Pheochromocytomas and Paragangliomas (PPGL) are rare neuroendocrine tumors with favorable prognosis, although a significant subset (20-25%) progress to metastasis, worsening patient prognosis. For metastatic cases, pharmacological interventions become essential, yet most tumors show poor response to treatment. While clinical trials are ongoing, there is no established treatment for metastatic PPGL. Like other neuroendocrine tumors, PPGL exhibit high membrane expression of somatostatin receptors, and despite Peptide Receptor Radionuclide Therapy, PRRT, strategies have successfully been implemented, trials with cold somatostatin analogs were abandoned prematurely due to inconsistent results. To investigate this issue and identify potential therapeutic tools, we widely profiled somatostatin receptors expression in PPGL and conducted a comprehensive functional screening on wild-type and SDHB knockdown PPGL cell lines of native and synthetic somatostatin analogs. Results revealed that pheochromocytomas and paragangliomas similarly display a predominant SSTR2 and SSTR1 expression regardless of molecular cluster. Treatment with somatostatin, cortistatin, octreotide or pasireotide did not exert clear antitumoral effects on model cell lines. Notably, the selective SST2 agonist BIM-23120 significantly reduced cell proliferation and induced apoptosis in an SST2-dependent manner, but only in SDHB knocked-down PPGL cells. Indeed, only SDHB KD cells showed stronger membrane-enriched SST2 and clear receptor internalization upon BIM-23120 treatment. Molecular analysis revealed a generalized dephosphorylation affecting key proliferation, growth and cell survival pathways in response to BIM-23120 (unlike when treating with octreotide). Altogether, our results provide novel information on the status of the somatostatin system in PPGL and identify new potential therapeutic tools selectively targeting somatostatin receptors on this refractory tumor.

Precision cancer medicine (PCM), targeting cancer treatment to patients' individual genomic profiles, has the potential to improve diagnosis and outcomes substantially. Implementing PCM in healthcare systems requires that extended molecular diagnostics are accessible as part of routine practice. We conducted a mixed-methods study to identify and inform the infrastructure necessary for the implementation of extended molecular diagnostics as part of the health care system.

Osteosarcoma is a highly malignant bone tumor which primarily affects the juvenile population and is characterized by high rate of recurrence and metastasis. RNA editing has emerged as a key process in cancer progression. Herein, we investigated the role of RNA editing enzyme ADAR2 (Adenosine Deaminase Acting on RNA 2) in osteosarcoma. We demonstrated that ADAR2 expression increases during osteoblast differentiation and inversely correlates with the aggressiveness of osteosarcoma cells. Interestingly, the overexpression of ADAR2 in osteosarcoma cell lines reduces their tumoral properties and promotes their differentiation in osteoblast-like cells, as shown by gene expression analysis and mineralization assays. These results were also confirmed by in vivo experiments; indeed, intratibial injection of ADAR2-overexpressing osteosarcoma cells in NSG mice resulted in less aggressive tumors compared to mice injected with pEmpty or pInactive ADAR2 E/A vector-transfected cells. To elucidate the mechanisms by which ADAR2 overexpression induces osteogenic terminal differentiation of osteosarcoma cells, we performed RNA-seq analysis of Saos-2 cells and identified IGFBP7 (Insulin-like Growth Factor Binding Protein 7) as the most highly edited transcript in ADAR2-overexpressing cells. We showed that the editing activity of ADAR2 on IGFBP7 abolishes its proliferative effect on osteosarcoma cells and triggers terminal differentiation. Overall, our results indicate that ADAR2 acts as a tumor suppressor in osteosarcoma and may represent a novel therapeutic target for this aggressive pediatric tumor.

The RHO GTPase family regulates cytoskeleton-dependent processes, including proliferation and migration. Although their dysregulation is well described in solid tumors, little is known about their role in hematologic malignancies. We investigated the expression of ten RHO GTPase genes in bone marrow samples from patients with acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) and analyzed TCGA AML data for prognostic associations. RHOBTB2, RND2, and RHOQ were differentially expressed compared with healthy controls. RHOBTB2 was elevated in both MDS and AML and associated with inferior overall and disease-free survival, including in intermediate-risk AML. Our findings reveal distinct dysregulation patterns of RHO GTPases in myeloid malignancies and confirm RHOBTB2 as a candidate prognostic marker in AML with a potential oncogenic role. These data support further investigation into the functional roles of RHO GTPases in leukemogenesis and their utility as emerging biomarkers in hematologic cancers.

Research in the 1970s showed that while retroviruses had been a key to identification of oncogenes, they were not actually a major cause of human cancer. Moreover, cells contained additional proto-oncogenes that did not necessarily have viral oncogene counterparts. In this excerpt from his forthcoming book, Joe Lipsick remembers the groundbreaking work on DNA transfection, chromosomal rearrangements, and gene amplification that identified the smoking guns responsible for activation of oncogenes such as RAS and revealed how translocations in immune cells produce cancer drivers like the Philadelphia chromosome.

Ewing sarcoma (ES) and its variants are rare and aggressive malignancies, occurring in paediatric and younger adult populations. Adamantinoma-like ES (ALES) is one of its variants, characterised by EWSR1::FLI1 fusions, and is exceptionally rare, especially in older adults. There are a few similar cases reported in the literature. We report a rare case of an older adult with a complicated medical history and reported a left neck mass on a follow-up visit; the mass developed over nine months. After evaluation, he was found to have a rare diagnosis of ALES in this age group, specifically with this Ewing Sarcoma RNA binding protein 1 and nuclear factor of activated T cells cytoplasmic 2 (EWSR1::NFATC2) gene fusion. This case highlights the challenges of diagnosing and the multidisciplinary management of rare variants of ES with uncommon gene fusions and raises awareness for the future potential of molecular diagnostics and treatment-specific applications for improved access to care and better outcomes for this population.

Osteosarcoma (OS) is a malignant tumor originating from osteoblasts. Methyltransferase-like 14 (METTL14) is an N6-methyladenosine (m6A) methyltransferase that has been reported to promote OS progression; however, its underlying mechanism remains unclear.

Macrocephaly, defined as a large head size, has a very broad differential and sometimes can be challenging to differentiate as benign versus indicative of pathology. In this review, we outline a stepwise approach to improving diagnosis of neurogenetic disorders versus other causes using the example of PTEN (phosphatase and TENsin homolog) Hamartoma Tumor Syndrome (PHTS). PHTS is a multiple hamartoma syndrome with medical management implications including the need for tumor surveillance, but often cases are not diagnosed until later in adulthood. Our review emphasizes the utility of using head circumference z scores in combination with other features as a triage tool for genetic identification of disorders such as PHTS.

Cancer predisposition due to constitutional (germline) genetic variants in high-risk or moderate-risk cancer predisposition genes presents clinical opportunities for risk mitigation. Focusing genetic testing only on patients who are most likely to be positive for germline variants might enhance the clinical utility of positive results, but this approach could fail to assess the rate and pattern of such variants in patients with cancer overall. We aimed to assess the frequency and nature of constitutional variants in cancer predisposition genes in patients with cancer in the UK health-care system.

Fulzerasib, a KRASG12C inhibitor, has shown clinical activity in previously treated non-small-cell lung cancer (NSCLC). Clinical studies indicate that combining a KRASG12C inhibitor with an anti-EGFR antibody is effective in colorectal cancer; however, its benefit in NSCLC remains to be explored.

mRNA can be engineered to overcome cancer evolution.

Cell reprogramming can be used to short-circuit the cancer-immunity cycle.

Extrachromosomal circular DNA (eccDNA) are molecules that originate from chromosomal DNA but exist independently. While large eccDNA (ecDNA) contributes to tumorigenesis, the role of smaller eccDNA (<100,000 base pairs) in cancer remains unclear. Our analysis of 25 colorectal cancer (CRC) tumors and normal adjacent tissues revealed that eccDNA is significantly more abundant in tumor tissues, correlating strongly with chromosomal amplifications. The presence of whole intact genes on 1.29% of eccDNA was nonrandom. We identified 84 genes that recurred across tumors of multiple patients when present on eccDNA, with 19% of genes being cancer-associated. eccDNA-borne genes were often accompanied by increased expression, and their contribution to expression was much larger than that from linear amplifications and the larger ecDNA. The cytokine gene CXCL5 exemplified this phenomenon, showing substantial copy-number increase and upregulation when present on eccDNA. Functional validation in cell lines showed that CXCL5 eccDNA enhanced transcriptional output and immune cell recruitment function. The recurrence and overexpression of CRC-related genes on eccDNA indicate their selection in tumors, suggest that eccDNA can serve as an additional mechanism for dynamically influencing gene expression and is capable of conferring cancer phenotypes on cells. Analysis of chromatin landscapes revealed that eccDNA preferentially forms at sites of open chromatin and active transcription, with architectural boundaries marked by CTCF protein. Clinically, higher eccDNA levels correlated with poorer relapse-free survival in a small patient cohort. These findings suggest that circular DNA elements across the entire size spectrum participate in cancer evolution and warrant further investigation in larger cohorts.

Mutations in PIK3CA are one of several actionable mutations for patients with hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer. Alpelisib in combination with fulvestrant was the first approved PI3K inhibitor and was introduced in clinical practice in 2019. A lack of evidence for the use of alpelisib in the context of current treatment options like cyclin-dependent 4/6 inhibitor (CDK4/6i), highlights the importance of this analysis. We provide a real-world analysis of the use of alpelisib with the prospective German PRAEGNANT registry (NCT02338167).

Hepatocyte nuclear factor 4 alpha (HNF4α) is a conserved nuclear receptor that governs epithelial identity and metabolic homeostasis across endoderm-derived tissues. In cancer, HNF4α can function as either an oncogene or a tumor suppressor. In colorectal and hepatocellular carcinoma, reduced HNF4α activity accompanies loss of differentiation and tumor progression, consistent with tumor-suppressive functions. In contrast, in pancreatic ductal adenocarcinoma, invasive mucinous adenocarcinoma, and other lineage-defined epithelial tumors, HNF4α can also participate in transcriptional programs that sustain malignant identity, metabolic adaptation, and therapeutic resistance. However, these effects are highly context-dependent and do not imply a uniformly oncogenic role in these tumor types. These divergent functions are shaped by isoform usage, chromatin state, epigenetic regulation, metabolic cues, and transcription factor networks. Rather than acting as a classical oncogene or tumor suppressor in all settings, HNF4α is better understood as a context-dependent regulator of lineage state whose activity may either restrain tumor progression or support tumor maintenance. This mini review highlights the molecular mechanisms that shape HNF4α activity, including isoform biology and epigenetic control, and discusses emerging strategies for selectively inhibiting HNF4α in dependency states or restoring its differentiation-promoting functions in tumors where it is lost.

To evaluate whether 7-T susceptibility-weighted imaging (SWI) can predict glioma's histological grade, Ki-67 labeling index (LI), isocitrate dehydrogenase 1 (IDH1) mutation, 1p/19q co-deletion, telomerase reverse transcriptase (TERT) promoter mutation, and O-6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status of gliomas.

Immunotherapy has revolutionized cancer treatment, yet characterizing the spatial complexity of the tumor immune microenvironment remains a challenge. In this study, we established a comprehensive computational framework integrating multi-omics profiling across 27 cancer types to decode immune-related non-coding RNA regulatory networks. Moving beyond traditional bulk analysis, we utilized spatial transcriptomics to dissect the spatial localization of these regulators. We identified the SNHG6-BIRC5 axis as a critical driver of the "immune-cold" phenotype in lung adenocarcinoma. We provide visual evidence that this axis localizes to tumor nests and negatively correlates with T- cell infiltration, elucidating a mechanism of spatial immune exclusion. Validating the clinical relevance of these findings, genome-scale CRISPR-Cas9 screening data confirmed the functional essentiality of these targets for cancer cell survival. Furthermore, pharmacogenomic analysis revealed that high expression of this axis correlates with sensitivity to chemotherapy agents like Vinblastine, suggesting a potential stratification strategy for patients with immune-excluded tumors. To expand the clinical utility to immunotherapy prediction, we developed a pan-cancer XGBoost machine learning model incorporating 14 high-performance regulatory features. This model achieved robust performance in distinguishing immunotherapy responders from non-responders with an AUC of 0.771, outperforming traditional markers such as PD-L1. Collectively, this study highlights spatial determinants of immune exclusion and chemotherapy sensitivity- and presents a generalized machine- learning tool for precision immunotherapy stratification. The developed online resource is freely available to facilitate community-wide biomarker discovery.

The Muscleblind-like (MBNL) family comprises evolutionarily conserved RNA-binding proteins that interact with target RNAs via zinc finger domains. MBNLs orchestrate RNA processing, particularly alternative splicing, driving the developmental fetal-to-adult isoform switch across numerous target transcripts. This transition is a cornerstone in the process of MBNL-maintained cellular homeostasis and fails in many pathological conditions associated with deregulated expression or function of specific MBNL paralogs. This review provides current insights into the roles of MBNL genes and proteins in both health and disease. We examine their genomic architecture and protein organization and synthesize key insights from animal models to delineate the selective and compensatory functions of individual MBNL paralogs in physiology. To illustrate the roles of MBNLs in disease, we outline nucleotide repeat expansion disorders marked by their functional depletion, with a primary focus on myotonic dystrophy (DM). We also highlight selected cancer studies that have demonstrated the dual roles of MBNLs in tumorigenesis, encompassing both pro-oncogenic and tumor suppressive functions. Finally, using DM as a model, we review evidence for the therapeutic potential of endogenous MBNL gene modulation and argue that analogous strategies could be adapted and tailored to restore MBNL homeostasis in other disorders involving their dysregulation.

DNA microarray is a transformative technique in genomics, enabling simultaneous examination of thousands of gene expression levels. However, noise, high dimensionality (typically 12,000-22,000 genes), small sample sizes (155-1097 samples) and class imbalance complicate the extraction of meaningful diagnostic patterns. This paper presents MICRO-AI (Microarray Classification and Recognition using Artificial Intelligence), a comprehensive machine learning framework for DNA microarray analysis and automated disease diagnosis. The framework integrates advanced preprocessing (quantile normalisation, ComBat batch correction, KNN imputation), attention-weighted adaptive feature selection using recursive feature elimination with cross-validation, and heterogeneous ensemble classification combining gradient boosting machines, random forests and support vector machines with adaptive weight optimisation. A novel attention-based feature fusion mechanism dynamically prioritises discriminative gene expression signatures, reducing dimensionality by over 99% (from ∼20,000 to ∼127 genes) without loss of biological significance. MICRO-AI is validated on six benchmark datasets from three repositories: Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) and ArrayExpress, spanning breast cancer, gastric cancer, ovarian cancer and leukaemia across 2321 total samples. Experimental results demonstrate average classification accuracy of 96.8%, sensitivity of 95.2%, specificity of 97.4%, F1-score of 96.0%, Matthews correlation coefficient of 0.928, and area under the receiver operating characteristic curve of 0.983. Comparative benchmarking against 10 state-of-the-art methods shows that MICRO-AI achieves 1.2-7.5% higher accuracy with an average training time of 52.3 s, representing 2.4-6.0× faster execution than deep learning alternatives. The modular architecture enables seamless integration with medical informatics systems for scalable clinical diagnostic deployment.

Non-small cell lung cancer (NSCLC) is a malignant tumor characterized by high morbidity and mortality, as well as metabolic reprogramming. Enhanced serine synthesis plays a crucial role in the aberrant metabolism of NSCLC. Among the three key enzymes involved in serine synthesis, phosphoserine aminotransferase 1 (PSAT1) requires further investigation to elucidate its regulatory mechanisms in NSCLC.