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Cancers are typically fueled by sequential accumulation of driver mutations in a previously healthy cell. Some of these mutations, such as inactivation of the first copy of a tumor suppressor gene, can be neutral, and some, like those resulting in activation of oncogenes, may provide cells with a selective growth advantage. We study a multi-type branching process that starts with healthy tissue in homeostasis and models accumulation of neutral and advantageous mutations on the way to cancer. We provide results regarding the sizes of premalignant populations and the waiting times to the first cell with a particular combination of mutations, including the waiting time to malignancy. Finally, we apply our results to two specific biological settings: initiation of colorectal cancer and age incidence of chronic myeloid leukemia. Our model allows for any order of neutral and advantageous mutations and can be applied to other evolutionary settings., (© 2024. The Author(s).)

In this review article we will highlight the evidences that how oncogenes are formed due to the physical genetic variations in proto-oncogenes and tumor suppressor genes and various planned immunotherapies which will include- The immune checkpoint inhibitor-opposing antibodies, adoptive cell treatments, and biologic modifiers (cytokines and vaccines). We will make an effort to provide guidance and potential fixes for these issues, along with pertinent sources for foundational research. For suitable studies, a literature search was undertaken from various database sources such as PubMed, EMBASE, and Google Scholar. One type of gene known as an oncogene-a cellular gene that becomes dysfunctional owing to mutation and overexpression-is the cause of cancer. Certain oncogenes seem to inhibit the homeostatic mechanism by limiting the single cell lineage of leukemia stem cells. According to the clonal theory of oncogenes, tumors are thought to begin in a single cell, Moreover, the growth of tumors is closely linked to the prevention of apoptosis, or programmed cell death. These activities of oncogene can be minimized by some immunological therapies.

In cancer genome analysis, identifying pathogenic alterations and assessing their effects on oncogenic processes is important. Although whole exome sequencing (WES) can effectively detect such changes, driver alterations could not be identified in 27.8% of the cases, according to a previous study. The objectives of the present study were to evaluate the utility of whole genome sequencing (WGS) and clarify its differences with WES in terms of driver alteration detection. For this purpose, WGS analysis was conducted on 177 driverless WES samples, selected from 5,480 fresh frozen samples derived from 5,140 Japanese patients with cancer. These samples were selected as primary tumor, both WES and transcriptome profiling were performed, estimated tumor content of ≥ 30%, and no driver alterations were identified by WES. WGS identified driver and likely driver alterations in 68.4 and 22.6% of the samples, respectively. The most frequent alteration type was oncogene amplification, followed by tumor suppressor gene deletion and small variants located outside the coding region. In the remaining 9.0% of samples, no such signals were identified; therefore, further investigations are required. The current study clearly demonstrated the role and utility of WGS in identifying genomic alterations that contribute to tumorigenesis., (© 2024. The Author(s).)

Background: Hyperactive RNA Polymerase I (Pol I) transcription is canonical in cancer, associated with malignant proliferation, poor prognosis, epithelial-mesenchymal transition, and chemotherapy resistance. Despite its significance, the molecular mechanisms underlying Pol I hyperactivity remain unclear. This study aims to elucidate the role of long noncoding RNAs (lncRNAs) in regulating Pol I transcription in lung adenocarcinoma (LUAD)., Methods: Bioinformatics analyses were applied to identify lncRNAs interacting with Pol I transcriptional machinery. Fluorescence in situ hybridization was employed to examine the nucleolar localization of candidate lncRNA in LUAD cells. RNA immunoprecipitation assay validated the interaction between candidate lncRNA and Pol I components. Chromatin isolation by RNA purification and Chromatin Immunoprecipitation (ChIP) were utilized to confirm the interactions of candidate lncRNA with Pol I transcriptional machinery and the rDNA core promoter. Functional analyses, including lncRNA knock-in and knockdown, inhibition of Pol I transcription, quantitative PCR, cell proliferation, clonogenicity, apoptosis, cell cycle, wound-healing, and invasion assays, were performed to determine the effect of candidate lncRNA on Pol I transcription and associated malignant phenotypes in LUAD cells. ChIP assays and luminometry were used to investigate the transcriptional regulation of the candidate lncRNA., Results: We demonstrate that oncogenic LINC01116 scaffolds essential Pol I transcription factors TAF1A and TAF1D, to the ribosomal DNA promoter, and upregulate Pol I transcription. Crucially, LINC01116-driven Pol I transcription activation is essential for its oncogenic activities. Inhibition of Pol I transcription abrogated LINC01116-induced oncogenic phenotypes, including increased proliferation, cell cycle progression, clonogenicity, reduced apoptosis, increased migration and invasion, and drug sensitivity. Conversely, LINC01116 knockdown reversed these effects. Additionally, we show that LINC01116 upregulation in LUAD is driven by the oncogene c-Myc, a known Pol I transcription activator, indicating a functional regulatory feedback loop within the c-Myc-LINC01116-Pol I transcription axis., Conclusion: Collectively, our findings reveal, for the first time, that LINC01116 enhances Pol I transcription by scaffolding essential transcription factors to the ribosomal DNA promoter, thereby driving oncogenic activities in LUAD. We propose the c-Myc-LINC01116-Pol I axis as a critical oncogenic pathway and a potential therapeutic target for modulating Pol I transcription in LUAD., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC) is a widespread primary liver cancer with a high fatality rate. Despite several genes with oncogenic effects in HCC have been identified, many remain undiscovered. In this study, we conducted a comprehensive computational analysis to explore the involvement of genes within the same families as known driver genes in HCC. Specifically, we expanded the concept beyond single-gene mutations to encompass gene families sharing homologous structures, integrating various omics data to comprehensively understand gene abnormalities in cancer. Our analysis identified 74 domains with an enriched mutation burden, 404 domain mutation hotspots, and 233 dysregulated driver genes. We observed that specific low-frequency somatic mutations may contribute to HCC occurrence, potentially overlooked by single-gene algorithms. Furthermore, we systematically analyzed how abnormalities in the ubiquitinated proteasome system (UPS) impact HCC, finding that abnormal genes in E3, E2, DUB families, and Degron genes often result in HCC by affecting the stability of oncogenic or tumor suppressor proteins. In conclusion, expanding the exploration of driver genes to include gene families with homologous structures emerges as a promising strategy for uncovering additional oncogenic alterations in HCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Genetic heterogeneity in tumors can show a remarkable selectivity when two or more independent genetic events occur in the same gene. This phenomenon, called composite mutation, points toward a selective pressure, which frequently causes therapy resistance to mutation-specific drugs. Since composite mutations have been described to occur in sub-clonal populations, they are not always captured through biopsy sampling. Here, we provide a proof of concept to predict composite mutations to anticipate which patients might be at risk for sub-clonally driven therapy resistance. We found that composite mutations occur in 5% of cancer patients, mostly affecting the PIK3CA, EGFR, BRAF, and KRAS genes, which are common precision medicine targets. Furthermore, we found a strong and significant relationship between the frequencies of composite mutations with commonly co-occurring mutations in a non-composite context. We also found that co-mutations are significantly enriched on the same chromosome. These observations were independently confirmed using cell line data. Finally, we show the feasibility of predicting compositive mutations based on their co-mutations (AUC 0.62, 0.81, 0.82, and 0.91 for EGFR, PIK3CA, KRAS, and BRAF, respectively). This prediction model could help to stratify patients who are at risk of developing therapy resistance-causing mutations., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose: Chronic hepatitis B virus (HBV) infection is the primary risk factor for the malignant progression of hepatocellular carcinoma (HCC). It has been reported that HBV X protein (HBx) possesses oncogenic properties, promoting hepatocarcinogenesis and chemoresistance. However, the detailed molecular mechanisms are not fully understood. Here, we aim to investigate the effects of miR-128-3p/SPG21 axis on HBx-induced hepatocarcinogenesis and chemoresistance., Methods: The expression of SPG21 in HCC was determined using bioinformatics analysis, quantitative real-time PCR (qRT-PCR), western blotting, and immunohistochemistry (IHC). The roles of SPG21 in HCC were elucidated through a series of in vitro and in vivo experiments, including real-time cellular analysis (RTCA), matrigel invasion assay, and xenograft mouse model. Pharmacologic treatment and flow cytometry were performed to demonstrate the potential mechanism of SPG21 in HCC., Results: SPG21 expression was elevated in HCC tissues compared to adjacent non-tumor tissues (NTs). Moreover, higher SPG21 expression correlated with poor overall survival. Functional assays revealed that SPG21 fostered HCC tumorigenesis and invasion. MiR-128-3p, which targeted SPG21, was downregulated in HCC tissues. Subsequent analyses showed that HBx amplified TRPM7-mediated calcium influx via miR-128-3p/SPG21, thereby activating the c-Jun N-terminal kinase (JNK) pathway. Furthermore, HBx inhibited doxorubicin-induced apoptosis by engaging the JNK pathway through miR-128-3p/SPG21., Conclusion: The study suggested that SPG21, targeted by miR-128-3p, might be involved in enhancing HBx-induced carcinogenesis and doxorubicin resistance in HCC via the TRPM7/Ca 2+ /JNK signaling pathway. This insight suggested that SPG21 could be recognized as a potential oncogene, offering a novel perspective on its role as a prognostic factor and a therapeutic target in the context of HCC., (© 2024. Springer Nature Switzerland AG.)

Late diagnosis is considered one of the main reasons of high mortality rate among cancer patients that results in therapeutic failure and tumor relapse. Therefore, it is needed to evaluate the molecular mechanisms associated with tumor progression to introduce efficient markers for the early tumor detection among cancer patients. The remarkable stability of microRNAs (miRNAs) in body fluids makes them potential candidates to use as the non-invasive tumor biomarkers in cancer screening programs. MiR-135b has key roles in prognosis and survival of cancer patients by either stimulating or inhibiting cell proliferation, invasion, and angiogenesis. Therefore, in the present review we assessed the molecular biology of miR-135b during tumor progression to introduce that as a novel tumor marker in cancer patients. It has been reported that miR-135b mainly acts as an oncogene by regulation of transcription factors, signaling pathways, drug response, cellular metabolism, and autophagy. This review paves the way to suggest miR-135b as a tumor marker and therapeutic target in cancer patients following the further clinical trials and animal studies., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Targeting oncogene addictions have changed the history of subsets of malignancies and continues to represent an excellent therapeutic opportunity. Nonetheless, alternative strategies are required to treat malignancies driven by undruggable oncogenes or loss of tumor suppressor genes and to overcome drug resistance also occurring in cancers addicted to actionable drivers. The discovery of non-oncogene addiction (NOA) uncovered novel therapeutically exploitable "Achilles' heels". NOA refers to genes/pathways not oncogenic per sé but essential for the tumor cell growth/survival while dispensable for normal cells. The clinical success of several classes of conventional and molecular targeted agents can be ascribed to their impact on both tumor cell-associated intrinsic as well as microenvironment-related extrinsic NOA. The integration of genetic, computational and pharmacological high-throughput approaches led to the identification of an expanded repertoire of synthetic lethality interactions implicating NOA targets. Only a few of them have been translated into the clinics as most NOA vulnerabilities are not easily druggable or appealing targets. Nonetheless, their identification has provided in-depth knowledge of tumor pathobiology and suggested novel therapeutic opportunities. Here, we summarize conceptual framework of intrinsic and extrinsic NOA providing exploitable vulnerabilities. Conventional and emerging methodological approaches used to disclose NOA dependencies are reported together with their limits. We illustrate NOA paradigmatic and peculiar examples and outline the functional/mechanistic aspects, potential druggability and translational interest. Finally, we comment on difficulties in exploiting the NOA-generated knowledge to develop novel therapeutic approaches to be translated into the clinics and to fully harness the potential of clinically available drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The pathogenesis of cancer is complex, involving abnormalities in some genes in organisms. Accurately identifying cancer genes is crucial for the early detection of cancer and personalized treatment, among other applications. Recent studies have used graph deep learning methods to identify cancer driver genes based on biological networks. However, incompleteness and the noise of the networks will weaken the performance of models. To address this, we propose a cancer driver gene identification method based on self-supervision for graph convolutional networks, which can efficiently enhance the structure of the network and further improve predictive accuracy. The reliability of SSCI is verified by the area under the receiver operating characteristic curves (AUROC), the area under the precision-recall curves (AUPRC), and the F1 score, with respective values of 0.966, 0.964, and 0.913. The results show that our method can identify cancer driver genes with strong discriminative power and biological interpretability.

The study by Canisius et al. (2022) explores the expression of decitabine-targeted oncogenes (TRIM58, FAM84B, ELOVL2, DIO3) in meningiomas, aiming to evaluate decitabine's therapeutic potential for high-grade tumors. Using immunohistochemical staining and RT-PCR in over 100 patient samples, the authors found significant correlations between oncogene expression and tumor grade, with elevated ELOVL2 levels being linked to tumor recurrence. This work highlights the role of decitabine in modulating oncogene expression and suggests its potential in treating refractory meningiomas. Despite the robust methodology, limitations such as the small sample size and the lack of comprehensive molecular data were noted. Future research should incorporate larger sample sizes and advanced genomic techniques like RNA sequencing to better understand oncogenic mechanisms. The study emphasizes the need for further in situ analyses of decitabine's efficacy, setting the foundation for future neuro-oncological treatments., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Recent advances in high-resolution mapping of spatial interactions among regulatory elements support the existence of complex topological assemblies of enhancers and promoters known as enhancer-promoter hubs or cliques. Yet, organization principles of these multi-interacting enhancer-promoter hubs and their potential role in regulating gene expression in cancer remain unclear. Here, we systematically identify enhancer-promoter hubs in breast cancer, lymphoma, and leukemia. We find that highly interacting enhancer-promoter hubs form at key oncogenes and lineage-associated transcription factors potentially promoting oncogenesis of these diverse cancer types. Genomic and optical mapping of interactions among enhancer and promoter elements further show that topological alterations in hubs coincide with transcriptional changes underlying acquired resistance to targeted therapy in T cell leukemia and B cell lymphoma. Together, our findings suggest that enhancer-promoter hubs are dynamic and heterogeneous topological assemblies with the potential to control gene expression circuits promoting oncogenesis and drug resistance., (© 2024. The Author(s).)

Background: Clear cell renal cell carcinoma (ccRCC) remains one of the most lethal urological malignancies even though a great number of improvements in diagnosis and management have achieved over the past few decades. Accumulated evidence revealed that histone deacetylases (HDACs) play vital role in cell proliferation, differentiation and apoptosis. Nevertheless, the biological functions of histone deacetylation modification related genes in ccRCC remains poorly understood., Method: Bulk transcriptomic data and clinical information of ccRCC patients were obtained from the TCGA database and collected from the Chinese PLA General Hospital. A total of 36 histone deacetylation genes were selected and studied in our research. Univariate cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression, random forest (RF) analysis, and protein-protein interaction (PPI) network analysis were applied to identify key genes affecting the prognosis of ccRCC. The 'oncoPredict' algorithm was utilized for drug-sensitive analysis. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to explore the potential biological function. The ssGSEA algorithm was used for tumor immune microenvironment analysis. The expression levels of HDAC10 were validated by RT-PCR and immunohistochemistry (IHC). 5-ethynyl-2'-deoxyuridine (EdU assay), CCK-8 assay, cell transwell migration and invasion assay and colony formation assay were performed to detect the proliferation and invasion ability of ccRCC cells. A nomogram incorporating HDAC10 and clinicopathological characteristics was established to predict the prognosis of ccRCC patients., Result: Two machine learning algorithms and PPI analysis identified four histone deacetylation genes that have a significant association with the prognosis of ccRCC, with HDAC10 being the key gene among them. HDAC10 is highly expressed in ccRCC and its high expression is associated with poor prognosis for ccRCC patients. Pathway enrichment and the experiments of EdU staining, CCK-8 assay, cell transwell migration and invasion assay and colony formation assay demonstrated that HDAC10 mediated the proliferation and metastasis of ccRCC cells and involved in reshaping the tumor microenvironment (TME) of ccRCC. A clinically reliable prognostic predictive model was established by incorporating HDAC10 and other clinicopathological characteristics ( https://nomogramhdac10.shinyapps.io/HDAC10_Nomogram/ )., Conclusion: Our study found the increased expression of HDAC10 was closely associated with poor prognosis of ccRCC patients. HDAC10 showed a pro-tumorigenic effect on ccRCC and promote the proliferation and metastasis of ccRCC, which may provide new light on targeted therapy for ccRCC., (© 2024. The Author(s).)

Although the study of leukemogenesis has traditionally focused on protein-coding genes, the role of enhancer dysregulation is becoming increasingly recognized. The advent of high-throughput sequencing, together with a better understanding of enhancer biology, has revealed how various genetic and epigenetic lesions produce oncogenic enhancers that drive transformation. These aberrations include translocations that lead to enhancer hijacking, point mutations that modulate enhancer activity, and copy number alterations that modify enhancer dosage. In this review, we describe these mechanisms in the context of leukemia and discuss potential therapeutic avenues to target these regulatory elements. Significance: Large-scale sequencing projects have uncovered recurrent gene mutations in leukemia, but the picture remains incomplete: some patients harbor no such aberrations, whereas others carry only a few that are insufficient to bring about transformation on their own. One of the missing pieces is enhancer dysfunction, which only recently has emerged as a critical driver of leukemogenesis. Knowledge of the various mechanisms of enhancer dysregulation is thus key for a complete understanding of leukemia and its causes, as well as the development of targeted therapies in the era of precision medicine., (©2024 American Association for Cancer Research.)

Anoikis, a form of programmed cell death induced by loss of cell contact, is closely associated with tumor invasion and metastasis, making it highly significant in lung cancer research. We examined the expression patterns and prognostic relevance of Anoikis-related genes (ARGs) in lung adenocarcinoma (LUAD) using the TCGA-LUAD database. This study identified molecular subtypes associated with Anoikis in LUAD and conducted functional enrichment analyses. We constructed an ARG risk score using univariate least absolute shrinkage and selection operator (LASSO) Cox regression, validated externally with GEO datasets and clinical samples. The clinical applicability of the prognostic model was evaluated using nomograms, calibration curves, decision curve analysis (DCA), and time-dependent AUC assessments. We identified four prognostically significant genes (PLK1, SLC2A1, CDKN3, PHLDA2) and two ARG-related molecular subtypes. ARGs were generally upregulated in LUAD and correlated with multiple pathways including the cell cycle and DNA replication. The prognostic model indicated that the low-risk group had better outcomes and significant correlations with clinicopathological features, tumor microenvironment, immune therapy responses, drug sensitivity, and pan-RNA epigenetic modification-related genes. Patients with low-risk LUAD were potential beneficiaries of immune checkpoint inhibitor (ICI) therapy. Prognostic ARGs' distribution and expression across various immune cell types were further analyzed using single-cell RNA sequencing. The pivotal role of CDKN3 in LUAD was confirmed through qRT-PCR and gene knockout experiments, demonstrating that CDKN3 knockdown inhibits tumor cell proliferation, migration, and invasion. Additionally, we constructed a ceRNA network involving CDKN3/hsa-miR-26a-5p/SNHG6, LINC00665, DUXAP8, and SLC2A1/hsa-miR-218-5p/RNASEH1-AS1, providing new insights for personalized and immune therapy decisions in LUAD patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: As one of the most prevalent cancers, gastric cancer (GC) exhibits a remarkably high morbidity and mortality rate. To date, effective diagnostic and prognostic markers and therapeutic targets for GC are still lacking. Kinetochore associated 1 (KNTC1) is one of the proteins involved in chromosome segregation. However, the diagnostic and prognostic value of KNTC1 and its biological function in GC remain unknown., Methods: In this study, Gene Expression Omnibus (GEO) datasets were utilized to identify differentially expressed genes (DEGs). Prognostic and diagnostic value were assessed by Kaplan-Meier plotter and receiver operating characteristic (ROC) curve. The expression of KNTC1 was verified by q-PCR, immunohistochemistry (IHC) and Western blotting. Subsequently, KNTC1 knockdown was employed to investigate its effect on GC cells. Gene set enrichment analysis (GSEA) revealed a pathway regulated by KNTC1, which was further verified by Western blotting., Results: Four highly expressed genes (ESPL1, RAD54L, KNTC1, TACC3) were identified as biomarkers for GC diagnosis and prognosis. Notably, the value of KNTC1 as a biomarker for GC was newly revealed. Single-cell and immune analyses revealed that KNTC1 contributed to the suppression of the GC immune microenvironment. In clinical samples, we demonstrated high expression of KNTC1 in GC tissues. KNTC1 knockdown suppressed proliferation and migration while promoting apoptosis of GC cells. Additionally, KNTC1 may affect GC cells by regulating the PI3K/Akt/mTOR pathway., Conclusions: KNTC1 acts as a potential diagnostic and prognostic marker for GC. It may promote proliferation and migration while inhibiting apoptosis of GC cells via the PI3K/Akt/mTOR pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The major driver oncogenes MYC, mutant KRAS, and mutant TP53 often coexist and cooperate to promote human neoplasia, which results in anticancer therapeutic opportunities within their downstream molecular programs. However, little research has been conducted on whether redundancy and competition among oncogenes affect their programs and ability to drive neoplasia. By CRISPR‒Cas9-mediated downregulation we evaluated the downstream proteomics and transcriptomics programs of MYC, mutant KRAS, and mutant TP53 in a panel of cell lines with either one or three of these oncogenes activated, in cancers of the lung, colon and pancreas. Using RNAi screening of the commonly activated molecular programs, we found a signature of three proteins - RUVBL1, HSPA9, and XPO1, which could be efficiently targeted by novel drug combinations in the studied cancer types. Interestingly, the signature was controlled by the oncoproteins in a redundant or competitive manner rather than by cooperation. Each oncoprotein individually upregulated the target genes, while upon oncogene co-expression each target was controlled preferably by a dominant oncoprotein which reduced the influence of the others. This interplay was mediated by redundant routes of target gene activation - as in the case of mutant KRAS signaling to c-Jun/GLI2 transcription factors bypassing c-Myc activation, and by competition - as in the case of mutant p53 and c-Myc competing for binding to target promoters. The global transcriptomics data from the cell lines and patient samples indicate that the redundancy and competition of oncogenic programs are broad phenomena, that may constitute even a majority of the genes dependent on oncoproteins, as shown for mutant p53 in colon and lung cancer cell lines. Nevertheless, we demonstrated that redundant oncogene programs harbor targets for efficient anticancer drug combinations, bypassing the limitations for direct oncoprotein inhibition., (© 2024. The Author(s).)

The identification of cancer driver genes (CDGs) poses challenges due to the intricate interdependencies among genes and the influence of measurement errors and noise. We propose a novel energy-constrained diffusion (ECD)-based model for identifying CDGs, termed ECD-CDGI. This model is the first to design an ECD-Attention encoder by combining the ECD technique with an attention mechanism. ECD-Attention encoder excels at generating robust gene representations that reveal the complex interdependencies among genes while reducing the impact of data noise. We concatenate topological embedding extracted from gene-gene networks through graph transformers to these gene representations. We conduct extensive experiments across three testing scenarios. Extensive experiments show that the ECD-CDGI model possesses the ability to not only be proficient in identifying known CDGs but also efficiently uncover unknown potential CDGs. Furthermore, compared to the GNN-based approach, the ECD-CDGI model exhibits fewer constraints by existing gene-gene networks, thereby enhancing its capability to identify CDGs. Additionally, ECD-CDGI is open-source and freely available. We have also launched the model as a complimentary online tool specifically crafted to expedite research efforts focused on CDGs identification., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Backgroundsand Aims . Colorectal cancer (CRC) represents a major global health challenge, necessitating comprehensive investigations into its underlying molecular mechanisms to enhance diagnostic and therapeutic strategies. This study focuses on elucidating the oncogenic role of Membrane-Associated Ring-CH-Type Finger 9 (MARCHF9), a RING-Type E3 ubiquitin transferase, in CRC. We aim to assess MARCHF9's clinical significance, functional impact on CRC progression, and its potential as a prognostic biomarker. Methods . We leveraged data from the Cancer Genome Atlas (TCGA) cohort to evaluate MARCHF9 expression profiles in CRC. In vitro experiments involved siRNA-mediated MARCHF9 knockdown in COAD cell lines (SW480 and LoVo). Cell proliferation and invasion assays were conducted to investigate MARCHF9's functional relevance. Survival analyses were performed to assess its prognostic role. Results . Our analysis revealed significantly elevated MARCHF9 expression in CRC tissues compared to normal colorectal tissues ( P < 0.05). High MARCHF9 expression correlated with advanced clinical stages, distant metastases, and the presence of residual tumors in CRC patients. Survival analyses demonstrated that high MARCHF9 expression predicted unfavorable overall and disease-free survival outcomes ( P < 0.05). In vitro experiments further supported its oncogenic potential, with MARCHF9 knockdown inhibiting COAD cell proliferation and invasion. Conclusions . This study unveils the oncogenic role of MARCHF9 in CRC, highlighting its clinical relevance as a potential biomarker and therapeutic target. MARCHF9's association with adverse clinicopathological features and its functional impact on cancer cell behavior underscore its significance in CRC progression. Further research is essential to elucidate precise mechanisms by which MARCHF9 enhances tumorigenesis and to explore its therapeutic potential in CRC management., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Jiayan Zhang et al.)

Chimeric RNAs, which can arise from gene recombination at the DNA level or non-canonical splicing events at the RNA level, have been identified as important roles in human tumors. Dysregulated gene expression caused by somatic mutations and altered splicing patterns of oncogenes or tumor suppressor genes can contribute to the development of tumors. Therefore, investigating the formation mechanism of chimeric RNAs via somatic mutations is critical for understanding tumor pathogenesis. This project is the first to propose studying the association between somatic single nucleotide variants and chimeric RNAs, identifying around 2900 somatic SNVs affecting chimeric RNAs in pan-cancer level. The somatic SNVs on chimeric RNAs were commonly observed in various types of tumor tissues, providing a valuable resource for future study. Additionally, these SNVs show distinct tumor specificity, and those with high frequency had a significant impact on the survival time of patients with tumors. Further research revealed that somatic SNVs associated with chimeric RNA (chiR-SNVs) were typically found within 10 nt of the junction site of chimeric RNAs and had a particularly significant effect on chimeric RNAs from different chromosomes. The enrichment analysis revealed that chiR-SNVs were significantly overrepresented in oncogenes and genes related to RNA binding proteins involved in RNA splicing, which could imply that chiR-SNVs may disrupt the process of RNA splicing and induce the occurrence of chimeric RNAs. This study sheds light on the potential molecular interaction mechanism between somatic SNVs and chimeric RNAs, which opens up a new avenue for researching disease pathway and tumorigenesis development., (© 2024 UICC.)

Objective: The American Thyroid Association (ATA) Pediatric Guidelines recommend selective, prophylactic central neck dissection (pCND) for patients with papillary thyroid carcinoma (PTC) based on tumor focality, tumor size, and the surgeon's experience. With the expansion of pre-surgical somatic oncogene testing and continued controversy over the benefits of pCND, oncogenic alteration data may provide an opportunity to stratify pCND. This study compared lymph node (LN) involvement in pediatric patients with PTC between tumors with low- and high-invasive-associated alterations to explore the potential utility of preoperative oncogenic alterations in the stratification of pCND., Methods: This is retrospective cohort study of pediatric patients who underwent somatic oncogene testing post thyroidectomy for PTC between July 2003 and July 2022., Results: Of 192 eligible PTC patients with postoperative somatic oncogene data, 19 tumors harbored somatic alterations associated with low-invasive disease (19/192, 10%), and 128 tumors harbored a BRAFV600E alteration (45/192, 23%) or an oncogenic fusion (83/192, 43%). Tumors with low-invasive alterations were less likely to present malignant preoperative cytology (2/18, 11%) than those with high-invasive alterations (97/124, 78%; P < 0.001). Twelve patients with low-invasive alterations had LNs dissected from the central neck (12/19, 63%) compared to 127 patients (127/128, 99%) with high-invasive alterations. LN metastasis was identified in two patients with low-invasive alterations (2/19, 11%) compared to 107 patients with high-invasive alterations (107/128, 84%; P < 0.001)., Conclusion: Pediatric patients with low-invasive somatic oncogenic alterations are at low risk for metastasis to central neck LNs. Our findings suggest that preoperative knowledge of somatic oncogene alterations provides objective data to stratify pediatric patients who may not benefit from pCND.

Ras genes are important oncogenes that are frequently mutated in cancer. Human oncogenic variants exhibit functional distinctions in terms of their representation in different cancer types, impact on cellular targets and sensitivity to pharmacological treatments. However, how these distinct variants influence and respond to the cellular networks in which they are embedded is poorly understood. To identify novel participants in the complex interplay between Ras genotype and cell interaction networks in vivo, we have developed and tested an experimental framework using a simple vulva-development assay in the nematode C. elegans. Using this system, we evaluated a set of Ras oncogenic substitution changes at G12, G13 and Q61. We found that these variants fall into distinct groups based on phenotypic differences, sensitivity to gene dosage and inhibition of the downstream kinase MEK and their response to genetic modulators that influence Ras activity in a non-autonomous manner. Together, our results demonstrated that oncogenic C. elegans Ras variants exhibit clear distinctions in how they interface with the vulva-development network and showed that extracellular modulators yield variant-restricted effects in vivo., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Macroautophagy (referred to as autophagy hereafter) is a highly conserved catabolic process which sequesters intracellular substrates for lysosomal degradation. Autophagy-related proteins have been shown to be involved in various aspects of tumor development by engaging with multiple cellular substrates. We recently uncovered a novel role for autophagy in regulating the signaling and levels of PDGFRA, a receptor tyrosine kinase amplified in several cancers. We discovered that PDGFRA can be targeted to autophagic degradation by binding the autophagy cargo receptor SQSTM1. Surprisingly, PDGFRA-mediated signaling is perturbed in the absence of autophagy despite enhanced receptor levels. We show that this is due to disrupted trafficking of the receptor to late endosomes where signaling activity persists. Conversely, prolonged autophagy inhibition results in a transcriptional downregulation of Pdgfra as a result of inhibited signaling activity demonstrating that short- and long-term autophagy inhibition have opposing effects on receptor levels. We further investigated the consequence of PDGFRA regulation by autophagy using a mouse model for gliomagenesis where we observed a disruption in PDGFA-driven tumor formation when autophagy is inhibited. Activation of downstream signaling through Pten mutation overrides the need for autophagy during tumor development suggesting a genotype-specific role for autophagy during tumorigenesis. Altogether, our findings provide a novel mechanism through which autophagy can support tumor growth.

Background: circRNA NFIX has been shown to exist as an oncogene in glioma. But its expression and role in NSCLC (non-small cell lung cancer) are still unclear. This research aimed to discover the expression and function of circRNA NFIX in NSCLC., Methods: In this research, qRT-PCR was utilized to investigate the expression levels of circRNA NFIX, miRNA-214-3p, and TRIAP1 in NSCLC tissues and cell lines. The binding sites between circRNA NFIX/TRIAP1 and miRNA-214-3p were predicted using the Starbase. These interactions were further validated using a double luciferase reporter assay. Cell proliferation and apoptosis were assessed through MTT and flow cytometry, respectively. The expression of apoptosis-related proteins was measured by western blot assay., Results: miRNA-214-3p could link with circRNA NFIX. circRNA NFIX was upregulated, while miRNA-214-3p was downregulated in NSCLC cell lines and clinical samples. Besides, suppression of circRNA NFIX repressed cell proliferation and induced apoptosis in NSCLC cells by upregulating miRNA-214-3p expression. Besides, the data indicated that TRIAP1 was a target of miRNA-214-3p, and it was negatively regulated by miRNA-214-3p in NSCLC cells. The excessive expression of miRNA-214-3p suppressed NSCLC cell proliferation and increased apoptosis. In addition, overexpression of TRIAP1 significantly reversed the effects on NSCLC cells caused by miRNA-214-3p mimic., Conclusion: circRNA NFIX silencing repressed the proliferation of NSCLC cells and induced cell apoptosis by regulating the miR-214-3p/TRIAP1 axis, which was a potential diagnostic and therapeutic target for NSCLC., (© 2024 The Author(s). The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Cancer driver genes can undergo positive selection for various types of genetic alterations, including gain-of-function or loss-of-function mutations and copy number alterations (CNA). We investigated the landscape of different types of alterations affecting driver genes in 17,644 cancer exomes and genomes. We find that oncogenes may simultaneously exhibit signatures of positive selection and also negative selection in different gene segments, suggesting a method to identify additional tumor types where an oncogene is a driver or a vulnerability. Next, we characterize the landscape of CNA-dependent selection effects, revealing a general trend of increased positive selection on oncogene mutations not only upon CNA gains but also upon CNA deletions. Similarly, we observe a positive interaction between mutations and CNA gains in tumor suppressor genes. Thus, two-hit events involving point mutations and CNA are universally observed regardless of the type of CNA and may signal new therapeutic opportunities. An analysis with focus on the somatic CNA two-hit events can help identify additional driver genes relevant to a tumor type. By a global inference of point mutation and CNA selection signatures and interactions thereof across genes and tissues, we identify 9 evolutionary archetypes of driver genes, representing different mechanisms of (in)activation by genetic alterations., (© 2024. The Author(s).)

The KRAS mutation stands out as one of the most influential oncogenic mutations, which directly regulates the hallmark features of cancer and interacts with other cancer-causing driver mutations. However, there remains a lack of precise information on their cooccurrence with mutated variants of KRAS and any correlations between KRAS and other driver mutations. To enquire about this issue, we delved into cBioPortal, TCGA, UALCAN, and Uniport studies. We aimed to unravel the complexity of KRAS and its relationships with other driver mutations. We noticed that G12D and G12V are the prevalent mutated variants of KRAS and coexist with the TP53 mutation in PAAD and CRAD, while G12C and G12V coexist with LUAD. We also noticed similar observations in the case of PIK3CA and APC mutations in CRAD. At the transcript level, a positive correlation exists between KRAS and PIK3CA and between APC and KRAS in CRAD. The existence of the co-mutation of KRAS and other driver mutations could influence the signaling pathway in the neoplastic transformation. Moreover, it has immense prognostic and predictive implications, which could help in better therapeutic management to treat cancer.

Natural killer (NK) cells play a crucial role in antitumoral and antiviral responses. Yet, cancer cells can alter themselves or the microenvironment through the secretion of cytokines or other factors, hindering NK cell activation and promoting a less cytotoxic phenotype. These resistance mechanisms, often referred to as the "hallmarks of cancer" are significantly influenced by the activation of oncogenes, impacting most, if not all, of the described hallmarks. Along with oncogenes, other types of genes, the tumor suppressor genes are frequently mutated or modified during cancer. Traditionally, these genes have been associated with uncontrollable tumor growth and apoptosis resistance. Recent evidence suggests oncogenic mutations extend beyond modulating cell death/proliferation programs, influencing cancer immunosurveillance. While T cells have been more studied, the results obtained highlight NK cells as emerging key protagonists for enhancing tumor cell elimination by modulating oncogenic activity. A few recent studies highlight the crucial role of oncogenic mutations in NK cell-mediated cancer recognition, impacting angiogenesis, stress ligands, and signaling balance within the tumor microenvironment. This review will critically examine recent discoveries correlating oncogenic mutations to NK cell-mediated cancer immunosurveillance, a relatively underexplored area, particularly in the era dominated by immune checkpoint inhibitors and CAR-T cells. Building on these insights, we will explore opportunities to improve NK cell-based immunotherapies, which are increasingly recognized as promising alternatives for treating low-antigenic tumors, offering significant advantages in terms of safety and manufacturing suitability., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Cancer development and progression are generally associated with gene dysregulation, often resulting from changes in the transcription factor (TF) sequence or expression. Identifying key TFs involved in cancer gene regulation provides a framework for potential new therapeutics. This study presents a large-scale cancer gene TF-DNA interaction network, as well as an extensive promoter clone resource for future studies. Highly connected TFs bind to promoters of genes associated with either good or poor cancer prognosis, suggesting that strategies aimed at shifting gene expression balance between these two prognostic groups may be inherently complex. However, we identified potential for oncogene-targeted therapeutics, with half of the tested oncogenes being potentially repressed by influencing specific activators or bifunctional TFs. Finally, we investigate the role of intrinsically disordered regions within the key cancer-related TF ESR1 in DNA binding and transcriptional activity, and found that these regions can have complex trade-offs in TF function. Altogether, our study broadens our knowledge of the TFs involved in cancer gene regulation and provides a valuable resource for future studies and therapeutics., (© 2024 Lu et al.)

Accumulating evidence suggests that caspase-3 plays critical roles beyond apoptosis, serving pro-survival functions in malignant transformation and tumorigenesis. However, the mechanism of non-apoptotic action of caspase-3 in oncogenic transformation remains unclear. In the present study, we show that caspase-3 is consistently activated in malignant transformation induced by exogenous expression of oncogenic cocktail (c-Myc, p53DD, Oct-4, and H-Ras) in vitro as well as in the mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) mouse model of breast cancer. Genetic ablation of caspase-3 significantly attenuated oncogene-induced transformation of mammalian cells and delayed breast cancer progression in MMTV-PyMT transgenic mice. Mechanistically, active caspase-3 triggers the translocation of endonuclease G (EndoG) from mitochondria, which migrates to the nucleus, thereby induces phosphorylation of Src-STAT3 signaling pathway to facilitate oncogenic transformation. Taken together, our data suggest that caspase-3 plays pivotal role in facilitating rather than suppressing oncogene-induced malignant transformation of mammalian cells., (© 2024. The Author(s).)

Lung cancer (LC) is a highly lethal cancer worldwide. Research on the distribution and nature of extrachromosomal DNA molecules (EcDNAm) in early LC is scarce. In this study, after removing linear DNA and mitochondrial circular DNA, EcDNAm were extracted from two paired LC tissue samples and amplified using rolling circle amplification. High throughput extrachromosomal DNA (EcDNA) or RNA sequencing and bioinformatics analysis were subsequently utilized to explore the distribution and nature of the EcDNAm. Additionally, to elucidate the role of oncogenes with large EcDNAm sizes, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed. The RNA sequencing results revealed significant differences in certain genes between tumors and corresponding normal samples. At the same time, slight distinctions were observed between relapsed and non-relapsed tumor samples. The nature of the EcDNAm was compared between LC samples and matched normal samples. There was a tendency for the number of EcDNAm with longer size (EcDNA) and its containing driver oncogenes to be higher in cancer samples. Enrichment analysis of the cancer samples revealed enrichment in biological processes, such as positive regulation of protein localization, axon development, and in-utero embryonic development. This study highlights the universal distribution and characteristics of EcDNAm in early LC. Moreover, our work fills the investigation of the EcDNAm gap and future studies should focus on the application of EcDNA as a potential biomarker in patients with early LC., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Although leucine zipper tumour suppressor 1 (LZTS1) has been considered a potential tumour suppressor, accumulating evidence suggests that LZTS1 is highly expressed in many cancer types. To unravel the exact role of LZTS1 in colorectal carcinogenesis, we performed the bioinformatic analysis of LZTS1, including expression differences, correlations between expression levels and survival, methylation status of LZTS1 promoter and related cellular pathways based on TCGA dataset, GEO databases and our own CRC patient cohort. Furthermore, we confirmed the oncogenic function of LZTS1 in human mammalian cells by employing a series of assays including tissue microarray, immunoblotting, cell proliferation and migration assay. We found that the expression of LZTS1 is higher in tumour samples compared to paired normal tissue in CRC cancer and its different clinical subtypes, which is, at least in part, due to the low methylation status of LZTS1 promoter in CRC tumour samples. Functional analysis identified the close relationship between high expression of LZTS1 and PI3K-AKT pathway and the epithelial-mesenchymal transition (EMT) process. Consistently, we found that the expression of LZTS1 positively correlated with the expression PIK3CD, N-cadherin in CRC tumour samples, while the expression of LZTS1 negatively correlated with the expression of E-cadherin and PTEN in CRC tumour samples. Experimental data further confirmed that overexpression of LZTS1 upregulated activity of AKT and promoted EMT process. Furthermore, depletion of LZTS1 repressed the proliferation and migration rate of CRC cells. Thus, this study indicates that LZTS1 plays an oncogenic role in colorectal carcinogenesis., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

A remote carcinogen exposure can predispose to breast cancer onset decades later, suggesting that carcinogen-induced mutations generate long-lived premalignant clones. How subsequent events influence the progression of specific premalignant clones remains poorly understood. Herein, multistage mouse models of mammary carcinogenesis were generated by combining chemical carcinogen exposure [using 7,12-dimethylbenzanthracene (DMBA)] with transgenes that enable inducible expression of one of two clinically relevant mammary oncogenes: c-MYC (MYC) or PIK3CA H1047R (PIK). In prior work, DMBA exposure generated mammary clones bearing signature Hras Q61L mutations, which only progressed to mammary cancer after inducible Wnt1 oncogene expression. Here, after an identical DMBA exposure, MYC versus PIK drove cancer progression from mammary clones bearing mutations in distinct Ras family paralogs. For example, MYC drove cancer progression from either Kras- or Nras-mutant clones, whereas PIK transformed Kras-mutant clones only. These Ras mutation patterns were maintained whether oncogenic transgenes were induced within days of DMBA exposure or months later. Completing a full-term pregnancy (parity) failed to protect against either MYC- or PIK-driven tumor progression. Instead, a postpartum increase in mammary tumor predisposition was observed in the context of PIK-driven progression. However, parity decreased the overall prevalence of tumors bearing Kras mut , and the magnitude of this decrease depended on both the number and timing of pregnancies. These multistage models may be useful for elucidating biological features of premalignant mammary neoplasia., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Drug-tolerance has emerged as one of the major non-genetic adaptive processes driving resistance to targeted therapy (TT) in non-small cell lung cancer (NSCLC). However, the kinetics and sequence of molecular events governing this adaptive response remain poorly understood. Here, we combine real-time monitoring of the cell-cycle dynamics and single-cell RNA sequencing in a broad panel of oncogenic addiction such as EGFR-, ALK-, BRAF- and KRAS-mutant NSCLC, treated with their corresponding TT. We identify a common path of drug adaptation, which invariably involves alveolar type 1 (AT1) differentiation and Rho-associated protein kinase (ROCK)-mediated cytoskeletal remodeling. We also isolate and characterize a rare population of early escapers, which represent the earliest resistance-initiating cells that emerge in the first hours of treatment from the AT1-like population. A phenotypic drug screen identify farnesyltransferase inhibitors (FTI) such as tipifarnib as the most effective drugs in preventing relapse to TT in vitro and in vivo in several models of oncogenic addiction, which is confirmed by genetic depletion of the farnesyltransferase. These findings pave the way for the development of treatments combining TT and FTI to effectively prevent tumor relapse in oncogene-addicted NSCLC patients., (© 2024. The Author(s).)

Background: Existing studies have found that circular RNAs (circRNAs) act as sponges for micro RNAs (miRNAs) to control downstream genes. However, the specific functionalities and mechanisms of circRNAs in human clear cell renal cell carcinoma (ccRCC) have yet to be thoroughly investigated., Methods: Patient cohorts from online databases were used to screen candidate circRNAs, while another cohort from our hospital was obtained for validation. CircSOD2 was identified as a potential oncogenic target, and its relevant characteristics were investigated during ccRCC progression through various assays. A positive feedback loop containing downstream miRNA and its target gene were identified using bioinformatics and validated by luciferase reporter assays, RNA pull-down, and high-throughput sequencing., Results: CircSOD2 expression was elevated in tumor samples and significantly correlated with overall survival (OS) and the tumor stage of ccRCC patients, which appeared in the enhanced proliferation, invasion, and migration of tumor cells. Through competitive binding to circSOD2, miR-532-3p can promote the expression of PAX5 and the progression of ccRCC, and such regulation can be salvaged by miR-532-3p inhibitor., Conclusion: A novel positive feedback loop, PAX5/circSOD2/miR-532-3p/PAX5 was identified in the study, indicating that the loop may play an important role in the diagnosis and prognostic prediction in ccRCC patients., (© 2024. The Author(s).)

Background: Breast cancer (BC) is the most prevalent malignant disease affecting women globally. PANoptosis, a novel form of cell death combining features of pyroptosis, apoptosis, and necroptosis, has recently gained attention. However, its precise function in BC and the predictive values of PANoptosis-related genes remain unclear., Methods: We used the expression data and clinical information of BC tissues or normal breast tissues from public databases, and then successfully developed and verified a BC PANoptosis-related risk model through a combination of univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression, and Kaplan-Meier (KM) analysis. A nomogram was constructed to estimate survival probability, and its accuracy was assessed using calibration curves., Results: Among 37 PANoptosis-related genes, we identified 4 differentially expressed genes related to overall survival (OS). Next, a risk model incorporating these four PANoptosis-related genes was established. Patients were stratified into low/high-risk groups based on the median risk score, with the low-risk group showing better prognoses and higher levels of immune infiltration. Utilizing the risk score and clinical features, we developed a nomogram to predict 1-, 3- and 5-year survival probability. X-linked inhibitor of apoptosis protein (XIAP) emerged as a potentially risky factor with the highest hazard ratio. In vitro experiments demonstrated that XIAP inhibition enhances the antitumor effect of doxorubicin through the PANoptosis pathway., Conclusion: PANoptosis holds an important role in BC prognosis and treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Whether programmed cell death-1/ligand-1 (PD-1/PD-L1) blockade-based neoadjuvant treatment may benefit locally advanced oncogene-mutant non-small cell lung cancer (NSCLC) patients remains controversial. This retrospective study was designed to observe the efficacy and safety of neoadjuvant PD-1/PD-L1 blockade plus chemotherapy versus chemotherapy and corresponding tyrosine kinase inhibitors (TKIs) in patients with resectable oncogene-positive NSCLC., Methods: Patients with potential resectable NSCLC harbouring oncogene alterations who had received neoadjuvant treatment were retrospectively recruited, and an oncogene-negative cohort of patients who received neoadjuvant PD-(L)1 blockade-based neoadjuvant treatment was reviewed for comparison during the same period. The primary aim was to observe the treatment efficacy and event-free survival (EFS) of these agents. Safety profile, molecular target, and immunologic factor data, including PD-L1 expression and tumour mutational burden (TMB), were also obtained., Results: A total of 46 patients were recruited. Thirty-one of them harboured oncogene alterations, including EGFR, KRAS, ERBB2, ROS1, MET, RET, ALK, and FGFR3 alterations. Among the oncogene-positive patients, 18 patients received neoadjuvant PD-(L)1 blockade immunotherapy plus chemotherapy (oncogene-positive IO group), 13 patients were treated with neoadjuvant chemotherapy and/or corresponding TKIs or TKIs alone (oncogene-positive chemo/TKIs group), and the other 15 patients were oncogene negative and received neoadjuvant PD-(L)1 blockade plus chemotherapy (oncogene-negative IO group). The pathological complete response (pCR) and major pathological response (MPR) rates were 22.2% (4 of 18) and 44.4% (8 of 18) in the oncogene-positive IO group, 0% (P = 0.120) and 23.1% (3 of 13) (P = 0.276) in the oncogene-positive chemo/TKIs group, and 46.7% (7 of 15) (P = 0.163) and 80.0% (12 of 15) (P = 0.072) in the oncogene-negative IO group, respectively. By the last follow-up, the median EFS time had not reached in the oncogene-positive IO group, and was 29.5 months in the oncogene-positive chemo/TKIs group and 38.4 months in the oncogene-negative IO group., Conclusion: Compared with chemotherapy/TKIs treatment, neoadjuvant treatment with PD-(L)1 blockade plus platinum-based chemotherapy was associated with higher pCR/MPR rates in patients with partially resectable oncogene-mutant NSCLC, while the pCR/MPR rates were lower than their oncogene-negative counterparts treated with PD-(L)1 blockade-based treatment. Specifically, oncogene alteration types and other predictors of response to immunotherapy should be taken into account in clinical practice., (© 2024. The Author(s).)

Non-small cell lung cancers (NSCLC) in nonsmokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET and fusions involving ALK and RET. In addition to occurring in nonsmokers, alterations in these "nonsmoking-related oncogenes" (NSRO) also occur in smokers. To better understand the clonal architecture and genomic landscape of NSRO-driven tumors in smokers compared with typical-smoking NSCLCs, we investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 NSCLC patients. NSRO-driven NSCLCs in smokers and nonsmokers had similar genomic landscapes. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs, which was confirmed in two large NSCLC data sets from other geographic regions. However, NSRO-driven NSCLCs in smokers had higher transcriptomic activities related to the regulation of the cell cycle. These findings suggest that, whereas the genomic landscape is similar between NSRO-driven NSCLC in smokers and nonsmokers, smoking still affects the tumor phenotype independently of genomic alterations., Significance: Non-small cell lung cancers driven by nonsmoking-related oncogenes do not harbor genomic scars caused by smoking regardless of smoking history, indicating that the impact of smoking on these tumors is mainly nongenomic., (©2024 American Association for Cancer Research.)

Background: Enhancers are important gene regulatory elements that promote the expression of critical genes in development and disease. Aberrant enhancer can modulate cancer risk and activate oncogenes that lead to the occurrence of various cancers. However, the underlying mechanism of most enhancers in cancer remains unclear. Here, we aim to explore the function and mechanism of a crucial enhancer in melanoma., Methods: Multi-omics data were applied to identify an enhancer (enh17) involved in melanoma progression. To evaluate the function of enh17, CRISPR/Cas9 technology were applied to knockout enh17 in melanoma cell line A375. RNA-seq, ChIP-seq and Hi-C data analysis integrated with luciferase reporter assay were performed to identify the potential target gene of enh17. Functional experiments were conducted to further validate the function of the target gene ETV4. Multi-omics data integrated with CUT&Tag sequencing were performed to validate the binding profile of the inferred transcription factor STAT3., Results: An enhancer, named enh17 here, was found to be aberrantly activated and involved in melanoma progression. CRISPR/Cas9-mediated deletion of enh17 inhibited cell proliferation, migration, and tumor growth of melanoma both in vitro and in vivo. Mechanistically, we identified ETV4 as a target gene regulated by enh17, and functional experiments further support ETV4 as a target gene that is involved in cancer-associated phenotypes. In addition, STAT3 acts as a transcription factor binding with enh17 to regulate the transcription of ETV4., Conclusions: Our findings revealed that enh17 plays an oncogenic role and promotes tumor progression in melanoma, and its transcriptional regulatory mechanisms were fully elucidated, which may open a promising window for melanoma prevention and treatment., (© 2024. The Author(s).)

Certain oncogenes, including mutant RAS and BRAF, induce a type of senescence known as oncogene-induced senescence (OIS) in normal cells in a cell-type-specific manner. OIS serves as a barrier to transformation by activated oncogenes. Our previous studies showed that mutant KRAS V12 did not efficiently induce OIS in an hTERT/Cdk4-immortalized normal human bronchial epithelial cell line (HBEC3), but it did enhance both anchorage-dependent and anchorage-independent growth. In this study, we investigated whether mutant BRAF, a well-known inducer of OIS, could trigger OIS in HBEC3 cells. We also assessed the impact of mutant BRAF on the growth of HBEC3 cells, as no previous studies have examined this using a normal bronchial epithelial cell line model. We established an HBEC3 cell line, designated as HBEC3-BIN, that expresses mutant BRAF V600E in a doxycycline-regulated manner. Unlike our previous finding that KRAS V12 upregulated both pERK and pAKT, mutant BRAF V600E upregulated pERK but not pAKT in HBEC3-BIN cells. Similar to KRAS V12 , BRAF V600E did not efficiently induce OIS. Interestingly, while BRAF V600E inhibited colony formation in anchorage-dependent conditions, it dramatically enhanced colony formation in anchorage-independent conditions in HBEC3-BIN. In HBEC3 cells without BRAF V600E or KRAS V12 expression, p21 was only detected in the cytoplasm, and its localization was not altered by the expression of BRAF V600E or KRAS V12 . Next-generation sequencing analysis revealed an enrichment of gene sets known to be involved in carcinogenesis, including IL3/JAK/STAT3, IL2, STAT5, and the EMT pathway. Our results indicate that, unlike KRAS V12 , which promoted both, BRAF V600E enhances anchorage-independent growth but inhibits anchorage-dependent growth of HBEC3. This contrast may result from differences in activation signaling in the downstream pathways. Furthermore, HBEC3 cells appear to be inherently resistant to OIS, which may be partly due to the fact that p21 remains localized in the cytoplasm upon expression of BRAF V600E or KRAS V12 ., Competing Interests: Declaration of competing interest On behalf of all authors above, I certify that all Authors have seen and approved the manuscript being submitted. We warrant that the article is the Authors' original work. We warrant that the article has not received prior publication and is not under consideration for publication elsewhere. On behalf of all Co-Authors, the corresponding Author shall bear full responsibility for the submission. This research has not been submitted for publication nor has it been published in whole or in part elsewhere. We attest to the fact that all Authors listed on the title page have contributed significantly to the work, have read the manuscript, attest to the validity and legitimacy of the data and its interpretation, and agree to its submission to the Journal of Experimental Cell Research. All authors agree that author list is correct in its content and order and that no modification to the author list can be made without the formal approval of the Editor-in-Chief, and all authors accept that the Editor-in-Chief's decisions over acceptance or rejection or in the event of any breach of the Principles of Ethical Publishing in the Journal of Epidemiology and Global Health being discovered of retraction are final. No additional authors will be added post submission, unless editors receive agreement from all authors and detailed information is supplied as to why the author list should be amended., (Copyright © 2024. Published by Elsevier Inc.)

Fibrosarcoma is a challenging cancer originating from fibrous tissues, marked by aggressive growth and limited treatment options. The discovery of non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and small interfering RNAs (siRNAs), has opened new pathways for understanding and treating this malignancy. These ncRNAs play crucial roles in gene regulation, cellular processes, and the tumor microenvironment. This review aims to explore the impact of ncRNAs on fibrosarcoma's pathogenesis, progression, and resistance to treatment, focusing on their mechanistic roles and therapeutic potential. A comprehensive review of literature from databases like PubMed and Google Scholar was conducted, focusing on the dysregulation of ncRNAs in fibrosarcoma, their contribution to tumor growth, metastasis, drug resistance, and their cellular pathway interactions. NcRNAs significantly influence fibrosarcoma, affecting cell proliferation, apoptosis, invasion, and angiogenesis. Their function as oncogenes or tumor suppressors makes them promising biomarkers and therapeutic targets. Understanding their interaction with the tumor microenvironment is essential for developing more effective treatments for fibrosarcoma. Targeting ncRNAs emerges as a promising strategy for fibrosarcoma therapy, offering hope to overcome the shortcomings of existing treatments. Further investigation is needed to clarify specific ncRNAs' roles in fibrosarcoma and to develop ncRNA-based therapies, highlighting the significance of ncRNAs in improving patient outcomes in this challenging cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Cells of multicellular organisms generate heterogeneity in a controlled and transient fashion during embryogenesis, which can be reactivated in pathologies such as cancer. Although genomic heterogeneity is an important part of tumorigenesis, continuous generation of phenotypic heterogeneity is central for the adaptation of cancer cells to the challenges of tumorigenesis and response to therapy. Here I discuss the capacity of generating heterogeneity, hereafter called cell hetness, in cancer cells both as the activation of hetness oncogenes and inactivation of hetness tumor suppressor genes, which increase the generation of heterogeneity, ultimately producing an increase in adaptability and cell fitness. Transcriptomic high hetness states in therapy-tolerant cell states denote its importance in cancer resistance to therapy. The definition of the concept of hetness will allow the understanding of its origins, its control during embryogenesis, its loss of control in tumorigenesis and cancer therapeutics and its active targeting., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Recent work has shown that besides inducing fusion genes, structural variations (SVs) can also contribute to oncogenesis by disrupting the three-dimensional genome organization and dysregulating gene expression. At the chromatin-loop level, SVs can relocate enhancers or silencers from their original genomic loci to activate oncogenes or repress tumor suppressor genes. On a larger scale, different types of alterations in topologically associating domains (TADs) have been reported in cancer, such as TAD expansion, shuffling, and SV-induced neo-TADs. Furthermore, the transformation from normal cells to cancerous cells is usually coupled with active or repressive compartmental switches, and cancer-specific compartments have been proposed. This review discusses the sites, and the other latest advances in studying how SVs disrupt higher-order genome structure in cancer, which in turn leads to oncogene dysregulation. We also highlight the clinical implications of these changes and the challenges ahead in this field., Competing Interests: Declaration of competing interest F.Y. is a cofounder of Sariant Therapeutics, Inc. Other author has no conflict of interest claim., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The exosomal pathway is an essential mechanism that regulates the abnormal content of microRNAs (miRNAs) in hepatocellular carcinoma (HCC). The directional transport of miRNAs requires the assistance of RNA‑binding proteins (RBPs). The present study found that RBPs participate in the regulation of miRNA content through the exosomal pathway in HCC cells. First, differential protein expression profiles in the serum exosomes of patients with HCC and benign liver disease were detected using mass spectrometry. The results revealed that ribosomal protein L9 (RPL9) was highly expressed in serum exosomes of patients with HCC. In addition, the downregulation of RPL9 markedly suppressed the proliferation, migration and invasion of HCC cells and reduced the biological activity of HCC‑derived exosomes. In addition, using miRNA microarrays, the changes in exosomal miRNA profiles in HCC cells caused by RPL9 knockdown were examined. miR‑24‑3p and miR‑185‑5p were most differentially expressed, as verified by reverse transcription‑quantitative PCR. Additionally, using RNA immunoprecipitation, it was found that RPL9 was directly bound to the two miRNAs and immunofluorescence assays confirmed that RPL9 was able to carry miRNAs into recipient cells via exosomes. Overexpression of miR‑24‑3p in cells increased the accumulation of miR‑24‑3p in exosomes and simultaneously upregulated RPL9. Excessive expression of miR‑24‑3p in exosomes also increased their bioactivity. Exosome‑mediated miRNA regulation and transfer require the involvement of RBPs. RPL9 functions as an oncogene, can directly bind to specific miRNAs and can be co‑transported to receptor cells through exosomes, thereby exerting its biological functions. These findings provide a novel approach for modulating miRNA profiles in HCC.

Epigenetic silencing through methylation is one of the major mechanisms for downregulation of tumor suppressor miRNAs in various malignancies. The aim of this study was to identify novel tumor suppressor miRNAs which are silenced by DNA hypermethylation and investigate the role of at least one of these in oral squamous cell carcinoma (OSCC) pathogenesis. We treated cells from an OSCC cell line SCC131 with 5-Azacytidine, a DNA methyltransferase inhibitor, to reactivate tumor suppressor miRNA genes silenced/downregulated due to DNA methylation. At 5-day post-treatment, total RNA was isolated from the 5-Azacytidine and vehicle control-treated cells. The expression of 2,459 mature miRNAs was analysed between 5-Azacytidine and control-treated OSCC cells by the microRNA microarray analysis. Of the 50 miRNAs which were found to be upregulated following 5-Azacytidine treatment, we decided to work with miR-6741-3p in details for further analysis, as it showed a mean fold expression of >4.0. The results of qRT-PCR, Western blotting, and dual-luciferase reporter assay indicated that miR-6741-3p directly targets the oncogene SRSF3 at the translational level only. The tumor-suppressive role of miR-6741-3p was established by various in vitro assays and in vivo study in NU/J athymic nude mice. Our results revealed that miR-6741-3p plays a tumor-suppressive role in OSCC pathogenesis, in part, by directly regulating SRSF3. Based on our observations, we propose that miR-6741-3p may serve as a potential biological target in tumor diagnostics, prognostic evaluation, and treatment of OSCC and perhaps other malignancies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 More et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Recent studies have revealed that arginine is the most favorable target of amino acid alteration in most cancer types and it has been suggested that the high preference for arginine mutations reflects the critical roles of this amino acid in the function of proteins. High rates of mutations of arginine residues in cancer, however, might also be due to increased mutability of arginine codons of the CGN family as the CpG dinucleotides of these codons may be methylated. In the present work we have analyzed spectra of single base substitutions of cancer genes (oncogenes, tumor suppressor genes) and passenger genes in cancer tissues to assess the contributions of CpG hypermutability and selection to arginine mutations. Our studies have shown that arginines encoded by the CGN codon family display higher rates of mutation in both cancer genes and passenger genes than arginine codons AGA and AGG that are devoid of CpG dinucleotide, suggesting that the predominance of arginine mutations in cancer is primarily due to CpG hypermutability, rather than selection for arginine replacement. Nevertheless, our results also suggest that CGN codons for arginines may serve as Achilles' heels of cancer genes. CpG hypermutability of key arginines of proto-oncogenes, leading to high rates of recurrence of driver mutations, contributes significantly to carcinogenesis. Similarly, our results indicate that hypermutability of the CpG dinucleotide of CGA codons (converting them to TGA stop codons) contributes significantly to recurrent truncation and inactivation of tumor suppressor genes., (© 2024. The Author(s).)

Cancer is a disease that many multicellular organisms have faced for millions of years, and species have evolved various tumour suppression mechanisms to control oncogenesis. Although cancer occurs across the tree of life, cancer related mortality risks vary across mammalian orders, with Carnivorans particularly affected. Evolutionary theory predicts different selection pressures on genes associated with cancer progression and suppression, including oncogenes, tumour suppressor genes and immune genes. Therefore, we investigated the evolutionary history of cancer associated gene sequences across 384 mammalian taxa, to detect signatures of selection across categories of oncogenes (GRB2, FGL2 and CDC42), tumour suppressors (LITAF, Casp8 and BRCA2) and immune genes (IL2, CD274 and B2M). This approach allowed us to conduct a fine scale analysis of gene wide and site-specific signatures of selection across mammalian lineages under the lens of cancer susceptibility. Phylogenetic analyses revealed that for most species the evolution of cancer associated genes follows the species' evolution. The gene wide selection analyses revealed oncogenes being the most conserved, tumour suppressor and immune genes having similar amounts of episodic diversifying selection. Despite BRCA2's status as a key caretaker gene, episodic diversifying selection was detected across mammals. The site-specific selection analyses revealed that the two apoptosis associated domains of the Casp8 gene of bats (Chiroptera) are under opposing forces of selection (positive and negative respectively), highlighting the importance of site-specific selection analyses to understand the evolution of highly complex gene families. Our results highlighted the need to critically assess different types of selection pressure on cancer associated genes when investigating evolutionary adaptations to cancer across the tree of life. This study provides an extensive assessment of cancer associated genes in mammals with highly representative, and substantially large sample size for a comparative genomic analysis in the field and identifies various avenues for future research into the mechanisms of cancer resistance and susceptibility in mammals., (© 2024. The Author(s).)

Despite decades of basic and clinical research and trials of promising new therapies, cancer remains a major cause of morbidity and mortality due to the emergence of drug resistance to anticancer drugs. These resistance events have a very well-understood underlying mechanism, and their therapeutic relevance has long been recognized. Thus, drug resistance continues to be a major obstacle to providing cancer patients with the intended "cure". PAQR4 (Progestin and AdipoQ Receptor Family Member 4) gene is a recently identified novel protein-coding gene associated with various human cancers and acts through different signaling pathways. PAQR4 has a significant influence on multiple proteins that may regulate various gene expressions and may develop chemoresistance. This review discusses the roles of PAQR4 in tumor immunity, carcinogenesis, and chemoresistance. This paper is the first review, discussing PAQR4 in the pathogenesis of cancer. The review further explores the PAQR4 as a potential target in various malignancies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The loss of RAB25 expression-RAS superfamily of GTPase characteristic of numerous breast cancers-corresponds with H-RAS point mutations, particularly in triple-negative breast cancers (TNBC), a subtype associated with a poor prognosis. To address the poorly understood factors dictating the progression of TNBC tumors, we examine the cooperative effects that loss of RAB25 expression in human mammary epithelial cell (HMEC) lines with H-RAS mutations confers in tumorigenesis. HMECs were immortalized by transduction with LXSN CDK4 R24C, a mutant form of cyclin-dependent kinase, followed by transduction with hTERT, a catalytic subunit of the telomerase enzyme. We found that with the loss of RAB25 and overexpression of mutant H-RAS61L, immortal HMECs transformed toward anchorage-independent growth and acquired an increased ability to migrate. Furthermore, cells express low CD24, high CD44, and low claudin levels, indicating stem-like properties upon transformation. Besides, loss of RAB25 and overexpression of H-RAS61L resulted in increased expression of transcription factors Snail and Slug that drive these cells to lose E-cadherin and undergo epithelial-mesenchymal transition (EMT). This study confirms that loss of RAB25 and overexpression of mutant H-RAS can drive HMECs toward a mesenchymal stem-like state. Our findings reveal that RAB25 functions as a tumor suppressor gene, and loss of RAB25 could serve as a novel biomarker of the claudin-low type of TNBC., Competing Interests: The authors have no relevant conflicts of interest to disclose., (Copyright © 2024 Pooja Joshi et al.)

UBE2F, a neddylation E2, neddylates CUL5 to activate cullin-RING ligase-5, upon coupling with neddylation E3 RBX2/SAG. Whether and how UBE2F controls pancreatic tumorigenesis is previously unknown. Here, we showed that UBE2F is essential for the growth of human pancreatic cancer cells with KRAS mutation. In the mouse Kras G12D pancreatic ductal adenocarcinoma (PDAC) model, Ube2f deletion suppresses cerulein-induced pancreatitis, and progression of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Mechanistically, Ube2f deletion inactivates the Mapk-c-Myc signals via blocking ubiquitylation of Diras2, a substrate of CRL5 Asb11 E3 ligase. Biologically, DIRAS2 suppresses growth and survival of human pancreatic cancer cells harboring mutant KRAS, and Diras2 deletion largely rescues the phenotypes induced by Ube2f deletion. Collectively, Ube2f or Diras2 plays a tumor-promoting or tumor-suppressive role in the mouse Kras G12D PDAC model, respectively. The UBE2F-CRL5 ASB11 axis could serve as a valid target for pancreatic cancer, whereas the levels of UBE2F or DIRAS2 may serve as prognostic biomarkers for PDAC patients., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)