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Simple Summary: Epstein-Barr virus (EBV) latently infects over 90% of adults worldwide and is linked to several cancers such as Burkitt lymphoma. Amongst the few factors expressed by the EBV during latent infection are microRNAs (miRNAs) that can regulate both viral and cellular gene expression. In this study, we examined cellular targets of EBV miRNAs. Through bioinformatics and molecular analysis, we provide evidence of 52 new functional interactions for EBV miRNAs with protein-coding transcripts involved in B cell differentiation, cell cycle, and intracellular trafficking. Collectively, these data provide a resource for EBV miRNA targets and yield important insight into functional roles for these viral factors in B cell cancers. MicroRNAs are key post-transcriptional regulators of gene expression and their dysregulation is often linked to cancer. Epstein-Barr virus encodes 22 BamHI A Rightward Transcript (BART) miRNAs, which are expressed in nearly all EBV-associated cancers and implicated in viral pathogenesis. To investigate biological targets for BART miRNAs in B cell lymphomas, we performed a meta-analysis of publicly available Ago-CLIP datasets from EBV-positive Burkitt lymphomas (BLs), primary effusion lymphomas (PELs), AIDS-associated diffuse large B cell lymphomas (DLBCLs), and lymphoblastoid cell lines (LCLs). Our analysis focused on comparing targets of EBV BART miRNAs across the different types of transformed B cells. Using reporter assays, we then experimentally validated over 50 functional interactions between BART miRNAs and cellular protein-coding transcripts involved in activities such as B cell differentiation (PRDM1, IRF4, and MYC), cell cycle regulation (UHMK1, CDKN1A, MDM2, and NPAT), apoptosis (MCL1), signaling and intracellular trafficking (GAB1, SOS1, MAPK1, RAB11A, CAV1, and RANBP9), and tumor suppression (CCDC6). Moreover, ectopic BART miRNA expression in several EBV-negative BL cells induced transcriptional changes that may influence molecular signatures of EBV-associated BLs. Collectively, our findings reveal novel, functional interactions for BART miRNAs in lymphomas and provide insights into their roles in these B cell cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: In tumorigenesis, aberrant DNA methylation may be an earlier and stronger modifier of gene expression than mutations. Herein, 128 serous ovarian tumors were analyzed, including borderline ovarian tumors (BOTS) with (BOT.V600E) and without (BOT) the BRAF V600E mutation, low-grade (lg), and high-grade (hg) ovarian cancers (OvCa). The methylome of the samples was profiled with Infinium MethylationEPIC microarrays. Global, genome-wide hypomethylation positively correlated with the increasing aggressiveness of tumors, being the strongest in hgOvCa. Remarkably, the ten most significant differentially methylated regions (DMRs) in the genome, discriminating BOT from lgOvCa, encompassed the MHC region on chromosome 6. We also identified hundreds of DMRs potentially useful as predictive biomarkers in BOTS and hgOvCa. DMRs with the best discriminative capabilities overlapped the following genes: BAIAP3, IL34, WNT10A, NEU1, SLC44A4, and HMOX1, TCN2, PES1, RP1-56J10.8, ABR, NCAM1, RP11-629G13.1, AC006372.4, NPTXR in BOTS and hgOvCa, respectively. By identifying potential biomarkers, this study might improve ovarian tumor outcome. Background: Changes in DNA methylation patterns are a pivotal mechanism of carcinogenesis. In some tumors, aberrant methylation precedes genetic changes, while gene expression may be more frequently modified due to methylation alterations than by mutations. Methods: Herein, 128 serous ovarian tumors were analyzed, including borderline ovarian tumors (BOTS) with (BOT.V600E) and without (BOT) the BRAF V600E mutation, low-grade (lg), and high-grade (hg) ovarian cancers (OvCa). The methylome of the samples was profiled with Infinium MethylationEPIC microarrays. Results: The biggest number of differentially methylated (DM) CpGs and regions (DMRs) was found between lgOvCa and hgOvCa. By contrast, the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups and, in relation to BOT, their genome was strongly downmethylated. Remarkably, the ten most significant DMRs, discriminating BOT from lgOvCa, encompassed the MHC region on chromosome 6. We also identified hundreds of DMRs, being of potential use as predictive biomarkers in BOTS and hgOvCa. DMRs with the best discriminative capabilities overlapped the following genes: BAIAP3, IL34, WNT10A, NEU1, SLC44A4, and HMOX1, TCN2, PES1, RP1-56J10.8, ABR, NCAM1, RP11-629G13.1, AC006372.4, NPTXR in BOTS and hgOvCa, respectively. Conclusions: The global genome-wide hypomethylation positively correlates with the increasing aggressiveness of ovarian tumors. We also assume that the immune system may play a pivotal role in the transition from BOTS to lgOvCa. Given that the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups, when methylome is considered, such tumors might be placed in-between BOT and OvCa. [ABSTRACT FROM AUTHOR]

Simple Summary: Pathogenic variants in the PALB2 gene significantly increase the risk of developing breast, ovarian, and pancreatic cancers. However, the prevalence of these mutations in East Asian populations, particularly Koreans, has not been well studied. This research aims to estimate the prevalence of PALB2 variants in these populations by analyzing large-scale genomic databases. Understanding the frequency of PALB2 variants can help in identifying individuals at higher risk for these cancers and guide the development of targeted screening and prevention strategies. The findings from this study provide valuable reference data that can enhance genetic counseling and improve cancer risk management in East Asian populations, ultimately contributing to better health outcomes in these communities. PALB2 is a tumor suppressor gene. Heterozygous germline pathogenic variants of PALB2 significantly increase the lifetime risk of breast cancer and moderately increase the risk of ovarian and pancreatic cancers. This study analyzed the estimated prevalence of PALB2 variants globally, focusing on East Asian and Korean populations, where limited data were previously available. We examined 125,748 exomes from the Genome Aggregation Database (gnomAD), including 9197 East Asians, and additional data from 5305 individuals in the Korean Variant Archive and 1722 in the Korean Reference Genome Database. All PALB2 variants were interpreted according to guidelines from the American College of Medical Genetics and Genomics and the Clinical Genome Resource. The global prevalence of PALB2 variants was 0.18%, with the highest prevalence in Finnish populations (0.41%) and the lowest in Ashkenazi Jewish populations (0.04%). East Asians had a prevalence of 0.09%. By combining data from Korean genome databases and gnomAD totaling 8936 individuals, the overall prevalence of PALB2 variants in the Korean population was determined to be 0.13%. This study is the first comprehensive investigation of PALB2 variant prevalence in East Asians and Koreans using gnomAD and Korean genome databases. These findings provide essential reference data for future research and highlight the importance of region-specific genetic studies that will inform genetic counseling and hereditary cancer risk management. [ABSTRACT FROM AUTHOR]

Simple Summary: p53 mutations are prevalent across a variety of human cancers and are regarded as a major obstacle in cancer therapy. These mutations can confer resistance to apoptosis and cell cycle arrest, contributing to multidrug resistance in tumors. Recent studies have uncovered important immunomodulatory functions of p53, but these functions are still underappreciated compared to its other well-known roles. This review aims to summarize the latest literature on immune evasion in p53-mutant tumors and explore the potential of targeting p53 to enhance anti-tumor immunity. Mutation in p53 is the most frequent event in cancer development and a leading cause of cancer therapy resistance due to evasion of the apoptosis cascade. Beyond chemotherapies and radiation therapies, growing evidence indicates that p53-mutant tumors are resistant to a broad range of immune-based therapies, such as immune checkpoint inhibitors, chimeric antigen receptor (CAR) T, and hematopoietic stem cell transplantation (HSCT). This highlights the role of p53 mutations in driving immune evasion of tumor cells. In this review, we first summarize recent studies revealing mechanisms by which p53-mutant tumors evade immune surveillance from T cells, natural killer (NK) cells, and macrophages. We then review how these mutant tumor cells reshape the tumor microenvironment (TME), modulating bystander cells such as macrophages, neutrophils, and regulatory T (Treg) cells to foster immunosuppression. Additionally, we review clinical observations indicative of immune evasion associated with p53 loss or mutations. Finally, we discuss therapeutic strategies to enhance immune response in p53 wild-type (WT) or mutant tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Long non-coding RNAs (lncRNAs) exert their influence on transcriptional regulation and genome organization by associating with transcription factors, chromatin, RNAs and various proteins. In particular, studies have established a widespread involvement of cross-talks between lncRNAs and nuclear receptors (NRs) in pathology of diseases such as cancer. A deeper understanding of these cross-talks will not only help gain greater insights into cancer physiology, but also guide the development for newer and improved therapeutic strategies aimed at cancer. Long non-coding RNAs (lncRNAs) play key roles in various epigenetic and post-transcriptional events in the cell, thereby significantly influencing cellular processes including gene expression, development and diseases such as cancer. Nuclear receptors (NRs) are a family of ligand-regulated transcription factors that typically regulate transcription of genes involved in a broad spectrum of cellular processes, immune responses and in many diseases including cancer. Owing to their many overlapping roles as modulators of gene expression, the paths traversed by lncRNA and NR-mediated signaling often cross each other; these lncRNA-NR cross-talks are being increasingly recognized as important players in many cellular processes and diseases such as cancer. Here, we review the individual roles of lncRNAs and NRs, especially growth factor modulated receptors such as androgen receptors (ARs), in various types of cancers and how the cross-talks between lncRNAs and NRs are involved in cancer progression and metastasis. We discuss the challenges involved in characterizing lncRNA-NR associations and how to overcome them. Furthering our understanding of the mechanisms of lncRNA-NR associations is crucial to realizing their potential as prognostic features, diagnostic biomarkers and therapeutic targets in cancer biology. [ABSTRACT FROM AUTHOR]

Simple Summary: Advances in next-generation sequencing have initiated a paradigm shift in cancer treatment, transitioning from traditional, organ-specific protocols to precision medicine. However, interpreting the clinical implications of an ever-growing catalog of genetic mutations remains challenging. This review explores the direct connections between genetic alterations and targeted therapies, addressing key genetic factors, the challenges in clinical application and research, and strategies for maximizing the therapeutic impact of these treatments. Advances in next-generation sequencing (NGS) have catalyzed a paradigm shift in cancer treatment, steering the focus from conventional, organ-specific protocols to precision medicine. Emerging targeted therapies offer a cutting-edge approach to cancer treatment, while companion diagnostics play an essential role in aligning therapeutic choices with specific molecular changes identified through NGS. Despite these advances, interpreting the clinical implications of a rapidly expanding catalog of genetic mutations remains a challenge. The selection of therapies in the presence of multiple mutations requires careful clinical judgment, supported by quality-centric genomic testing that emphasizes actionable mutations. Molecular tumor boards can play an increasing role in assimilating genomic data into clinical trials, thereby refining personalized treatment approaches and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Individualized medicine means understanding how each tumor is different from normal cells and how each tumor is different from other tumors, including profiling mutations, non-mutational epigenetic changes, and differences in gene expression. This allows the discovery of key processes each tumor absolutely depends on for survival and growth, which are intrinsic weaknesses. This profiling means selecting treatments to specifically target each tumor's survival-dependent pathways, killing them. Tip60 is a master controller of processes that maintain genome stability and signaling regulating gene expression. While disrupted in many cancers, Tip60 is essential for cell survival, and inhibiting Tip60 kills tumors. While we understand some key aspects of the molecular roles Tip60 plays, much more remains to be discovered. A more complete understanding of the diverse roles and functions of Tip60 in cancer, and how targeting Tip60 kills cancer cells, will lead to better treatments for patients and increased survival. Precision (individualized) medicine relies on the molecular profiling of tumors' dysregulated characteristics (genomic, epigenetic, transcriptomic) to identify the reliance on key pathways (including genome stability and epigenetic gene regulation) for viability or growth, and then utilises targeted therapeutics to disrupt these survival-dependent pathways. Non-mutational epigenetic changes alter cells' transcriptional profile and are a key feature found in many tumors. In contrast to genetic mutations, epigenetic changes are reversable, and restoring a normal epigenetic profile can inhibit tumor growth and progression. Lysine acetyltransferases (KATs or HATs) protect genome stability and integrity, and Tip60 is an essential acetyltransferase due to its roles as an epigenetic and transcriptional regulator, and as master regulator of the DNA double-strand break response. Tip60 is commonly downregulated and mislocalized in many cancers, and the roles that mislocalized Tip60 plays in cancer are not well understood. Here we categorize and discuss Tip60-regulated genes, evaluate Tip60-interacting proteins based on cellular localization, and explore the therapeutic potential of Tip60-targeting compounds as epigenetic inhibitors. Understanding the multiple roles Tip60 plays in tumorigenesis will improve our understanding of tumor progression and will inform therapeutic options, including informing potential combinatorial regimes with current chemotherapeutics, leading to improvements in patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer arises through the accumulation of somatic mutations in key biological pathways. This paper aims to develop a probabilistic approach to delineate the temporal order of mutations during cancer development based on mutation profile data from a cohort of patients. A unique feature of our method is that it incorporates intra-tumor heterogeneity (ITH) information, which refers to the heterogeneous cell populations within a tumor and characterizes the evolutionary history of the tumor. We showed that by integrating ITH, pathways, and functional annotation information, our method yielded high accuracy in inferring the temporal order of pathway mutations during carcinogenesis. The development of cancer involves the accumulation of somatic mutations in several essential biological pathways. Delineating the temporal order of pathway mutations during tumorigenesis is crucial for comprehending the biological mechanisms underlying cancer development and identifying potential targets for therapeutic intervention. Several computational and statistical methods have been introduced for estimating the order of somatic mutations based on mutation profile data from a cohort of patients. However, one major issue of current methods is that they do not take into account intra-tumor heterogeneity (ITH), which limits their ability to accurately discern the order of pathway mutations. To address this problem, we propose PATOPAI, a probabilistic approach to estimate the temporal order of mutations at the pathway level by incorporating ITH information as well as pathway and functional annotation information of mutations. PATOPAI uses a maximum likelihood approach to estimate the probability of pathway mutational events occurring in a specific sequence, wherein it focuses on the orders that are consistent with the phylogenetic structure of the tumors. Applications to whole exome sequencing data from The Cancer Genome Atlas (TCGA) illustrate our method's ability to recover the temporal order of pathway mutations in several cancer types. [ABSTRACT FROM AUTHOR]

Simple Summary: This review explores the challenges of drug resistance in cancer treatment and discusses innovative strategies to overcome them. Researchers aim to understand how cancer cells develop resistance to therapies and explore new ways to improve treatment outcomes. They investigate advanced genomic technologies, immunotherapies like CAR-T cells, and targeted therapies that specifically attack cancer cells. By identifying these mechanisms and developing novel approaches, this research aims to enhance the effectiveness of cancer treatments and improve patient survival rates. Insights gained could lead to significant advancements in how we combat drug resistance in cancer, offering hope for better outcomes in the future. The rise of drug resistance in cancer cells presents a formidable challenge in modern oncology, necessitating the exploration of innovative therapeutic strategies. This review investigates the latest advancements in overcoming drug resistance mechanisms employed by cancer cells, focusing on emerging therapeutic modalities. The intricate molecular insights into drug resistance, including genetic mutations, efflux pumps, altered signaling pathways, and microenvironmental influences, are discussed. Furthermore, the promising avenues offered by targeted therapies, combination treatments, immunotherapies, and precision medicine approaches are highlighted. Specifically, the synergistic effects of combining traditional cytotoxic agents with molecularly targeted inhibitors to circumvent resistance pathways are examined. Additionally, the evolving landscape of immunotherapeutic interventions, including immune checkpoint inhibitors and adoptive cell therapies, is explored in terms of bolstering anti-tumor immune responses and overcoming immune evasion mechanisms. Moreover, the significance of biomarker-driven strategies for predicting and monitoring treatment responses is underscored, thereby optimizing therapeutic outcomes. For insights into the future direction of cancer treatment paradigms, the current review focused on prevailing drug resistance challenges and improving patient outcomes, through an integrative analysis of these emerging therapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: The atavistic theory of cancer suggests that cancer development proceeds through cells reverting to ancient survival mechanisms. The Serial Atavism Model (SAM) expands on this, proposing that cancer progresses through multiple stages of reversion to earlier evolutionary forms with cells losing modern traits and regaining primitive ones. One example is the Warburg effect, where cancer cells prefer a type of energy production used by ancient cells before Earth's atmosphere had oxygen. However, this review argues that cancer metabolism is too complex to be fully explained by this theory. Cancer cells exhibit a wide range of metabolic behaviors that do not fit neatly into a pattern of reverting to an ancient state, indicating that the SAM may not provide a complete understanding of cancer. The atavistic theory of cancer posits that cancer emerges and progresses through the reversion of cellular phenotypes to more ancestral types with genomic and epigenetic changes deactivating recently evolved genetic modules and activating ancient survival mechanisms. This theory aims at explaining the known cancer hallmarks and the paradox of cancer's predictable progression despite the randomness of genetic mutations. Lineweaver and colleagues recently proposed the Serial Atavism Model (SAM), an enhanced version of the atavistic theory, which suggests that cancer progression involves multiple atavistic reversions where cells regress through evolutionary stages, losing recently evolved traits first and reactivating primitive ones later. The Warburg effect, where cancer cells upregulate glycolysis and lactate production in the presence of oxygen instead of using oxidative phosphorylation, is one of the key feature of the SAM. It is associated with the metabolism of ancient cells living on Earth before the oxygenation of the atmosphere. This review addresses the question of whether cancer metabolism can be considered as an atavistic reversion. By analyzing several known characteristics of cancer metabolism, we reach the conclusion that this version of the atavistic theory does not provide an adequate conceptual frame for cancer research. Cancer metabolism spans a whole spectrum of metabolic states which cannot be fully explained by a sequential reversion to an ancient state. Moreover, we interrogate the nature of cancer metabolism and discuss its characteristics within the framework of the SAM. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer remains a leading cause of cancer-related mortality globally, requiring new diagnostic and therapeutic approaches. This research arises from the need to improve diagnostic accuracy and treatment effectiveness for patients with non-small cell lung cancer. The authors aim to systematically evaluate the potential of emerging biomarkers, including circulating tumor DNA, microRNAs and mutational load of blood tumors and their relationship with different treatments. The findings of this study could have a significant impact on the research community by providing a basis for integrating these biomarkers into clinical practice, thereby improving personalized treatment strategies and patient outcomes in non-small cell lung cancer. Non-small-cell lung cancer (NSCLC) comprises approximately 85% of all lung cancer cases, often diagnosed at advanced stages, which diminishes the effective treatment options and survival rates. This systematic review assesses the utility of emerging biomarkers—circulating tumor DNA (ctDNA), microRNAs (miRNAs), and the blood tumor mutational burden (bTMB)—enhanced by next-generation sequencing (NGS) to improve the diagnostic accuracy, prognostic evaluation, and treatment strategies in NSCLC. Analyzing data from 37 studies involving 10,332 patients from 2020 to 2024, the review highlights how biomarkers like ctDNA and PD-L1 expression critically inform the selection of personalized therapies, particularly beneficial in the advanced stages of NSCLC. These biomarkers are critical for prognostic assessments and in dynamically adapting treatment plans, where high PD-L1 expression and specific genetic mutations (e.g., ALK fusions, EGFR mutations) significantly guide the use of targeted therapies and immunotherapies. The findings recommend integrating these biomarkers into standardized clinical pathways to maximize their potential in enhancing the treatment precision, ultimately fostering significant advancements in oncology and improving patient outcomes and quality of life. This review substantiates the prognostic and predictive value of these biomarkers and emphasizes the need for ongoing innovation in biomarker research. [ABSTRACT FROM AUTHOR]

Simple Summary: Ribosomes are essential for the life of all cells. A reduction in the production of ribosomes always leads to a delay in cell cycle progression and to impaired growth, at least at the cellular level. We define ribosomopathies as a number of inherited monogenic diseases characterized by the partial loss of ribosomal factors. Not surprisingly, ribosomopathies show multi-organ signs and reduced cellular fitness. Strikingly, cancer is also a common comorbidity of ribosomopathies. The reconciliation of reduced growth with increased cancer risk poses an interpretative challenge. However, if we consider cancer as a systemic disease in which tumor cells thrive in a favorable microenvironment, we may find the right answers. Ribosomopathies are defined as inherited diseases in which ribosomal factors are mutated. In general, they present multiorgan symptoms. In spite of the fact that in cellular models, ribosomal insufficiency leads to a reduced rate of oncogenic transformation, patients affected by ribosomopathies present a paradoxical increase in cancer incidence. Several hypotheses that explain this paradox have been formulated, mostly on the assumption that altered ribosomes in a stem cell induce compensatory changes that lead to a cancer cell. For instance, the lack of a specific ribosomal protein can lead to the generation of an abnormal ribosome, an oncoribosome, that itself leads to altered translation and increased tumorigenesis. Alternatively, the presence of ribosomal stress may induce compensatory proliferation that in turns selects the loss of tumor suppressors such as p53. However, modern views on cancer have shifted the focus from the cancer cell to the tumor microenvironment. In particular, it is evident that human lymphocytes are able to eliminate mutant cells and contribute to the maintenance of cancer-free tissues. Indeed, many tumors develop in conditions of reduced immune surveillance. In this review, we summarize the current evidence and attempt to explain cancer and ribosomopathies from the perspective of the microenvironment. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian serous borderline tumor (SBT) is a known precursor of low-grade serous carcinoma, and it has been reported that about 50% of SBTs are BRAF-mutated and that these tumors have a better prognosis. Therefore, early identification of the mutation is important for accurate treatment and follow-up of patients with SBT. It has been shown that eosinophilic cells (ECs) can be a histologic sign of a BRAF mutation. Therefore, the aim of our retrospective study was to evaluate the interobserver reproducibility for these cells. A BRAFV600E mutation was found in 45% of cases. The interobserver reproducibility in the assessment of ECs was substantial. The sensitivity and specificity for predicting the mutation were 79% and 91%, respectively, so ECs in ovarian SBTs can be used for initial screening of the BRAFV600E mutation to stratify patients and establish a prognosis. According to recent reports, ovarian serous borderline tumor (SBT) harboring the BRAF V600E mutation is associated with a lower risk of progression to low-grade serous carcinoma. Preliminary observations suggest that there may be an association between eosinophilic cells (ECs) and the above-mentioned mutation, so this study aimed to evaluate interobserver reproducibility for assessing ECs. Forty-two samples of SBTs were analyzed for ECs with abundant eosinophilic cytoplasm. Immunohistochemical staining and genetic pro-filing were performed in all cases to verify the BRAF V600E mutation. A BRAF V600E mutation was found in 19 of 42 (45%) cases. Inter-observer reproducibility in the assessment of ECs was substantial (κ = 0.7). The sensitivity and specificity for predicting the mutation were 79% and 91%, respectively. Patients with BRAF-mutated SBTs were significantly younger than those without mutation (p = 0.005). SBTs with BRAF mutation were less likely to be accompanied by non-invasive implants than wild-type SBT: 12% (2/17) versus 33% (6/18). Seven cases were excluded due to incomplete cytoreductive surgery. Nevertheless, Fisher's exact test showed no significant differences between the two groups (p = 0.228). Overall, this study strengthens the idea that ECs in ovarian SBTs may represent a mutation with prognostic significance, which can serve as a primary screening test for BRAF V600E mutation in this pathologic entity. [ABSTRACT FROM AUTHOR]

Simple Summary: The purpose of this study is to emphasize the importance of genetic testing for healthy individuals with a strong family history of hereditary malignancies. A total of 103 healthy subjects with at least two relatives with cancer were enrolled. By NGS analysis of 27 genes, 5% were found to carry a pathogenic variant in a hereditary cancer susceptibility gene. In the era of personalized medicine, genetic testing of healthy subjects in the absence of a living affected collateral is crucially important for early diagnosis, clinical surveillance and surgical choice. Hereditary cancer syndromes caused by germline mutations account for 5–10% of all cancers. The finding of a genetic mutation could have far-reaching consequences for pharmaceutical therapy, personalized prevention strategies, and cascade testing. According to the National Comprehensive Cancer Network's (NCCN) and the Italian Association of Medical Oncology (AIOM) guidelines, unaffected family members should be tested only if the affected one is unavailable. This article explores whether germline genetic testing may be offered to high-risk families for hereditary cancer even if a living affected relative is missing. A retrospective study was carried out on 103 healthy subjects tested from 2017 to 2023. We enrolled all subjects with at least two first- or second-degree relatives affected by breast, ovarian, pancreatic, gastric, prostate, or colorectal cancer. All subjects were tested by Next Generation Sequencing (NGS) multi-gene panel of 27 cancer-associated genes. In the study population, 5 (about 5%) pathogenic/likely pathogenic variants (PVs/LPVs) were found, while 40 (42%) had a Variant of Uncertain Significance (VUS). This study highlights the importance of genetic testing for individuals with a strong family history of hereditary malignancies. This approach would allow women who tested positive to receive tailored treatment and prevention strategies based on their personal mutation status. [ABSTRACT FROM AUTHOR]

Simple Summary: Transfer learning is a technique utilizing a pre-trained model's knowledge in a new task. This helps reduce the sample size and time needed for training. These characteristics of transfer learning make it a perfect candidate to use in genetic research. The aim of our study is to review the current uses of transfer learning in genetic research. Here, we overview the use of transfer learning in the mutation detection of different cancers (lung, gastrointestinal, breast, glioma), gene expression, genetic syndrome detection (Down's syndrome, Noonan syndrome, Williams–Beuren syndrome) based on the phenotype of patients, and identifying possible genotype–phenotype association. Using transfer learning in model development increases the final performance of the model compared with models trained from scratch. Artificial intelligence (AI), encompassing machine learning (ML) and deep learning (DL), has revolutionized medical research, facilitating advancements in drug discovery and cancer diagnosis. ML identifies patterns in data, while DL employs neural networks for intricate processing. Predictive modeling challenges, such as data labeling, are addressed by transfer learning (TL), leveraging pre-existing models for faster training. TL shows potential in genetic research, improving tasks like gene expression analysis, mutation detection, genetic syndrome recognition, and genotype–phenotype association. This review explores the role of TL in overcoming challenges in mutation detection, genetic syndrome detection, gene expression, or phenotype–genotype association. TL has shown effectiveness in various aspects of genetic research. TL enhances the accuracy and efficiency of mutation detection, aiding in the identification of genetic abnormalities. TL can improve the diagnostic accuracy of syndrome-related genetic patterns. Moreover, TL plays a crucial role in gene expression analysis in order to accurately predict gene expression levels and their interactions. Additionally, TL enhances phenotype–genotype association studies by leveraging pre-trained models. In conclusion, TL enhances AI efficiency by improving mutation prediction, gene expression analysis, and genetic syndrome detection. Future studies should focus on increasing domain similarities, expanding databases, and incorporating clinical data for better predictions. [ABSTRACT FROM AUTHOR]

Simple Summary: Increasing demand for genetic testing and counseling among families with hereditary cancers has drawn attention to the genetic skills and knowledge of healthcare professionals (HCPs). However, many HCPs face challenges regarding confidence in communicating genetic risk to their patients and accessing genetic training programs. Developing genomic educational strategies and standardizing the curriculum for HCPs is critical to improving genetic care. This systematic review identified the learning needs of HCPs and compared them across professions, along with their perspectives on essential information for families affected by hereditary cancer. While HCPs recognized the importance of providing a wide range of information to families affected by hereditary cancer and emphasized enhancing practical counseling skills, their learning needs varied by profession. Our findings have implications for developing training programs for HCPs, underscoring the importance of developing targeted training programs and resources aligned with their specific profession. Background: The increased demand for genetic testing and counseling necessitates healthcare professionals (HCPs) to improve their genetic competency through training programs. This systematic review identified HCPs' learning needs and their perspectives on essential information for families with hereditary cancer. Methods: This review covered studies published from 2013 to 2024 across five databases. Data were analyzed using a content analysis. Results: Thirteen studies involving 332 HCPs were analyzed. Most studies focused on the learning needs of physicians caring for families affected by Hereditary Breast and Ovarian Cancer in North America and Europe. HCPs required training emphasizing practical counseling skills over the basics of genetics. Learning needs varied by profession: physicians needed training in assessing cancer risk and supporting decision-making in risk management; nurses required information on resources and the genetic care system; genetic counselors sought guidance on family communication and planning. Essential information identified for families included risk-reducing strategies, personalized cancer risk assessment, family implications, psychological issues, (cascade) genetic testing, and social concerns. Conclusions: The findings have implications for the development of training programs for HCPs, emphasizing the need for tailored training based on professions. Future research should explore the needs of HCPs caring for families with diverse hereditary cancers and cultural backgrounds. [ABSTRACT FROM AUTHOR]

Simple Summary: In this literature review, we explore the milestone events from the discovery of BRAF mutations to present-day clinical intervention strategies. We delve into the role of the BRAF gene in various cancer types such as melanoma, non-small-cell lung cancer, colorectal cancer, and thyroid cancer. Additionally, we reviewed clinical trials that led to the FDA approval of therapeutic regimens as monotherapy or, more recently, as combinatorial approaches to treat cancer types harboring BRAF hotspot mutations. Since their discovery in 2002, BRAF mutations have been identified as clear drivers of oncogenesis in several cancer types. Currently, their incidence rate is nearly 7% of all solid tumors with BRAF V600E constituting approximately 90% of these diagnoses. In melanoma, thyroid cancer, and histiocytic neoplasms, BRAF hotspot mutations are found at a rate of about 50%, while in lung and colorectal cancers they range from 3% to 10% of reported cases. Though present in other malignancies such as breast and ovarian cancers, they constitute a small portion of diagnoses (<1%). Given their frequency along with advancements in screening technologies, various methods are used for the detection of BRAF-mutant cancers. Among these are targeted next-generation sequencing (NGS) on tumor tissue or circulating tumor DNA (ctDNA) and immunohistochemistry (IHC)-based assays. With advancements in detection technologies, several approaches to the treatment of BRAF-mutant cancers have been taken. In this review, we retrace the milestones that led to the clinical development of targeted therapies currently available for these tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: In cancer, hotspots are those mutations emerging recurrently in tumors. Hotspots are highly likely to be functional because tumors tend to keep those mutations that provide physiological advantages. However, few hotspots have been studied, mainly because it is costly and time-consuming. Here, we systematically test more than 1400 hotspots for their association with patient survival and provide the results, including more than 300 significant associations, accessible on the web. This would help prioritize hotspots that are likely functional and affect patient survival, accelerating our knowledge of cancer and improving patient care. Background: Cofactors, biomarkers, and the mutational status of genes such as TP53, EGFR, IDH1/2, or PIK3CA have been used for patient stratification. However, many genes exhibit recurrent mutational positions known as hotspots, specifically linked to varying degrees of survival outcomes. Nevertheless, few hotspots have been analyzed (e.g., TP53 and EGFR). Thus, many other genes and hotspots remain unexplored. Methods: We systematically screened over 1400 hotspots across 33 TCGA cancer types. We compared the patients carrying a hotspot against (i) all cases, (ii) gene-mutated cases, (iii) other mutated hotspots, or (iv) specific hotspots. Due to the limited number of samples in hotspots and the inherent group imbalance, besides Cox models and the log-rank test, we employed VALORATE to estimate their association with survival precisely. Results: We screened 1469 hotspots in 6451 comparisons, where 314 were associated with survival. Many are discussed and linked to the current literature. Our findings demonstrate associations between known hotspots and survival while also revealing more potential hotspots. To enhance accessibility and promote further investigation, all the Kaplan–Meier curves, the log-rank tests, Cox statistics, and VALORATE-estimated null distributions are accessible on our website. Conclusions: Our analysis revealed both known and putatively novel hotspots associated with survival, which can be used as biomarkers. Our web resource is a valuable tool for cancer research. [ABSTRACT FROM AUTHOR]

Simple Summary: As a tumor grows, DNA fragments from cancer cells shed into the bloodstream. Known as circulating tumor DNA (ctDNA), these fragments can be used to inform on cancer diagnosis, treatment, and prognosis. However, despite the potential for these uninavasive liquid biopsies to revolutionize cancer monitoring and treatment, ctDNA can show poor genetic concordance between blood and the main tumor tissue, hampering its general clinical utility. For liquid biopsy technologies and ctDNA analyses to transform cancer care, from early screening and diagnosis through treatment and long-term follow-up, we need to better understand how to interpret the genetic diversity measured in the blood and how it can be used to describe the true composition of the tumor tissue. In this work we study the evolutionary processes that can lead to genetic discordance between a blood sample and the main tumor tissue and specifically, how tumor spatial heterogeneity shapes these genetic differences. We find that spatial heterogeneity in apoptosis and cellular shedding across different regions of a tumor can significantly bias the mutational composition of ctDNA and emphasize important directions for further theoretical and clinical investigation into the effect of the microenvironment on ctDNA origin and quantification. Circulating tumor DNA (ctDNA) monitoring, while sufficiently advanced to reflect tumor evolution in real time and inform cancer diagnosis, treatment, and prognosis, mainly relies on DNA that originates from cell death via apoptosis or necrosis. In solid tumors, chemotherapy and immune infiltration can induce spatially variable rates of cell death, with the potential to bias and distort the clonal composition of ctDNA. Using a stochastic evolutionary model of boundary-driven growth, we study how elevated cell death on the edge of a tumor can simultaneously impact driver mutation accumulation and the representation of tumor clones and mutation detectability in ctDNA. We describe conditions in which invasive clones are over-represented in ctDNA, clonal diversity can appear elevated in the blood, and spatial bias in shedding can inflate subclonal variant allele frequencies (VAFs). Additionally, we find that tumors that are mostly quiescent can display similar biases but are far less detectable, and the extent of perceptible spatial bias strongly depends on sequence detection limits. Overall, we show that spatially structured shedding might cause liquid biopsies to provide highly biased profiles of tumor state. While this may enable more sensitive detection of expanding clones, it could also increase the risk of targeting a subclonal variant for treatment. Our results indicate that the effects and clinical consequences of spatially variable cell death on ctDNA composition present an important area for future work. [ABSTRACT FROM AUTHOR]

Simple Summary: BRAF mutations are classified into four categories based on molecular characteristics, but only Class 1 BRAF V600 have effective targeted treatment strategies. With increasing access to next-generation sequencing, oncologists are more frequently uncovering non-V600 BRAF mutations, where there remains a scarcity of effective therapies. Responsiveness to MAPK pathway inhibitors differs according to the BRAF mutation class and primary tumor type. For this reason, we sought to determine whether key demographic, genomic, and transcriptomic differences existed between classes. This cross-sectional study analyzes the largest dataset of BRAF-mutated cancers to date. Our findings propose insights to optimize clinical trial design and patient selection in the pursuit of developing effective treatment strategies for patients whose tumors harbor non-V600 BRAF mutations. This study also offers insights into the potential of targeting alternative pathways in addition to the MAPK pathway as part of combinatorial treatment strategies. Background: BRAF mutations are classified into four molecularly distinct groups, and Class 1 (V600) mutant tumors are treated with targeted therapies. Effective treatment has not been established for Class 2/3 or BRAF Fusions. We investigated whether BRAF mutation class differed according to clinical, genomic, and transcriptomic variables in cancer patients. Methods: Using the AACR GENIE (v.12) cancer database, the distribution of BRAF mutation class in adult cancer patients was analyzed according to sex, age, primary race, and tumor type. Genomic alteration data and transcriptomic analysis was performed using The Cancer Genome Atlas. Results: BRAF mutations were identified in 9515 (6.2%) samples among 153,834, with melanoma (31%), CRC (20.7%), and NSCLC (13.9%) being the most frequent cancer types. Class 1 harbored co-mutations outside of the MAPK pathway (TERT, RFN43) vs. Class 2/3 mutations (RAS, NF1). Across all tumor types, Class 2/3 were enriched for alterations in genes involved in UV response and WNT/β-catenin. Pathway analysis revealed enrichment of WNT/β-catenin and Hedgehog signaling in non-V600 mutated CRC. Males had a higher proportion of Class 3 mutations vs. females (17.4% vs. 12.3% q = 0.003). Non-V600 mutations were generally more common in older patients (aged 60+) vs. younger (38% vs. 15% p < 0.0001), except in CRC (15% vs. 30% q = 0.0001). Black race was associated with non-V600 BRAF alterations (OR: 1.58; p < 0.0001). Conclusions: Class 2/3 BRAFs are more present in Black male patients with co-mutations outside of the MAPK pathway, likely requiring additional oncogenic input for tumorigenesis. Improving access to NGS and trial enrollment will help the development of targeted therapies for non-V600 BRAF mutations. [ABSTRACT FROM AUTHOR]

Simple Summary: UGT enzymes metabolize and detoxify numerous small molecules that are important in cancer, including carcinogens, endogenous growth regulators, and anticancer drugs. Alternatively spliced UGT transcripts can encode truncated proteins that inhibit canonical UGTs, thus reducing detoxification activity. We assessed the expression of specific variant transcripts, designated as UGT1A_v2 and _v3, in six different cancers using RNA-seq datasets with large cohorts of paired normal and tumor tissues. Our results show high interindividual variation in v2 and v3 transcript abundance, as well as tissue- and tumor-specific expression patterns. These findings suggest that the variants have tissue-specific impacts on glucuronidation and may have a more significant role in tumors than in normal tissues. The high interindividual variability is likely relevant to differing personalized drug metabolisms through the UGT conjugation pathway. Finally, our discovery of novel UGT1A variant transcripts further highlights the diversity of the UGT1A transcriptome and proteome. The UGT1A locus generates over 60 different alternatively spliced transcripts and 30 circular RNAs. To date, v2 and v3 transcripts are the only variant UGT1A transcripts that have been functionally characterized. Both v2 and v3 transcripts encode the same inactive variant UGT1A proteins (i2s) that can negatively regulate glucuronidation activity and influence cancer cell metabolism. However, the abundance and interindividual variability in the expression of v2 and v3 transcripts in human tissues and their potential deregulation in cancers have not been comprehensively assessed. To address this knowledge gap, we quantified the expression levels of v1, v2, and v3 transcripts using RNA-seq datasets with large cohorts of normal tissues and paired normal and tumor tissues from patients with six different cancer types (liver, kidney, colon, stomach, esophagus, and bladder cancer). We found that v2 and v3 abundance varied significantly between different tissue types, and that interindividual variation was also high within the same tissue type. Moreover, the ratio of v2 to v3 variants varied between tissues, implying their differential regulation. Our results showed higher v2 abundance in gastrointestinal tissues than liver and kidney tissues, suggesting a more significant negative regulation of glucuronidation by i2 proteins in gastrointestinal tissues than in liver and kidney tissues. We further showed differential deregulation of wildtype (v1) and variant transcripts (v2, v3) in cancers that generally increased the v2/v1 and/or v3/v1 expression ratios in tumors compared to normal tissues, indicating a more significant role of the variants in tumors. Finally, we report ten novel UGT1A transcripts with novel 3′ terminal exons, most of which encode variant proteins with a similar structure to UGT1A_i2 proteins. These findings further emphasize the diversity of the UGT1A transcriptome and proteome. [ABSTRACT FROM AUTHOR]

Simple Summary: This study examined the efficacy and diagnostic yield of founder variant testing as an initial screening method for individuals with a personal or family history of cancer. The results indicate that this approach is ineffective and has a limited ability to detect significant germline variants. Given these findings, we raise doubts about the benefits of employing such testing and suggest a transition from a two-step approach to expansive genetic testing. Founder pathogenic variants (PVs) are prevalent in Israel. This study investigated the current practice of offering cancer patients two-step genetic testing, starting with targeted testing for recurring founder PVs, followed, if negative, by next-generation sequencing. A total of 2128 subjects with cancer or a positive family history underwent oncogenetic testing with a panel of 51 recurring PVs at a tertiary medical center in March 2020–January 2023. Those with a known familial PV (n = 370) were excluded from the analysis. Among the remainder, 128/1758 (7%) were heterozygous for at least one variant, and 44 (34%) carried a PV of medium-high penetrance (MHPV). Cancer was diagnosed in 1519/1758 patients (86%). The diagnostic yield of founder MHPV testing was 2% in cancer patients and 4% in healthy individuals with a positive family history. It was higher in Ashkenazi Jews than non-Ashkenazi Jews and Arabs, but not over 10% for any type of cancer, and it was significantly higher in younger (<40 years) than older (>50 years) individuals (7% vs. 1%). Eighty-four of the heterozygotes (66%), mostly Ashkenazi Jews, harbored a low-penetrance variant (LPV) not associated with the diagnosed cancer, usually APC c.3902T>A. These findings question the advantage of two-step testing. LPVs should not be included in targeted testing because this can lead to an overestimation of the yield, and their detection does not preclude further comprehensive testing. [ABSTRACT FROM AUTHOR]

Simple Summary: This study addresses the global healthcare challenge of cancer by investigating hereditary cancer syndromes (HCS) and their genetic underpinnings. Using a multigene hereditary cancer panel, we examined Russian patients with suspected HCS, revealing that 21.6% had pathogenic or likely pathogenic genetic variants. Predominant mutations were found in BRCA1/BRCA2, CHEK2, and ATM genes, and we identified 16 previously undescribed variants in MUTYH, GALNT12, MSH2, MLH1, MLH3, EPCAM, and POLE genes. Our findings underscore the importance of comprehensive genetic testing for personalized cancer prevention and treatment. This research contributes essential genetic insights, particularly in regions like Russia where epidemiological data are limited, establishing the way for improved understanding and management of hereditary cancer syndromes. Cancer is a major global public health challenge, affecting both quality of life and mortality. Recent advances in genetic research have uncovered hereditary cancer syndromes (HCS) that predispose individuals to malignant neoplasms. While traditional single-gene testing has focused on high-penetrance genes, the past decade has seen a shift toward multigene panels, which facilitate the analysis of multiple genes associated with specific HCS. This approach reveals variants in less-studied gene regions and improves our understanding of cancer predisposition. In a study composed of Russian patients with clinical signs of HCS, we used a multigene hereditary cancer panel and revealed 21.6% individuals with pathogenic or likely pathogenic genetic variants. BRCA1/BRCA2 mutations predominated, followed by the CHEK2 and ATM variants. Of note, 16 previously undescribed variants were identified in the MUTYH, GALNT12, MSH2, MLH1, MLH3, EPCAM, and POLE genes. The implications of the study extend to personalized cancer prevention and treatment strategies, especially in populations lacking extensive epidemiological data, such as Russia. Overall, our research provides valuable genetic insights that give the way for further investigation and advances in the understanding and management of hereditary cancer syndromes. [ABSTRACT FROM AUTHOR]

Simple Summary: The protein translation machinery, of which tRNA is an essential part, is critical in controlling the growth of tumor cells. The development of cancer is also influenced by translational dysregulation. Understanding the rewiring of gene expression at the translational level, which underpins the development of transformational phenotypes during cancer, has made tremendous strides in recent years. We have found that the mode of translation regulation centered on tRNAs affects the translation system in various cancer types in a variety of different ways. In addition to the expression level of tRNA itself, codon and amino acid usage bias, tRNA modification regulation, and tRNA-derived fragments all play important roles. This review discusses recent developments and new insights to elucidate the role of tRNA-centered translational regulatory models in some aspects of carcinogenic and cancer cell activity. Cancer is a leading cause of morbidity and mortality worldwide. While numerous factors have been identified as contributing to the development of malignancy, our understanding of the mechanisms involved remains limited. Early cancer detection and the development of effective treatments are therefore critical areas of research. One class of molecules that play a crucial role in the transmission of genetic information are transfer RNAs (tRNAs), which are the most abundant RNA molecules in the human transcriptome. Dysregulated synthesis of tRNAs directly results in translation disorders and diseases, including cancer. Moreover, various types of tRNA modifications and the enzymes responsible for these modifications have been implicated in tumor biology. Furthermore, alterations in tRNA modification can impact tRNA stability, and impaired stability can prompt the cleavage of tRNAs into smaller fragments known as tRNA fragments (tRFs). Initially believed to be random byproducts lacking any physiological function, tRFs have now been redefined as non-coding RNA molecules with distinct roles in regulating RNA stability, translation, target gene expression, and other biological processes. In this review, we present recent findings on translational regulatory models centered around tRNAs in tumors, providing a deeper understanding of tumorigenesis and suggesting new directions for cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The tumour microenvironment comprises cellular components and the extracellular matrix, which surround the core of cancer cells and play a vital role in their development. Among these components are various immune cells such as T-regulatory cells, dendritic cells, and tumour-infiltrating lymphocytes, as well as other cells such as adipocytes, endothelial cells, cancer-associated fibroblasts (CAFs), cancer stem cells, and neuroendocrine cells, among others. The Wnt signalling pathway is a central pathway involved in tumour development. This review explores the significance of Wnt signalling in the communication between cellular components within the tumour microenvironment. Understanding this signalling pathway opens up possibilities for modifying the tumour microenvironment, potentially leading to insights into tumour development and progression. Additionally, this review delves into Wnt inhibition and inhibitors and their potential application in cancer therapeutics. Cancer therapeutics face significant challenges due to drug resistance and tumour recurrence. The tumour microenvironment (TME) is a crucial contributor and essential hallmark of cancer. It encompasses various components surrounding the tumour, including intercellular elements, immune system cells, the vascular system, stem cells, and extracellular matrices, all of which play critical roles in tumour progression, epithelial–mesenchymal transition, metastasis, drug resistance, and relapse. These components interact with multiple signalling pathways, positively or negatively influencing cell growth. Abnormal regulation of the Wnt signalling pathway has been observed in tumorigenesis and contributes to tumour growth. A comprehensive understanding and characterisation of how different cells within the TME communicate through signalling pathways is vital. This review aims to explore the intricate and dynamic interactions, expressions, and alterations of TME components and the Wnt signalling pathway, offering valuable insights into the development of therapeutic applications. [ABSTRACT FROM AUTHOR]

Simple Summary: During the last few decades, the basis for a genetic predisposition for several cancer syndromes has been clarified, and the highly penetrant/high-risk genes mutated in familial cases are currently subjected to genetic diagnostic screening programs. Mutation testing in these genes has a major impact on genetic counseling, defines the prognosis of carriers, identifies the most appropriate and personalized prophylactic measures, and increases the chance of survival. We aim to underline the effectiveness of the multigene panel in increasing the detection rate of germline mutations in cancer patients and consequently improve the healthy carriers' identification. Background: Several hereditary–familial syndromes associated with various types of tumors have been identified to date, evidencing that hereditary cancers caused by germline mutations account for 5–10% of all tumors. Advances in genetic technology and the implementation of Next-Generation Sequencing (NGS) have accelerated the discovery of several susceptibility cancer genes, allowing for the detection of cancer-predisposing mutations in a larger number of cases. The aim of this study is to highlight how the application of an NGS-multigene panel to a group of oncological patients subsequently leads to improvement in the identification of carriers of healthy pathogenic variants/likely pathogenic variants (PVs/LPVs) and prevention of the disease in these cases. Methods: Starting from a total of 110 cancer patients carrying PVs/LPVs in genes involved in cancer susceptibility detected via a customized NGS panel of 27 cancer-associated genes, we enrolled 250 healthy collateral family members from January 2020 to July 2022. The specific PVs/LPVs identified in each proband were tested in healthy collateral family members via Sanger sequencing. Results: A total of 131 out of the 250 cases (52%) were not carriers of the mutation detected in the affected relative, while 119 were carriers. Of these, 81/250 patients carried PVs/LPVs on BRCA1/2 (33%), 35/250 harbored PVs/LPVs on other genes beyond BRCA1 and BRCA2 (14%), and 3/250 (1%) were PVs/LPVs carriers both on BRCA1/2 and on another susceptibility gene. Conclusion: Our results show that the analysis of BRCA1/2 genes would have only resulted in a missed diagnosis in a number of cases and in the lack of prevention of the disease in a considerable percentage of healthy carriers with a genetic mutation (14%). [ABSTRACT FROM AUTHOR]

Simple Summary: Alternative splicing generates transcripts that can promote tumorigenesis, but intron retention (IR), a form of alternative splicing, remains understudied. We investigated the role of IR in tumorigenesis and its potential clinical applications at the pan-cancer level. We identified IR events from The Cancer Genome Atlas (TCGA) that differ between tumor and normal samples, as well as IR events associated with patient survival. These IR events may modulate the expression of host genes, including those that play a role in cancer biology. For example, we experimentally validated a novel IR event within the STN1 5′UTR. The excellent performance of IR-based diagnostic and prognostic models and their biological importance in cancer suggest that IR is a potential biomarker and drug target. Alternative splicing can produce transcripts that affect cancer development and thus shows potential for cancer diagnosis and treatment. However, intron retention (IR), a type of alternative splicing, has been studied less in cancer biology research. Here, we generated a pan-cancer IR landscape for more than 10,000 samples across 33 cancer types from The Cancer Genome Atlas (TCGA). We characterized differentially retained introns between tumor and normal samples and identified retained introns associated with survival. We discovered 988 differentially retained introns in 14 cancers, some of which demonstrated diagnostic potential in multiple cancer types. We also inferred a large number of prognosis-related introns in 33 cancer types, and the associated genes included well-known cancer hallmarks such as angiogenesis, metastasis, and DNA mutations. Notably, we discovered a novel intron retention inside the 5′UTR of STN1 that is associated with the survival of lung cancer patients. The retained intron reduces translation efficiency by producing upstream open reading frames (uORFs) and thereby inhibits colony formation and cell migration of lung cancer cells. Besides, the IR-based prognostic model achieved good stratification in certain cancers, as illustrated in acute myeloid leukemia. Taken together, we performed a comprehensive IR survey at a pan-cancer level, and the results implied that IR has the potential to be diagnostic and prognostic cancer biomarkers, as well as new drug targets. [ABSTRACT FROM AUTHOR]

Simple Summary: The association between HPV and cancer has been the focus of research, but there has been a lack of a comprehensive high-level evidence studies to systematically examine the relationship between them. Using Mendelian randomization, this paper provided an extensive analysis of the causal effect of HPV in cancer development. Our study conclusively identified HPV16 as a risk factor implicated in the development of bladder cancer, colorectal cancer, and breast cancer, while HPV18 was identified as a risk factor for prostate cancer, ovarian cancer, lung cancer and breast cancer. The results of Mendelian randomization also showed that HPV16 may be a protective factor for prostate cancer, anal cancer, lung cancer and oropharyngeal cancer, while HPV18 may be a protective factor for vaginal cancer. Introduction: More and more studies have focused on the associations between human papillomavirus (HPV) infection and pan-cancers. However, current evidence is largely based on retrospective studies, which are susceptible to confounding factors and do not enable the establishment of causal relationships. Methods: A bidirectional two-sample Mendelian randomization (MR) design was employed to thoroughly evaluate the causal relationships between HPV and 12 site-specific cancers except cervical cancer. Single nucleoside polymers (SNPs) with strong evidence from genome-wide association studies (GWAS) were selected from HPV exposure datasets and used as instrumental variables (IVs) in this study. For the MR analysis results, MR-Egger's intercept P test, MR-PRESSO global test, Cochran's Q test and a leave-one-out test were applied for sensitivity analysis. Using HPVTIMER, we also performed immune infiltration analyses in head and neck squamous cell carcinoma (HNSCC), oropharyngeal squamous cell carcinoma (OPSCC) and vulval squamous cell carcinoma (VSCC) to evaluate the tumor-immune microenvironment. Results: Based on the evidence of MR analysis, our study conclusively identified HPV16 as a risk factor implicated in the development of bladder cancer, colorectal cancer, and breast cancer, while HPV18 was identified as a risk factor for prostate cancer, ovarian cancer, lung cancer and breast cancer. The MR results also showed that HPV16 may be a protective factor for prostate cancer, anal cancer, lung cancer and oropharyngeal cancer, while HPV18 may be a protective factor for vaginal cancer. Conclusion: An HPV infection may modulate the immune microenvironment and therefore has a potential inhibitory effect on the development of certain cancers. These conclusions provided new insights into the potential mechanisms of carcinogenesis and needed further research for validation. [ABSTRACT FROM AUTHOR]

Simple Summary: Liquid biopsy is a promising tool for the detection of low-frequency variants present in cancer and mosaic disease and is more and more adopted in clinical practice. Still, accurate validation and standardization across laboratories is lacking. Here, we show that the reference materials used during validation have a significant impact on a liquid biopsy next-generation-sequencing (NGS) assays analytical performance evaluation. With our findings, we developed a guide for the selection of suitable reference materials to eventually enable comparable results for patients across different laboratories. Highly sensitive and precise liquid biopsy NGS assays are critical to ensure accurate clinical interpretation. Background: Liquid biopsy enables the non-invasive analysis of genetic tumor variants in circulating free DNA (cfDNA) in plasma. Accurate analytical validation of liquid biopsy NGS assays is required to detect variants with low variant allele frequencies (VAFs). Methods: Six types of commercial cfDNA reference materials and 42 patient samples were analyzed using a duplex-sequencing-based liquid biopsy NGS assay. Results: We comprehensively evaluated the similarity of commercial cfDNA reference materials to native cfDNA. We observed significant differences between the reference materials in terms of wet-lab and sequencing quality as well as background noise. No reference material resembled native cfDNA in all performance metrics investigated. Based on our results, we established guidelines for the selection of appropriate reference materials for the different steps in performance evaluation. The use of inappropriate materials and cutoffs could eventually lead to a lower sensitivity for variant detection. Conclusion: Careful consideration of commercial reference materials is required for performance evaluation of liquid biopsy NGS assays. While the similarity to native cfDNA aids in the development of experimental protocols, reference materials with well-defined variants are preferable for determining sensitivity and precision, which are essential for accurate clinical interpretation. [ABSTRACT FROM AUTHOR]

Simple Summary: R-loops are three-stranded structures consisting of an RNA–DNA hybrid and an unpaired single-stranded DNA (ssDNA), with biological implications in cellular physiology and pathological conditions. R-loops interfere with DNA repair pathways and activate oncogenes, leading to dysregulated cell proliferation, genome instability, and cancer development. R-loops accumulate in several types of cancer cells, including breast, ovarian, prostate, and lung cancer. Studying the biological roles of R-loops in cancer development is potentially beneficial for innovative diagnostic and treatment approaches for cancer. In this review, we focus on recent advances in R-loops' roles in genome instability, DNA repair, and oncogenic events. R-loops are unique, three-stranded nucleic acid structures that primarily form when an RNA molecule displaces one DNA strand and anneals to the complementary DNA strand in a double-stranded DNA molecule. R-loop formation can occur during natural processes, such as transcription, in which the nascent RNA molecule remains hybridized with the template DNA strand, while the non-template DNA strand is displaced. However, R-loops can also arise due to many non-natural processes, including DNA damage, dysregulation of RNA degradation pathways, and defects in RNA processing. Despite their prevalence throughout the whole genome, R-loops are predominantly found in actively transcribed gene regions, enabling R-loops to serve seemingly controversial roles. On one hand, the pathological accumulation of R-loops contributes to genome instability, a hallmark of cancer development that plays a role in tumorigenesis, cancer progression, and therapeutic resistance. On the other hand, R-loops play critical roles in regulating essential processes, such as gene expression, chromatin organization, class-switch recombination, mitochondrial DNA replication, and DNA repair. In this review, we summarize discoveries related to the formation, suppression, and removal of R-loops and their influence on genome instability, DNA repair, and oncogenic events. We have also discussed therapeutical opportunities by targeting pathological R-loops. [ABSTRACT FROM AUTHOR]

Simple Summary: Polo-like kinase 4 (PLK4) is associated with tumorigenesis and prognosis in various types of cancer. Prognostic analysis of PLK4 expression and data analysis of its association with the somatic mutation and drug resistance through clustering were performed using the Cancer Genome Atlas-lung adenocarcinoma (TCGA-LUAD) dataset. According to these results, PLK4 expression is associated with poor prognosis, TP53 mutations, and drug resistance in patients with LUAD. (1) Background: This study investigated whether polo-like kinase 4 (PLK4) is a suitable therapeutic target or biomarker for lung adenocarcinoma (LUAD). (2) Methods: We acquired LUAD data from The Cancer Genome Atlas (TCGA) database through the UCSC Xena data portal. Gene expression, clinical, survival, and mutation data from multiple samples were analyzed. Gene enrichment analysis, unsupervised clustering of PLK4-related pathways, and differential gene expression analyses were performed. Additionally, correlations, t-tests, survival analyses, and statistical analyses were performed. (3) Results: PLK4 expression was higher in LUAD tissues than in normal tissues and was associated with poor prognosis for both overall and progression-free survival in LUAD. PLK4 was highly correlated with cell-proliferation-related pathways using Gene Ontology (GO) biological process terms. PLK4 expression and pathways that were highly correlated with PLK4 expression levels were upregulated in patients with LUAD with the TP53 mutation. (4) Conclusions: PLK4 expression affects the survival of patients with LUAD and is a potential therapeutic target for LUAD with TP53 mutations. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cells are characterized by the accumulation of genetic mutations due to failures of the repair machinery. In some cases, excessive "repair" may cause DNA damage if the machinery runs amok and acts on DNA sequences that have not been damaged. In this report, we interrogate mutations in the FBH1 gene, which restrains homologous recombination, one mechanism of DNA double-strand break repair in eukaryotes. We find that mutations in FBH1 co-occur with mutations in the breast cancer susceptibility gene BRCA2 and other DNA damage repair genes. These findings suggest that FBH1 contributes to the general destabilization of the repair machinery in cancer cells. Homologous recombination (HR) is the major mechanism of rescue of stalled replication forks or repair of DNA double-strand breaks (DSBs) during S phase or mitosis. In human cells, HR is facilitated by the BRCA2-BRCA1-PALB2 module, which loads the RAD51 recombinase onto a resected single-stranded DNA end to initiate repair. Although the process is essential for error-free repair, unrestrained HR can cause chromosomal rearrangements and genome instability. F-box DNA Helicase 1 (FBH1) antagonizes the role of BRCA2-BRCA1-PALB2 to restrict hyper-recombination and prevent genome instability. Here, we analyzed reported FBH1 mutations in cancer cells using the Catalogue of Somatic Mutations in Cancers (COSMIC) to understand how they interact with the BRCA2-BRCA1-PALB2. Consistent with previous results from yeast, we find that FBH1 mutations co-occur with BRCA2 mutations and to some degree BRCA1 and PALB2. We also describe some co-occurring mutations with RAD52, the accessory RAD51 loader and facilitator of single-strand annealing, which is independent of RAD51. In silico modeling was used to investigate the role of key FBH1 mutations on protein function, and a Q650K mutation was found to destabilize the protein structure. Taken together, this work highlights how mutations in several DNA damage repair genes contribute to cellular transformation and immortalization. [ABSTRACT FROM AUTHOR]

Simple Summary: In blood cancers and solid tumors, genetic changes serve to initiate and promote cancer. These genetic changes can include rearrangements to genes which can alter gene function. Identification of gene rearrangements through molecular laboratory tests may help guide clinical care in patients with cancer. Different types of gene rearrangements can occur, including those within a gene and those between genes. Rearrangements occurring within a gene can be difficult to identify using current computational approaches. Our clinical laboratory designed sequencing panels for blood cancers and solid tumors to detect rearrangements within and between genes. In this study, we discuss our three-year experience using a laboratory method of targeted sequencing to detect gene rearrangements. We highlight our approach and the clinical utility for the reporting of rearrangements both within and between genes. Gene fusions are a form of structural rearrangement well established as driver events in pediatric and adult cancers. The identification of such events holds clinical significance in the refinement, prognostication, and provision of treatment in cancer. Structural rearrangements also extend beyond fusions to include intragenic rearrangements, such as internal tandem duplications (ITDs) or exon-level deletions. These intragenic events have been increasingly implicated as cancer-promoting events. However, the detection of intragenic rearrangements may be challenging to resolve bioinformatically with short-read sequencing technologies and therefore may not be routinely assessed in panel-based testing. Within an academic clinical laboratory, over three years, a total of 608 disease-involved samples (522 hematologic malignancy, 86 solid tumors) underwent clinical testing using Anchored Multiplex PCR (AMP)-based RNA sequencing. Hematologic malignancies were evaluated using a custom Pan-Heme 154 gene panel, while solid tumors were assessed using a custom Pan-Solid 115 gene panel. Gene fusions, ITDs, and intragenic deletions were assessed for diagnostic, prognostic, or therapeutic significance. When considering gene fusions alone, we report an overall diagnostic yield of 36% (37% hematologic malignancy, 41% solid tumors). When including intragenic structural rearrangements, the overall diagnostic yield increased to 48% (48% hematologic malignancy, 45% solid tumor). We demonstrate the clinical utility of reporting structural rearrangements, including gene fusions and intragenic structural rearrangements, using an AMP-based RNA sequencing panel. [ABSTRACT FROM AUTHOR]

Simple Summary: The human genome produces various types of RNA molecules. A significant portion of these are long non-coding RNAs (lncRNAs) exceeding 200 nts without an obvious open reading frame. There are more than 200,000 lncRNAs, but we have limited understanding of their functions. LncRNAs can influence gene activity by interacting with proteins or nucleic acids. Some lncRNAs regulate genes involved in cancer, either promoting or suppressing tumor growth. One lncRNA of interest is ANRIL (Antisense Noncoding RNA in the INK4 Locus), which can affect gene expression through different ways. However, ANRIL's exact role in cancer is complex and varies in different situations, making it a challenging area to study. This review strives to offer a thorough comprehension of ANRIL's role in regulating genes and its impact on the development of cancer. ANRIL (Antisense Noncoding RNA in the INK4 Locus), a long non-coding RNA encoded in the human chromosome 9p21 region, is a critical factor for regulating gene expression by interacting with multiple proteins and miRNAs. It has been found to play important roles in various cellular processes, including cell cycle control and proliferation. Dysregulation of ANRIL has been associated with several diseases like cancers and cardiovascular diseases, for instance. Understanding the oncogenic role of ANRIL and its potential as a diagnostic and prognostic biomarker in cancer is crucial. This review provides insights into the regulatory mechanisms and oncogenic significance of the 9p21 locus and ANRIL in cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Out of the billions of nucleotides comprising the human DNA, a substantial proportion (98%) represents non-coding DNA, meaning DNA that is not translated into proteins. Among the various types of non-coding DNA, pseudogenes stand out as duplicates of protein-coding genes that have undergone multiple alterations, rendering them unable to produce the protein they originally encoded. Despite their inability to generate functional proteins, recent studies have revealed the involvement of pseudogenes in several diseases, including cancer. In this review, we aim to provide a comprehensive overview of pseudogene formation, the mechanisms governing their expression, and the potential roles they may play in promoting tumorigenesis. Pseudogenes are duplicates of protein-coding genes that have accumulated multiple detrimental alterations, rendering them unable to produce the protein they encode. Initially disregarded as "junk DNA" due to their perceived lack of functionality, research on their biological roles has been hindered by this assumption. Nevertheless, recent focus has shifted towards these molecules due to their abnormal expression in cancer phenotypes. In this review, our objective is to provide a thorough overview of the current understanding of pseudogene formation, the mechanisms governing their expression, and the roles they may play in promoting tumorigenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: The EPH/ephrin signaling axis holds a pivotal role in a plethora of physiologic processes during embryonic development and adult life, while more recent studies highlight its implication in the pathogenesis of multiple types of solid tumors. Different patterns of EPH/ephrin expression have been identified in normal hematopoiesis concerning the maintenance, differentiation, and function of hematopoietic stem cells and their mature offspring. Emerging data suggest that EPH/ephrin aberrations contribute to the pathogenesis of various hematologic malignancies, exerting both tumor-promoting and tumor-suppressive functions. Thus, unraveling the intricate role of EPH/ephrin signaling in the setting of hematologic neoplasia can contribute to the development of promising therapeutic targets to overcome unmet needs. Erythropoietin-producing hepatocellular carcinoma receptors (EPHs) represent the largest family of receptor tyrosine kinases (RTKs). EPH interaction with ephrins, their membrane-bound ligands, holds a pivotal role in embryonic development, while, though less active, it is also implicated in various physiological functions during adult life. In normal hematopoiesis, different patterns of EPH/ephrin expression have been correlated with hematopoietic stem cell (HSC) maintenance and lineage-committed hematopoietic progenitor cell (HPC) differentiation, as well as with the functional properties of their mature offspring. Research in the field of hematologic malignancies has unveiled a rather complex involvement of the EPH/ephrinsignaling pathway in the pathophysiology of these neoplasms. Aberrations in genetic, epigenetic, and protein levels have been identified as possible players implicated both in tumor progression and suppression, while correlations have also been highlighted regarding prognosis and response to treatment. Initial efforts to therapeutically target the EPH/ephrin axis have been undertaken in the setting of hematologic neoplasia but are mainly confined to the preclinical level. To this end, deciphering the complexity of this signaling pathway both in normal and malignant hematopoiesis is necessary. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor Suppressor Candidate 2 (TUSC2) is an important tumor suppressor that negatively regulates cancer growth and progression in multiple cancer types. TUSC2 was first discovered as a candidate tumor suppressor gene that is located on a frequently deleted region of chromosome 3p21.3 in lung cancer. Since its initial discovery in lung cancer, TUSC2 loss has also been reported in glioma, sarcoma, and cancers of the breast, ovaries, and thyroid. When TUSC2 is re-expressed in these cancer types, it reduces cancer cell growth and promotes cell death. In normal cells, TUSC2 regulates the immune system and prevents the development of autoimmune diseases. TUSC2 also regulates calcium movement within the cell and the mitochondria, which is important for overall cellular function. Lastly, TUSC2 loss promotes premature aging with the development of hearing loss and sporadic Alzheimer's disease. Altogether, these findings define a vital role that TUSC2 plays in normal and cancerous cells. Tumor Suppressor Candidate 2 (TUSC2) was first discovered as a potential tumor suppressor gene residing in the frequently deleted 3p21.3 chromosomal region. Since its discovery, TUSC2 has been found to play vital roles in normal immune function, and TUSC2 loss is associated with the development of autoimmune diseases as well as impaired responses within the innate immune system. TUSC2 also plays a vital role in regulating normal cellular mitochondrial calcium movement and homeostasis. Moreover, TUSC2 serves as an important factor in premature aging. In addition to TUSC2′s normal cellular functions, TUSC2 has been studied as a tumor suppressor gene that is frequently deleted or lost in a multitude of cancers, including glioma, sarcoma, and cancers of the lung, breast, ovaries, and thyroid. TUSC2 is frequently lost in cancer due to somatic deletion within the 3p21.3 region, transcriptional inactivation via TUSC2 promoter methylation, post-transcriptional regulation via microRNAs, and post-translational regulation via polyubiquitination and proteasomal degradation. Additionally, restoration of TUSC2 expression promotes tumor suppression, eventuating in decreased cell proliferation, stemness, and tumor growth, as well as increased apoptosis. Consequently, TUSC2 gene therapy has been tested in patients with non-small cell lung cancer. This review will focus on the current understanding of TUSC2 functions in both normal and cancerous tissues, mechanisms of TUSC2 loss, TUSC2 cancer therapeutics, open questions, and future directions. [ABSTRACT FROM AUTHOR]

Simple Summary: This review describes how the two processes of angiogenesis (the generation of new blood vessels) and neurogenesis (the generation of new nerve fibers) act together to drive cancer progression. It also describes how they are both associated with a lower rate of patient survival. These two processes share signaling pathways and, in many cases, the initiation of one leads to the initiation of the other. Both processes require tissue alterations and are reliant on cell migration. They favor cancer progression by supplying the tumor with nutrients and facilitating communication/movements within the tumor. Thus, these two processes contribute to the spread of cancers, as tumors can use nerve fibers and blood vessels as a routes to migrate from the initial point of cancer development to the surrounding area or to the distal sites of the body. Angiogenesis, the generation of new blood vessels, is one of the hallmarks of cancer. The growing tumor requires nutrients and oxygen. Recent evidence has shown that tumors release signals to attract new nerve fibers and stimulate the growth of new nerve fibers. Neurogenesis, neural extension, and axonogenesis assist in the migration of cancer cells. Cancer cells can use both blood vessels and nerve fibers as routes for cells to move along. In this way, neurogenesis and angiogenesis both contribute to cancer metastasis. As a result, tumor-induced neurogenesis joins angiogenesis and immunosuppression as aberrant processes that are exacerbated within the tumor microenvironment. The relationship between these processes contributes to cancer development and progression. The interplay between these systems is brought about by cytokines, neurotransmitters, and neuromodulators, which activate signaling pathways that are common to angiogenesis and the nervous tissue. These include the AKT signaling pathways, the MAPK pathway, and the Ras signaling pathway. These processes also both require the remodeling of tissues. The interplay of these processes in cancer provides the opportunity to develop novel therapies that can be used to target these processes. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this review is to highlight recent work performed on the activity of a class of cancer drugs (PARP inhibitor) in various cell lines, either expressing or not expressing proteins interacting with the DNA repair protein SLX4. This could be at the basis of the development of new therapeutic strategies in cancer treatment. PARP inhibitors are small molecules currently used with success in the treatment of certain cancer patients. Their action was first shown to be specific to cells with DNA repair deficiencies, such as BRCA-mutant cancers. However, recent work has suggested clinical interest of these drugs beyond this group of patients. Preclinical data on relationships between the activity of PARP inhibitors and other proteins involved in DNA repair exist, and this review will only highlight findings on the SLX4 protein and its interacting protein partners. As suggested from these available data and depending on further validations, new treatment strategies could be developed in order to broaden the use for PARP inhibitors in cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Uterine serous carcinomas (USC) represent a rare and aggressive subtype of uterine cancer. Patients often receive adjuvant therapy including chemotherapy and/or radiation after surgery, which has limited efficacy in preventing high rates of recurrence. Understanding the tumor microenvironment in USC is paramount to developing new targeted therapies at the time of progression. This study evaluated the genomic instability score (GIS), tumor mutational burden (TMB), and tumor-infiltrating lymphocytes (TILs) in 53 patients with USC. In this cohort, the median TMB was 1.35 mutations/megabase (mt/Mb); patients with TMB greater than the median had improved survival outcomes. The median GIS was 31, and a higher GIS was not associated with improved survival. We characterized immune cell populations and found that increased immune populations were not associated with a better prognosis. Background: Uterine serous carcinomas represent 10% of uterine carcinomas but account for nearly 40% of deaths from the disease. Improved molecular characterization of these tumors is instrumental in guiding targeted treatment and improving outcomes. This study assessed the genomic instability score (GIS), tumor mutational burden (TMB), and tumor-infiltrating lymphocytes (TILs) in patients with USC. Methods: A retrospective cohort study evaluated patients with USC following staging surgery. The GIS and TMB were determined from archived specimens. We evaluated the tumoral expression of CD3, CD4, CD8, FOXP3, and CD68 using immunohistochemistry. T-tests were used to assess associations of TILs with the GIS. Results: We evaluated 53 patients with USC. The median GIS was 31 (range: 0–52) and a higher GIS was not associated with progression-free (PFS) or overall survival (OS). The median TMB was 1.35 mt/Mb; patients with TMB > 1.35 mt/Mb had improved PFS and OS (p = 0.005; p = 0.002, respectively). Tumors with increased CD3+ and CD4+ immune cells had a higher mean GIS (p = 0.013, p = 0.002). Conclusions: TMB > 1.35 mt/Mb was associated with improved survival in USC patients, whereas the GIS was not. Lower TMB thresholds may provide prognostic value for less immunogenic tumors such as USC. In this limited cohort, we observed that increased TIL populations were correlated with a higher GIS. [ABSTRACT FROM AUTHOR]

Simple Summary: In just less than 30 years since the cloning of RANBP1 (RAN binding protein 1), this review represents the first attempt for a comprehensive and analytical compilation of the main works that have characterized the history of this gene. Originally defined as an accessory element of not well-defined proteins involved in nuclear transport, RANBP1 has been demonstrated, over time, to play an essential role in maintaining both nuclear import/export machinery and spindle check-point formation. Since the first biochemical characterization, knowledge has accumulated that paints a very complex picture of how RANBP1 and its Small-GTPase-related complex plays a fine regulation of cellular homeostasis, with a differentially phase-cell-dependent role. From its molecular context, up to the role in neoplastic and other pathologies of complex traits, RANBP1 always embodies further the missing piece of a gene signature that recapitulates several aspects of mammalian cell biology. RANBP1 encoded by RANBP1 or HTF9A (Hpall Tiny Fragments Locus 9A), plays regulatory functions of the RAN-network, belonging to the RAS superfamily of small GTPases. Through this function, RANBP1 regulates the RANGAP1 activity and, thus, the fluctuations between GTP-RAN and GDP-RAN. In the light of this, RANBP1 take actions in maintaining the nucleus–cytoplasmic gradient, thus making nuclear import–export functional. RANBP1 has been implicated in the inter-nuclear transport of proteins, nucleic acids and microRNAs, fully contributing to cellular epigenomic signature. Recently, a RANBP1 diriment role in spindle checkpoint formation and nucleation has emerged, thus constituting an essential element in the control of mitotic stability. Over time, RANBP1 has been demonstrated to be variously involved in human cancers both for the role in controlling nuclear transport and RAN activity and for its ability to determine the efficiency of the mitotic process. RANBP1 also appears to be implicated in chemo-hormone and radio-resistance. A key role of this small-GTPases related protein has also been demonstrated in alterations of axonal flow and neuronal plasticity, as well as in viral and bacterial metabolism and in embryological maturation. In conclusion, RANBP1 appears not only to be an interesting factor in several pathological conditions but also a putative target of clinical interest. [ABSTRACT FROM AUTHOR]

Simple Summary: Human DNA is ~2 m long, but is efficiently packaged in cell nucleus that is a million times smaller. The concerted action of several enzymes enables this packaging through hierarchical folding of DNA. These enzymes deposit unique marks on the DNA and DNA-binding proteins collectively called the histone code. The histone code determines when and how a segment of DNA will open and be expressed. Pathogenic changes or mutations in the proteins produced by the cells alter this expression pattern. Here, we discuss how these mutations affect DNA packaging in cancer establishment, diversification, and therapeutic resistance. We also document available therapeutic approaches aimed at DNA packaging in cancer and the direction in which current research is heading. A hallmark of cancers is uncontrolled cell proliferation, frequently associated with an underlying imbalance in gene expression. This transcriptional dysregulation observed in cancers is multifaceted and involves chromosomal rearrangements, chimeric transcription factors, or altered epigenetic marks. Traditionally, chromatin dysregulation in cancers has been considered a downstream effect of driver mutations. However, here we present a broader perspective on the alteration of chromatin organization in the establishment, diversification, and therapeutic resistance of cancers. We hypothesize that the chromatin organization controls the accessibility of the transcriptional machinery to regulate gene expression in cancerous cells and preserves the structural integrity of the nucleus by regulating nuclear volume. Disruption of this large-scale chromatin in proliferating cancerous cells in conventional chemotherapies induces DNA damage and provides a positive feedback loop for chromatin rearrangements and tumor diversification. Consequently, the surviving cells from these chemotherapies become tolerant to higher doses of the therapeutic reagents, which are significantly toxic to normal cells. Furthermore, the disorganization of chromatin induced by these therapies accentuates nuclear fragility, thereby increasing the invasive potential of these tumors. Therefore, we believe that understanding the changes in chromatin organization in cancerous cells is expected to deliver more effective pharmacological interventions with minimal effects on non-cancerous cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Errors in the distribution of genetic information, contained in structures referred to as chromosomes, which are made up by DNA and proteins, during a cell division (mitosis) can cause developmental defects and contribute to malignant disease. To prevent the potentially detrimental consequences of unfaithful separation of chromosomes, or parts thereof, a process referred to as chromosomal instability (CIN), cells have developed different solutions. One such solution is the removal of chromosomally instable cells by suicide. This is achieved by the activation of a cell-intrinsic program, termed apoptosis. Lost cells are usually replenished by those that achieve the precise distribution of genetic information between daughter cells, in order to maintain a healthy balance in tissues (homeostasis). Mis-segregation of chromosomes reduces cellular fitness, e.g., due to accumulation of DNA damage during the process or imbalances in cellular protein levels arising from inheriting an uneven number of chromosomes (aneuploidy). All these events can trigger activation of the apoptosis machinery. Losing the ability to commit cellular suicide under such conditions can contribute to the rise of cancer, or foster drug-resistance in established tumours during treatment. Here, we discuss the mechanisms involved that promote cellular suicide in cells that show CIN or aneuploidy and how such cells may eventually manage to escape cell death. Aneuploidy is the gain or loss of entire chromosomes, chromosome arms or fragments. Over 100 years ago, aneuploidy was described to be a feature of cancer and is now known to be present in 68–90% of malignancies. Aneuploidy promotes cancer growth, reduces therapy response and frequently worsens prognosis. Chromosomal instability (CIN) is recognized as the main cause of aneuploidy. CIN itself is a dynamic but stochastic process consisting of different DNA content-altering events. These can include impaired replication fidelity and insufficient clearance of DNA damage as well as chromosomal mis-segregation, micronuclei formation, chromothripsis or cytokinesis failure. All these events can disembogue in segmental, structural and numerical chromosome alterations. While low levels of CIN can foster malignant disease, high levels frequently trigger cell death, which supports the "aneuploidy paradox" that refers to the intrinsically negative impact of a highly aberrant karyotype on cellular fitness. Here, we review how the cellular response to CIN and aneuploidy can drive the clearance of karyotypically unstable cells through the induction of apoptosis. Furthermore, we discuss the different modes of p53 activation triggered in response to mitotic perturbations that can potentially trigger CIN and/or aneuploidy. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a distinctly difficult disease to treat on account of the diverse cell populations/subpopulations that comprise a tumour. Such cells harbour varying genetic and epigenetic states, which contributes to their oncogenic phenotype. Of note to this review is the epigenetic modification DNA methylation. Aberrant DNA methylation is a well-explored contributor to oncogenic phenotype. Traditionally, thousands of cells within a tumour have been sequenced together, giving rise to averaged methylation profiles. With the emergence of single-cell sequencing technologies, the methylome of individual cells can now be acquired. This technology will have important research and clinical implications, such as informing our current understanding of cancer biology, discovery of novel biomarkers, and less invasive tests. Morphological, transcriptomic, and genomic defects are well-explored parameters of cancer biology. In more recent years, the impact of epigenetic influences, such as DNA methylation, is becoming more appreciated. Aberrant DNA methylation has been implicated in many types of cancers, influencing cell type, state, transcriptional regulation, and genomic stability to name a few. Traditionally, large populations of cells from the tissue of interest are coalesced for analysis, producing averaged methylome data. Considering the inherent heterogeneity of cancer, analysing populations of cells as a whole denies the ability to discover novel aberrant methylation patterns, identify subpopulations, and trace cell lineages. Due to recent advancements in technology, it is now possible to obtain methylome data from single cells. This has both research and clinical implications, ranging from the identification of biomarkers to improved diagnostic tools. As with all emerging technologies, distinct experimental, bioinformatic, and practical challenges present themselves. This review begins with exploring the potential impact of single-cell sequencing on understanding cancer biology and how it could eventually benefit a clinical setting. Following this, the techniques and experimental approaches which made this technology possible are explored. Finally, the present challenges currently associated with single-cell DNA methylation sequencing are described. [ABSTRACT FROM AUTHOR]

Simple Summary: A review of the molecular and cellular features of the major cancer syndromes associated with radiosensitivity revealed the importance of the ATM protein, either as an impaired kinase in the nucleus or as a complex in the cytoplasm, with the mutated protein responsible for the syndrome. There are a number of genetic syndromes associated with both high cancer risk and clinical radiosensitivity. However, the link between these two notions remains unknown. Particularly, some cancer syndromes are caused by mutations in genes involved in DNA damage signaling and repair. How are the DNA sequence errors propagated and amplified to cause cell transformation? Conversely, some cancer syndromes are caused by mutations in genes involved in cell cycle checkpoint control. How is misrepaired DNA damage produced? Lastly, certain genes, considered as tumor suppressors, are not involved in DNA damage signaling and repair or in cell cycle checkpoint control. The mechanistic model based on radiation-induced nucleoshuttling of the ATM kinase (RIANS), a major actor of the response to ionizing radiation, may help in providing a unified explanation of the link between cancer proneness and radiosensitivity. In the frame of this model, a given protein may ensure its own specific function but may also play additional biological role(s) as an ATM phosphorylation substrate in cytoplasm. It appears that the mutated proteins that cause the major cancer and radiosensitivity syndromes are all ATM phosphorylation substrates, and they generally localize in the cytoplasm when mutated. The relevance of the RIANS model is discussed by considering different categories of the cancer syndromes. [ABSTRACT FROM AUTHOR]

Simple Summary: The transcription factor SOX11 is a member of the SRY box-containing family. Recently, SOX11 research has shifted from embryogenesis to cancer development. Nevertheless, the roles of SOX11 in different cancer types remain controversial. Here, we systematically explored the characteristics of SOX11 by multiple omics analyses. Aberrant SOX11 expression has been observed in many types of human malignant tumors. Moreover, SOX11 expression could serve as an indicator of survival outcomes, tumor progression and cellular immune infiltration. Our work highlights the diverse role of SOX11 in different types of tumors, which points out several directions for future prospective studies on SOX11 in cancer. SRY-box transcription factor 11 (SOX11), as a member of the SOX family, is a transcription factor involved in the regulation of specific biological processes and has recently been found to be a prognostic marker for certain cancers. However, the roles of SOX11 in cancer remain controversial. Our study aimed to explore the various aspects of SOX11 in pan-cancer. The expression of SOX11 was investigated by the Genotype Tissue-Expression (GTEX) dataset and the Cancer Genome Atlas (TCGA) database. The protein level of SOX11 in tumor tissues and tumor-adjacent tissues was verified by human pan-cancer tissue microarray. Additionally, we used TCGA pan-cancer data to analyze the correlations among SOX11 expression and survival outcomes, clinical features, stemness, microsatellite instability (MSI), tumor mutation burden (TMB), mismatch repair (MMR) related genes and the tumor immune microenvironment. Furthermore, the cBioPortal database was applied to investigate the gene alterations of SOX11. The main biological processes of SOX11 in cancers were analyzed by Gene Set Enrichment Analysis (GSEA). As a result, aberrant expression of SOX11 has been implicated in 27 kinds of cancer types. Aberrant SOX11 expression was closely associated with survival outcomes, stage, tumor recurrence, MSI, TMB and MMR-related genes. In addition, the most frequent alteration of the SOX11 genome was mutation. Our study also showed the correlations of SOX11 with the level of immune infiltration in various cancers. In summary, our findings underline the multifaceted role and prognostic value of SOX11 in pan-cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: LINC01087 is a recently described long non-coding RNA. Its potential implication within oncology is being increasingly acknowledged. Here, we explored the clinical interest of LINC01087 in the diagnosis and prognostication of multiple cancer types. A series of in-depth in silico analyses revealed LINC01087 as a potential diagnostic indicator of some hormone-related tumors, including breast cancer (BC), ovarian carcinoma, and testicular germ cell tumors, as well as other cancer histotypes, such as esophageal and stomach cancers. Moreover, LINC01087 appears as a prognostic indicator in BC and renal papillary cell carcinoma. Therefore, the quantitation of LINC01087 in tissue specimens might have a clinical utility to improve the management of these pathologies in the future. (1) Background: Long non-coding RNAs may constitute epigenetic biomarkers for the diagnosis, prognosis, and therapeutic response of a variety of tumors. In this context, we aimed at assessing the diagnostic and prognostic value of the recently described long intergenic non-coding RNA 01087 (LINC01087) in human cancers. (2) Methods: We studied the expression of LINC01087 across 30 oncological indications by interrogating public resources. Data extracted from the TCGA and GTEx databases were exploited to plot receiver operating characteristic curves (ROC) and determine the diagnostic performance of LINC01087. Survival data from TCGA and KM-Plotter directories allowed us to graph Kaplan–Meier curves and evaluate the prognostic value of LINC01087. To investigate the function of LINC01087, gene ontology (GO) annotation and Kyoto Encyclopedia of Gene and Genomes (KEGG) enrichment analyses were performed. Furthermore, interactions between LINC01087 and both miRNA and mRNA were studied by means of bioinformatics tools. (3) Results: LINC01087 was significantly deregulated in 7 out of 30 cancers, showing a predominant upregulation. Notably, it was overexpressed in breast (BC), esophageal (ESCA), and ovarian (OV) cancers, as well as lung squamous cell carcinoma (LUSC), stomach adenocarcinoma (STAD), and uterine carcinosarcoma (UCS). By contrast, LINC01087 displayed downregulation in testicular germ cell tumors (TGCT). ROC curve analyses identified LINC01087 as a potential diagnostic indicator in BC, ESCA, OV, STAD, and TGCT. Moreover, high and low expression of LINC01087 predicted a favorable prognosis in BC and papillary cell carcinoma, respectively. In silico analyses indicated that deregulation of LINC01087 in cancer was associated with a modulation of genes related to ion channel, transporter, and peptide receptor activity. (4) Conclusions: the quantification of an altered abundance of LINC01087 in tissue specimens might be clinically useful for the diagnosis and prognosis of some hormone-related tumors, including BC, OV, and TGCT, as well as other cancer types such as ESCA and STAD. Moreover, our study revealed the potential of LINC01087 (and perhaps other lncRNAs) to regulate neuroactive molecules in cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Numerous studies have shown that long non-coding RNAs (lncRNAs) can regulate the development and progression of human cancers in various ways. Long intergenic non-coding RNA 173 (LINC00173), as a recently discovered non-coding gene, is dysregulated in 11 human cancers. Its aberrant expression is closely associated with diversified biological processes such as proliferation, migration, and invasion. This review systematically summarizes the latest findings concerning the expression and the regulatory mechanisms of LINC00173, which covers the tumorigenesis and chemoresistance, and regulatory targets of LINC00173, thus providing a novel biomarker for cancer prognosis and a therapeutic target. Long non-coding RNAs belong to non-coding RNAs (ncRNAs) with a length of more than 200 nucleotides and limited protein-coding ability. Growing research has clarified that dysregulated lncRNAs are correlated with the development of various complex diseases, including cancer. LINC00173 has drawn researchers' attention as one of the recently discovered lncRNAs. Aberrant expression of LINC00173 affects the initiation and progression of human cancers. In the present review, we summarize the recent considerable research on LINC00173 in 11 human cancers. Through the summary of the abnormal expression of LINC00173 and its potential molecular regulation mechanism in cancers, this article indicates that LINC00173 may serve as a potential diagnostic biomarker and a target for drug therapy, thus providing novel clues for future related research. [ABSTRACT FROM AUTHOR]