BRAF inhibitors (BRAFi) have transformed the treatment of BRAF mutant melanoma, but inherent and acquired resistance remains a major barrier to curative outcomes. Resistance arises from interconnected mechanisms: genetic alterations reactivating the MAPK pathway or bypass cascades (e.g., PI3K/AKT/RTK), epigenetic modulation, metabolic reprogramming, and the tumor microenvironment (TME) remodeling. Despite extensive research into these mechanisms, a cohesive framework linking each resistance module to targeted therapeutic strategies is lacking. This review systematically categorizes resistance into intrinsic and acquired subtypes: intrinsic resistance is driven by constitutive molecular traits of BRAF mutant melanoma (e.g., persistent MAPK activation, baseline PI3K/AKT hyperactivity), while acquired resistance emerges via therapeutic pressure-induced genetic mutations, epigenetic shifts, metabolic reprogramming, or TME modifications. For each identified resistance mechanism, we provide a detailed examination of corresponding therapeutic advancements. These encompass the development of next-generation BRAFi, strategically designed combination therapies, epigenetic modulators, immunotherapeutic approaches, and RNA-based therapeutic agents. Furthermore, we underscore the pivotal role of state-of-the-art technologies, such as liquid biopsies, single-cell multi-omics analyses, and artificial intelligence, in facilitating precise resistance monitoring and personalized therapy selection. By integrating these insights, we present a structured, translationally focused framework to guide basic research and clinical decision-making, ultimately advancing precision salvage therapy and trials aimed at preventing or overcoming BRAFi resistance.

Even for experts, the diagnosis of soft tissue tumors remains challenging, owing to their rarity, striking diversity, and sometimes subtle morphological differences. Over the past decade, however, significant advances have been made in our collective understanding of the molecular genetic pathogenesis of these rare lesions, especially with the discovery that many are characterized by the presence of characteristic gene fusions, which can be exploited for diagnostic purposes. This review article focuses on four fusion-driven soft tissue tumors which illustrate different aspects of our evolving understanding of these tumors: (1) NUTM1-rearranged sarcoma, a prototypical example of a novel, clinically significant entity defined almost entirely by molecular genetics; (2) SRF-rearranged myoid neoplasm, an entity whose recognition greatly clarifies our understanding of pediatric "leiomyosarcomas;" (3) superficial FET-ETS neurocristic tumor, a very recently described, clinically benign entity sharing identical fusion events with often-lethal Ewing sarcoma; and (4) an evolving family of glomoid/myoid neoplasms harboring EWSR1::WT1 fusions, but clearly differing from desmoplastic small round cell tumor. These examples illustrate the complexity of fusion-driven soft tissue tumors and the importance of integrating molecular genetic testing with other clinicopathological data, rather than viewing it in isolation.

Gallbladder cancer (GBC) is a rare yet highly aggressive malignancy of the biliary tract, characterized by a five-year survival rate of less than 5%. Its asymptomatic onset and the lack of reliable early diagnostic tools contribute to delayed detection and poor clinical outcomes. Although epidemiological and genetic studies have identified numerous risk factors, the molecular mechanisms linking these factors to tumor initiation and progression remain incompletely understood. This review integrates current evidence on the multifactorial etiology of GBC-including geographic variation, genetic predisposition, environmental exposures, chronic inflammation, and infections-with emerging insights into metabolic and molecular dysregulation. Particular focus is placed on metabolic reprogramming as a central driver of carcinogenesis. Altered lipid metabolism, bile acid signaling, and redox imbalance interact with inflammatory and oncogenic pathways, fostering a permissive microenvironment for malignant transformation. Key molecular cascades include inflammation-driven NF-κB activation, bile acid-induced oxidative stress, PI3K/AKT-mediated metabolic remodeling, and DNA damage and repair defects. By consolidating diverse epidemiological and mechanistic data into a unified molecular-metabolic framework, this narrative review identifies new opportunities for biomarker discovery, metabolic imaging, early detection, and targeted therapeutic development, advancing translational research to improve outcomes in this devastating disease.

Several genomic risk stratification tests are available to predict the risk of metastasis and mortality for prostate cancer patients at the time of diagnosis. However, the evidence supporting the clinical utility of genomic risk stratification tools is fragmented, posing challenges in assessing their real-world clinical impact and cost-effectiveness.

Prostate cancers harboring alterations of genes involved in DNA damage response and repair tend to be more aggressive and are associated with poorer survival outcomes. The application of poly (ADP-ribose) polymerase (PARP) enzyme inhibitors (PARPi) improves the survival of patients with prostate cancer carrying germline or somatic BRCA1 or BRCA2 gene mutations, whereas their role in tumors with alterations of DNA repair genes other than BRCA1/2 and proteins remains controversial, as inhibitors of such targets are currently in clinical development. In this study, we provide an overview of the most frequently observed genomic aberrations affecting DNA repair pathways in prostate cancer and discuss how patient selection needs improvement to identify the population that will eventually benefit from PARPi treatment beyond BRCA1/2 deficiency. Further, we explore emerging treatment approaches with novel DNA repair pathway inhibitors, highlighting the biological rationale and how they are believed to overcome current challenges posed by primary and secondary treatment resistance in this heterogeneous disease.

Cervical cancer, a serious gynecological malignancy, often leads to poor patient prognosis due to distant metastasis. The metastasis mechanism is not fully understood. This study explores the link between gene mutations and distant metastasis in cervical cancer. PDGFRA, TP53, and PIK3CA mutations significantly influence metastasis. Despite its low incidence, PDGFRA mutation is closely tied to lymph node and distant metastasis. TP53 mutation disrupts p53 protein function, promoting tumor cell proliferation, inhibiting apoptosis, and enhancing metastasis. PIK3CA mutation activates the PI3K/Akt pathway, stimulating cell proliferation and migration. Detecting these mutations is crucial for diagnosing distant metastasis. It helps identify high-risk patients early, improving diagnostic accuracy and specificity, and guiding clinical treatment decisions. Targeted therapies for PDGFRA and PIK3CA mutations can control tumor growth and metastasis but face challenges like drug resistance and high costs. This study offers a new theoretical basis and treatment strategy for cervical cancer, pointing to future research directions. Gene mutation detection enhances early identification of high-risk patients, improving diagnostic accuracy. Targeted therapies for PDGFRA and PIK3CA mutations control tumor growth but face drug resistance and cost issues. This study provides a new theoretical basis and treatment strategy for cervical cancer, guiding future research.

RNA-binding proteins (RBPs), as posttranscriptional regulators, can modulate the activity and stability of target RNAs and participate in the whole life cycle of RNA processing, localization, modification and translation. RNA-binding motif single-stranded interacting proteins (RBMSs) comprise a critical subgroup within the RNA-binding protein (RBP) family, sharing the same domain characteristics as other RBPs. Several studies have shown that RBMSs can participate in tumorigenesis and tumor progression through mechanisms such as regulating the expression of oncogenes, growth factors and cell cycle proteins. In this paper, we reviewed the role of RBPs and related research progress in breast, prostate, lung, liver, gastric and colorectal cancers.

This literature review explores the complex interaction between p53 and microRNAs (miRNAs) in the occurrence and progression of breast cancer (BC), the most common and lethal tumor type among women. BC is a multifactorial disease resulting from a combination of genetic and epigenetic alterations in cell DNA, influencing proliferation, differentiation, and migration. TP53 gene, which codifies p53 protein, is a known tumor suppressor, and it plays an important role in cell maintenance as DNA repair, cell proliferation control, and apoptosis activation. TP53 expression can be modulated by several miRNAs, as miR-30c, miR-34a, and the miR-200 family, inhibiting p53 production and silencing its tumor suppressor effects. On the other hand, p53 protein can modulate several miRNAs expression, as miR-146a, miR-192, and the miR-200 family, by acting as a transcription factor or by modulating miRNA processing, interfering with BC aggressiveness and progression. Understanding the role of p53 and miRNAs in BC may aid in identifying new biomarkers and developing new targeted therapies for patient treatment.

Metastatic brain tumors undergo profound metabolic-epigenetic reprogramming driven by the unique constraints of the brain microenvironment. Hypoxia-inducible factor-1α (HIF1α) enhances glycolytic flux, lactate accumulation, and histone lactylation, collectively supporting metastatic colonization and immune evasion. Key metabolites including acetyl-CoA, S-adenosylmethionine (SAM), α-ketoglutarate (α-KG), fumarate, and 2-hydroxyglutarate (2-HG)-directly modify chromatin states by regulating histone acetyltransferases, DNA/histone methyltransferases, and α-KG dependent dioxygenases such as Ten-Eleven Translocation (TET) enzymes and lysine demethylases (KDMs). These metabolic shifts result in aberrant DNA methylation, histone lysine residue at position 27 on Histone H3 (H3K27) trimethylation, and depletion of 5-hydroxymethylcytosine (5hmC), all of which are hallmark epigenetic alterations in brain metastasis and primary Central Nervous System (CNS) tumors. Additionally, the blood-brain barrier (BBB) and blood-tumor barrier (BTB) impose nutrient restrictions and induce metabolic dependency on glutamine, acetate, and lactate shuttling, thereby reshaping epigenetic enzyme activity. We synthesize current mechanistic evidence showing how metabolic pressures in the brain microenvironment remodel the epigenome to promote tumor plasticity, stemness, and therapeutic resistance. Understanding these coupled pathways reveals vulnerable nodes such as HIF1α signaling, α-KG-dependent demethylation, and lactate-driven epigenetic remodeling that may be exploited for targeted treatment of metastatic brain tumors. The present review aims to provide in-depth insights into epigenetic regulation, including chromatin and histone modifications as well as noncoding RNAs and metabolic reprogramming, highlighting how the two interplay in the development and progression of metastatic brain tumors and their therapeutic potential.

Tumor survival, genomic stability, and therapy resistance are dictated by the DNA damage response (DDR). Although poly (ADP-ribose) polymerase (PARP) inhibitors have established the DDR as a therapeutic target, many tumors evade first-generation drugs by rewiring their adaptive repair pathways and imposing microenvironmental constraints. This review synthesizes recent discoveries in key DDR pathways, such as PARP, ataxia telangiectasia and Rad3-related kinase (ATR), ataxia telangiectasia mutated kinase (ATM), checkpoint kinase 1 (CHK1), WEE1 G2 checkpoint kinase (WEE1), and DNA-dependent protein kinase (DNA-PK), and describes the next-generation inhibitors designed to increase selectivity and circumvent resistance. We also analyze the role of hypoxia, stromal remodeling, inflammatory cytokines, and immune-cell plasticity in the tumor microenvironment in determining DDR dependency and response. Special attention is paid to cGAS-STING, immunogenic signaling via damage-associated molecular patterns (DAMPs), and mechanisms that convert a cold tumor into a hot one. Lastly, we touch upon the new nanocarrier-based delivery approaches that enhance pharmacokinetics, target resistant tumor niches, and expand the possibilities for combinatorics with immunotherapy and radiotherapy. Collectively, these findings provide a guide to the implementation of next-generation DDR inhibitors and nanomedicines to deliver a more accurate, durable, and context-specific cancer therapy.

Acute myeloid leukemia (AML) remains a biologically heterogeneous disease with historically limited targeted therapies and poor outcomes. The development of menin inhibitors represents a promising shift, particularly for patients harboring KMT2A rearrangements (KMT2Ar) and NPM1 mutations (NPM1m). This manuscript reviews the molecular rationale of menin inhibition for aberrant homeobox/myeloid ectopic insertion site 1 (HOX/MEIS1)-driven gene expression and leukemogenesis, clinical trial outcomes, and safety data for menin inhibitors, with a focus on recently FDA-approved revumenib and several other agents in development, ziftomenib (KO-539), bleximenib (JNJ-75276617), and icovamenib (BMF-219). We also focused our discussion on future directions to include resistance mechanisms, biomarker identification and monitoring strategies, and combination therapies. Menin inhibition is now being clinically integrated into relapsed/refractory and frontline treatment settings.

Thyroid cancer is the most widespread endocrine malignancy. Of all the cases of thyroid cancer, approximately 95% arise from follicular cells. Familial non-medullary thyroid cancers constitute 3-9% of all the reported cases of thyroid cancer and are diagnosed by the presence of two or more first-degree relatives with cancer. Most familial cases of non-medullary thyroid cancer are caused by papillary thyroid cancer and its histological variants. Although some genes predisposing to familial papillary thyroid cancer have been identified, their functionality is unclear, and routine examination is not recommended. Some of these cases may be syndromic, but most cases (>95%) are non-syndromic. Various researchers have suggested an association between familial papillary thyroid cancers and earlier age of onset, higher multifocal tumor rate, extrathyroid enlargement, lymph node metastasis, and disease recurrence. Therefore, screening and close follow-up of other family members are essential when familial papillary cancer is diagnosed. This case report presents a familial papillary thyroid cancer series involving an index male patient with a breast cancer history and his three sisters with thyroid papillary cancer.

The RANO criteria remain the cornerstone for evaluating adult gliomas; however, they often fail in spinal cord gliomas due to anatomical constraints, molecular heterogeneity, and distinct biological behavior. Firstly, central nervous system (CNS) dissemination is a hallmark feature of spinal cord gliomas and a critical driver of mortality, distinguishing them from their brain counterparts where such spread is rare. ‌Moreover, T1-weighted contrast-enhanced MRI typically reveals non-enhancing primary lesions‌, a characteristic feature of ‌H3 K27M-mutant diffuse midline gliomas (DMG)‌ that constitute over 40% of spinal cord gliomas, while ‌non-contrast T2-weighted imaging demonstrates sensitivity and reproducibility. Given the narrow and elongated anatomy of the spinal cord and the unique surgical strategy required for spinal cord gliomas, we advocate for volumetric assessment as the primary evaluation method, utilizing millimeters (mm) rather than centimeters (cm) as the measurement unit, and consider all visually identifiable lesions as measurable. Furthermore, the spinal cord exhibits super-functional integration across motor, sensory, and reflex pathways, thereby accentuating the importance of clinical manifestations and neurological functional assessment in accurately and promptly tracking disease progression. Our objective is to develop the specialized response assessment criteria for spinal cord gliomas to serve clinical trials.

Introuduction: FAT atypical cadherin 1 (FAT1), the Hippo pathway and Yes-associated protein (YAP) signaling play significant roles in cell proliferation, differentiation, and apoptosis. Dysregulation of these pathways contributes to tumorigenesis in multiple cancers, including head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma (HCC), and breast cancer.

Premenopausal women carrying a BRCA1 or BRCA2 mutation are frequently advised to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) to lower their significantly increased lifetime risk of ovarian cancer. However, this procedure induces abrupt estrogen deprivation, resulting in premature menopause with well-documented consequences including vasomotor symptoms (e.g., hot flashes, night sweats), urogenital atrophy, and long-term risks such as osteoporosis, cardiovascular disease, and cognitive decline (Nelson in Lancet 371(9614):760-770, 2008; Shuster et al. in Maturitas 65(2):161-166, 2010). To alleviate symptoms and prevent sequelae, hormone replacement therapy (HRT) remains the most effective intervention. However, the issue becomes complex when the patient has a personal history of triple-negative breast cancer (TNBC). Although TNBC lacks hormone receptor expression, systemic HRT has traditionally been contraindicated in breast cancer survivors, as early studies indicated an increased risk of recurrence with hormone therapy, even in receptor-negative subtypes (Kenemans et al. Lancet Oncol 10(2):135-146, 2009a). This leads to a critical question: Is HRT appropriate in BRCA mutation carriers with a history of TNBC following BSO, and if so, under what clinical conditions? What do current international guidelines, evidence, and expert recommendations suggest?

Clonal haematopoiesis (CH) is an age-related condition increasingly recognised for its relevance in haematologic malignancies. In chronic lymphocytic leukaemia (CLL), its prevalence and clinical implications are gaining attention, particularly in the context of prolonged patient survival and the widespread adoption of targeted therapies. A comprehensive understanding of the biological and clinical significance of CH in CLL is therefore essential.

The aryl hydrocarbon receptor (AhR) is a ubiquitously expressed, ligand-activated transcription factor which has been extensively studied for its role in mediating the toxic effects of several common environmental pollutants. However, more recent findings associating AhR with carcinogenesis and tumor progression have expanded the scope of AhR research and established the preclinical significance of AhR as a possible target for cancer therapy. In this review, the current knowledge of the role of AhR in cancer will be discussed, and evidence from an array of experimental cancer and immune models will be presented. It has been observed that AhR potentiates oncogenic mutations through induction of genetic damage and transactivates EGFR to promote proproliferative signaling along the classical Ras/Raf/MAPK and PI3K/Akt pathways. Furthermore, AhR downregulates E-cadherin via multiple axes to facilitate epithelial-to-mesenchymal transition and contributes to a shift of the tumor immune microenvironment to a predominantly regulatory milieu. The sheer versatility of AhR as a protumor factor should provide sufficient grounds for further investigation of the persisting question of whether targeting AhR can disrupt tumor progression in vivo.

MicroRNAs (miRNAs) are small noncoding RNAs that mediate post-transcriptional gene silencing through a conserved pathway involving the sequential actions of DROSHA, DICER and Argonaute proteins. These RNA interference core components recognize and process precursor transcripts with structural precision to generate functional miRNA duplexes and guide-loaded Argonaute effector complexes. Recent genetic and structural studies have revealed disease-associated mutations in these proteins, particularly within their catalytic centers and RNA-binding interfaces, that impair miRNA biogenesis and contribute to human pathologies. Such mutations disrupt RNA cleavage fidelity, destabilize domain architecture or hinder small RNA loading, leading to cancers and developmental disorders, including Wilms tumor, DICER1 syndrome, myelodysplastic syndromes and Lessel-Kreienkamp syndrome. This Review highlights the structural basis of these pathogenic mutations and discusses how emerging insights from structural biology are shaping our understanding of RNA interference-related disease mechanisms and guiding potential therapeutic strategies.

The incidence and mortality of colorectal cancer (CRC) are steadily rising. Phosphatase-Tensin Homolog Deleted on Chromosome 10 (PTEN) expression is often dysregulated during tumourigenesis; however, its prognostic value in CRC remains debated. This study evaluated the correlation between PTEN expression and the clinicopathological characteristics of CRC patients, and its prognostic significance. A systematic literature review was conducted across Web of Science, PubMed, Cochrane Library, and CNKI up to June 2023. Thirteen studies with a total of 2,377 participants were included. PTEN expression was significantly lower in CRC tissues than in normal mucosa tissues. Positive PTEN expression was associated with better overall survival and favourable pathological features. No significant correlation was found with age, gender, differentiation grade, tumour size, or distant metastasis. Negative PTEN expression is a poor prognostic marker in CRC and may serve as a potential indicator for disease monitoring and outcome prediction. Key Words: PTEN, Colorectal cancer, Prognosis, Meta-analysis, Clinical characteristics.