor-intrinsic immune effects in PCa to understand mechanisms underlying its poor immunotherapy response. Transcriptional profiling of human (DU145, 22Rv1) and murine (Myc-CaP) PCa cells revealed that IGF-1 suppresses cytokine signalling, antigen processing and presentation, and additional immune regulatory pathways. We further examined the expression of components involved in cancer cell recognition and immune evasion: the antigen processing machinery and PD-L1 checkpoint. IGF-1 downregulated key elements such as transporters associated with antigen processing (TAPs), endoplasmic reticulum aminopeptidase-1 (ERAP-1), and Class I β2-microglobulin, without significantly altering Class I allele expression. These changes were associated with reduced surface presentation of Class I complexes on Myc-CaP cells, suggesting disrupted peptide transport, processing, and/or presentation. In contrast, IGF-1 upregulated the immune checkpoint CD274 (PD-L1) via IGF receptor/AKT/ERK-dependent signalling. Analysis of TCGA Firehose Legacy PCa data showed higher CD274 expression in tumors with elevated IGF1 and IGFBP5. Multiplex immunofluorescence in primary PCa confirmed increased PD-L1 in patients with high serum IGF-1, supporting its role in immune evasion. Overall, these findings reveal a novel IGF-1-driven immunosuppressive mechanism that may underlie PCa's resistance to immunotherapy.

As a leading cause of cancer-related fatalities among women, triple negative breast cancer (TNBC) still remains a clinical challenge. Increasing evidence points to long non-coding RNAs (lncRNAs) as significant regulators in its progression. The aim of this study is to investigate the function and working mechanism of LINC02159 in TNBC. The expression of LINC02159 in TNBC tissues and cells was detected by RT-qPCR analysis. Regulation of LINC02159 on TNBC is determined by the in vitro proliferation and migration assay. Binding of LINC02159 with the targets was tested by the luciferase reporter assay. The function of LINC02159 in the glycolysis of TNBC cells was evaluated via detecting the glucose uptake and lactate production. Our study identified that LINC02159 is overexpressed in TNBC tissues and correlates with decreased overall survival in patients. Functionally, silencing LINC02159 reduced TNBC cell proliferation and migration in vitro and suppressed the tumor growth in vivo. By acting as a competing endogenous RNA (ceRNA), LINC02159 directly engaged with miR-1285-3p to increase the expression of Glucose-6-phosphate isomerase (G6PI). In line with G6PI's role in glycolysis, reducing LINC02159 expression decreased glucose uptake and lactate production in TNBC cells. Restoring G6PI greatly reversed the impact of LINC02159 silencing on the proliferation and glycolysis of TNBC cells. These results demonstrated that LINC02159 drives the aerobic glycolysis and TNBC progression via modulating the miR-1285-3p/G6PI axis, and it might act as a potential target for TNBC anti-tumor therapy.

This study utilized TCGA database to explore the role of m6A modification and immune infiltration in AML. Through unsupervised clustering and WGCNA analysis, 8 hub genes were identified, and a risk model with EHBP1L1 and ZNF385A was established using LASSO regression. A nomogram incorporating hub gene risk score and age showed satisfactory prognostic prediction. External validation of GEO confirmed the model's effectiveness. TME analysis revealed correlations with monocytes and Treg cells, while immune checkpoints and HLA genes were associated with risk scores. Drug sensitivity analysis suggested potential responses to specific chemotherapy drugs. TIDE analysis indicated reduced ICI treatment benefit in high-risk patients. RT-qPCR validations revealed the significance of prognosis and risk stratification of ZNF385A. The noticeable trend of EHBP1L1 was observed. In addition, the accurate predictive capability of the risk model has been validated by clinical samples. Therefore, the risk model enables a quantitative evaluation of disease severity and progression risk in AML patients, based on their clinical and biological characteristics. This precise prediction not only informs treatment decisions but also guides the selection of chemotherapy regimens, overall improving patient outcomes.

Breast cancer remains a major global health issue, requiring novel strategies for prognostic evaluation and therapeutic decision-making. In this study, we leverage multi-omics data from The Cancer Genome Atlas to obtain deeper insights into breast cancer biology. By integrating genomics, transcriptomics, and epigenomics, we aim to identify complex molecular signatures that drive breast cancer progression and impact patient survival. To optimize the integration and feature selection process within the multi-omics dataset, we have employed genetic programming. Genetic programming helps us to optimize multi-omics integration, enabling the identification of robust biomarkers and more accurate survival analysis. The proposed framework consists of three key components: data preprocessing, adaptive integration and feature selection via genetic programming, and model development. The experimental results indicate that the integrated multi-omics approach yields a concordance index (C-index) of 78.31 during 5 fold cross-validation on the training set and 67.94 on the test set. In conclusion, our study demonstrates the potential of adaptive multi-omics integration in improving breast cancer survival analysis. It also highlights the importance of considering the complex interplay between different molecular layers. Furthermore, this framework provides a flexible and scalable approach that can be extended to other cancer types, offering valuable insights into oncological processes.

Identification of tumor driver genes in cancer has led to the discovery of specific allelic variants that are useful as predictive or prognostic markers. In colorectal cancer (CRC), the K-Ras GTPase is one of the most mutated oncoproteins; therefore, understanding the functional consequences of its mutations will allow us to exploit allele-specific vulnerabilities and propose potential mechanisms of resistance in cancer therapeutics. In this study, cellular phenotypic consequences of the K-Ras mutants K117I, K117N, A146T, E168K, and K172T identified in Filipino young-onset CRC (YO-CRC) patients were assessed in HCT116, Caco-2, and NIH3T3 cells. In assays assessing DNA doubling in 2D cultures and viability in 3D multicellular spheroids, only K117I, K117N, and A146T exhibited enhanced proliferation and supported a tumor-like property of increased size and viability. All mutants exhibited increased cellular migration in HCT116 and NIH3T3 but not in Caco-2 cells. None of them caused resistance to apoptosis. Compared to wild type, K117I, K117N, and A146T increased Elk1 reporter activation as well as phospho-Erk and phospho-Akt levels. All mutants induced extensive cytoskeletal remodeling including formation of migratory and invasive structures. Finally, GDP docking simulations suggested increased nucleotide exchange as a mechanism of activation.

The KRAS mutation represents the most prevalent oncogenic alteration observed in human cancers. Its primary role involves directly driving malignant tumor development and growth through the activation of downstream signaling pathways. Increasing evidence suggests that KRAS significantly affects the immune response of KRAS-mutant tumors by modulating immune-related signaling and inflammatory pathways. In addition to broadly regulating the KRAS-associated immune signaling, KRAS influences immune cell phenotype and function by triggering tumor metabolic pathways. Here, we reviewed the KRAS mutation-associated immune microenvironment features and discussed how KRAS remodels the immune microenvironment by regulating immune-related molecules, inflammatory factors, and multiple metabolic pathways, offering insights that could be useful for developing effective immune-responsive therapies for KRAS-mutant tumors.