Ongoing discoveries in cancer research keep expanding the landscape of renal cell carcinoma classification, particularly for "molecularly-defined" tumors like TFE3-rearranged and TFEB-altered renal cell carcinoma. However, scientific updates often do not align with pathologists' daily practice and resources. Herein, we present the results from a national Italian survey assessing physicians' personal experience on TFE3-rearranged and TFEB-altered renal cell carcinomas.

The aim of this study is to assess the impact of Oncotype DX on treatment decisions and healthcare economy.

Primary neuroendocrine carcinoma of the breast (NEBC) is a rare entity among breast malignancies, and is usually associated with a more aggressive clinical course compared to other types of invasive breast cancer. Although some studies have characterized the molecular profile of NEBCs using targeted sequencing, these tumors are often treated similarly to other primary breast carcinomas despite their unique morpho-phenotypic characteristics. In this study, we present the case of a woman with HER2-positive primary large cell NEBC with homolateral axillary nodal metastases. After neoadjuvant therapy, the patient underwent surgical resection of the breast, showing a partial pathological response. Next-generation sequencing was performed on pre- and post-treatment samples using a 174-genes panel. Both samples exhibited a similar molecular profile, including a somatic mutation in GATA3 and amplifications of CCND1, FGF19, and IGF1R. ERBB2 amplification was identified in the pre-operative biopsy but was lacking in the post-treatment surgical specimen. This study represents the first report of CCND1, FGF19, and IGF1R gene amplification in a breast neuroendocrine carcinoma. These findings provide new insights into the molecular profile of this entity and may contribute to future studies on precision oncology.

Despite the promising introduction of anti-PD-L1 therapy for advanced stage of prostate cancer (PCa), recent studies have demonstrated limited success, suggesting the need to improve patient selection.

Aryl hydrocarbon receptor nuclear transporter-like 2 (ARNTL2) can bind to clock circadian regulator (CLOCK) to regulate gene expression and is abnormally expressed in various cancers. Nevertheless, its effects on esophageal cancer (ESCC) are unclear. This work can uncover the intriguing mechanism of ARNTL2 in ESCC.

5-hydroxymethylcytosine (5hmC), an epigenetic modification derived from the oxidation of 5-methylcytosine (5mC) by the ten-eleven translocation (TET) family of dioxygenases, plays a pivotal role in the regulation of gene expression, cellular differentiation, and developmental plasticity. Once considered an intermediate in DNA demethylation, 5hmC is now recognized as a stable and functionally significant epigenetic mark with distinct genomic distributions and significant regulatory implications. This review provides a comprehensive analysis of the biological functions of 5hmC in normal cellular processes, including its role in maintaining tissue-specific gene expression, lineage commitment, and genomic integrity. We also describe its role in cancer, the mechanistic underpinnings of its loss or redistribution in tumor cells, and how these changes contribute to oncogenic signaling pathways, epithelial-mesenchymal transition, and tumor heterogeneity. Furthermore, we explore the utility of 5hmC as a biomarker in cancer diagnostics and prognostics, supported by recent advances in sequencing technologies and cell-free DNA profiling. We also examine the intersection of 5hmC and chemotherapy, highlighting how aberrant 5hmC levels can influence drug resistance and sensitivity, and assess the therapeutic potential of targeting TET enzymes and associated pathways. By integrating insights from basic epigenetics, cancer biology, and therapeutic research, this review underscores the multifaceted role of 5hmC in human malignancies and outlines the translational opportunities for exploiting 5hmC-related mechanisms in precision oncology.

To date, results on relationship between CYP3A4 gene polymorphism were limited and inconclusive, and no study focused on the influence of CYP3A4 gene-obesity interaction on breast cancer risk, especially in Chinese women. The purpose of this study was to evaluate the impact of four single nucleotide polymorphisms (SNPs) of CYP3A4 gene, the SNP-SNP and gene-environment interactions on the susceptibility to breast cancer in Chinese women.

von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome caused by germline pathogenic variants in the VHL gene. The current standard of care primarily involves surgical resection, which is arbitrarily recommended for renal tumours ≥ 3 cm to reduce the risk of metastasis. However, this approach often leads to repeated surgeries and increased patient morbidity. The key unmet clinical need for VHL patients is the ability to predict the most appropriate therapeutic strategy and the optimal timing for surgical intervention on an individualised basis. Here, we describe a methodology designed to create an integrated map of intra- and inter-tumour heterogeneity in VHL-associated clear cell renal cell carcinoma by combining radiomics, histology, RNA sequencing, whole genome sequencing, and patient-derived organoid cultures from multi-regional tumour biopsies. We hypothesise that decoding this heterogeneity through an integrated analysis of imaging, histopathology, and molecular profiling will enhance diagnostic accuracy and enable more informed and personalised therapeutic decisions for VHL patients. RELEVANCE STATEMENT: Due to the current lack of biological or molecular markers assisting clinical decision-making, VHL patients undergo multiple surgical interventions with an incremental risk of complications and morbidity. We expect that our multimodal data study protocol will give tools to guide clinical management. KEY POINTS: Multiregional needle biopsies enable comprehensive analysis even in small ccRCC. Imaging characteristics suggest the presence of intra- and inter-lesion heterogeneity. Tumours are clonally independent and harbour distinct chromosome 3p loss events. Tumours display both intra- and inter-tumour transcriptomics heterogeneity. Patient-derived organoids grow more easily from areas of low tumour density.

Human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive neurodegenerative disease affecting motor and sensory functions. While alterations in cerebrospinal fluid (CSF) have been used to identify disease biomarkers, the effects of such modified CSF on CNS cells remain unexplored. This study compared the effects of pools of CSF from HTLV-1 asymptomatic carriers (HAC) and HAM/TSP patients-categorized by disease progression as: very slow (HAMvs), typical (HAMt), and rapid (HAMr)-on the glioblastoma cell line U87-MG, a cellular model often used to study neurodegenerative diseases. RNA sequencing of U87-MG cells treated with a pool of CSFs from HAMr patients revealed a significant downregulation of transcription of mitochondrial genes after 24 h of treatment. Confocal microscopy showed phenotypical changes in the mitochondrial network: glioblastoma cells exposed to pooled HAMr CSF exhibited a less complex network compared to other patient groups. Despite these changes, U87-MG cells treated with CSF from HTLV-1-infected donors with distinct neurological outcomes presented similar mitochondrial oxygen consumption. In conclusion, these findings show that pooled HAMr CSF induces mitochondrial stress in glioblastoma cells, suggesting that CSF alterations may participate in rapidly progressing HAM/TSP pathogenesis.

Development shapes the growth and organization of organisms, enabling the emergence of complex biological structures and functions. Investigating the development process is vital for uncovering the formation of complex biological systems. However, current approaches to studying development from gene expression rely primarily on single-cell gene expression data to infer developmental trajectories, neglecting the spatial distribution of cells within tissues and their interactions. Although spatial transcriptomics provides spatial context for gene expression, existing algorithms focus mainly on identifying spatial regions without further exploring their developmental connections. In this study, we propose an algorithm for detecting spatial-temporal domains in tissue to trace developmental path (stTrace) using spatial transcriptomics. stTrace integrates the degree of cell development, gene expression, and spatial location to identify "spatial-temporal domains," regions where cells share similar functions and developmental stages within the tissue. Moreover, hierarchical relationships exist among these domains, reflecting developmental connections between cells in the tissue. Applied to mouse embryo and human breast cancer datasets, stTrace achieved higher resolution and developmental consistency than traditional spatial domain identification algorithms. In the mouse dataset, spatial-temporal domains identified by stTrace in brain and eye areas have significant gene expression differences, while in human cancer data, it enabled reconstruction of a developmental tree that inferred cancer cell spread directions consistent with marker gene expression patterns.

It has been observed that lung cancer patients are more susceptible to COVID-19. Establishing the causal relationships between lung cancer and COVID-19 susceptibility and severity is challenging due to numerous confounding factors. Mendelian randomization (MR) is an effective method to investigate the causal association between exposure and outcome variables. However, different studies have yielded conflicting conclusions regarding the role of lung cancer in COVID-19 susceptibility and severity. Lung cancer subtypes exhibit heterogeneity in genetic susceptibility, which may influence the assessment of the true relationship between lung cancer and COVID-19 susceptibility and severity. In this study, we utilized the most recent COVID-19 association data from The COVID-19 Host Genetics Initiative with more than two million samples in total, in combination with genetic data of different lung cancer subtypes with more than eighty-five thousand samples, and conducted a two-sample Mendelian randomization study. We examined the associations between lung cancer and its four subtypes with COVID-19 susceptibility, hospitalization, and severity. Our data indicates that lung cancer, overall, does not have a causal association with COVID-19 susceptibility, hospitalization, or severity. However, lung cancer in ever smokers is nominally associated with COVID-19 hospitalization p-value 0.035, false discover rate (FDR) [Formula: see text] and increased severity [Formula: see text], [Formula: see text]. Additionally, small cell lung carcinoma is associated with increased COVID-19 severity [Formula: see text], [Formula: see text].

Lineage plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to tumor heterogeneity and therapeutic resistance. Here, we identify KLF5 as a dynamic master regulator of epithelial lineage identity in PDAC, with dichotomous roles in promoting either classical or basal-like transcriptional programs. Through unbiased proteomic and genetic screens, we uncover the AAA+ ATPases RUVBL1 and RUVBL2 as essential coactivators of KLF5 across both lineage states. We demonstrate that ATP hydrolysis by RUVBL1/2 is required for the stable interaction with an intrinsically disordered region of KLF5, enabling its recruitment to lineage-specific enhancers and driving transcriptional regulation of identity-defining genes. Notably, small-molecule inhibitors of RUVBL1/2 ATPase activity, which have anti-PDAC activity in vivo, suppress KLF5-dependent transcription. These findings define a previously unrecognized mechanism of ATP hydrolysis-dependent transcriptional coactivation and highlight a potential therapeutic strategy for modulating aberrant lineage programs in cancer.

Prostate cancer is the second most common cancer in men. Although androgen deprivation therapy is initially effective, resistance inevitably develops. Most patients eventually progress to castration-resistant prostate cancer, a stage with limited treatment options and poor prognosis. Rho kinases (ROCK1 and ROCK2) have been implicated in cancer progression, but their therapeutic targeting remains limited. This study examined the pathological roles of ROCK1 and ROCK2 in epithelial-mesenchymal transition (EMT) and proliferation of prostate cancer cells. ROCK1 expression was comparable between human prostate epithelial cells (PrECs) and androgen-independent prostate cancer cells, PC-3 and DU145. In contrast, ROCK2 expression was higher in PC-3 cells than in PrECs and DU145 cells. EMT marker analysis revealed that PC-3 cells exhibited decreased E-cadherin and increased N-cadherin and Snail expression. ROCK2 knockdown reversed this EMT phenotype, reducing cell proliferation, migration, 3D tumor spheroid formation, and spheroid cell viability. Similar inhibitory effects were observed by the ROCK2-selective blocker KD025 (IC50 = 422 nM). Furthermore, ROCK2 deficiency attenuated the tumor growth of PC-3 cells in a xenograft mouse model. These findings indicate that ROCK2 promotes EMT process and tumor progression in PC-3 cells. Targeting ROCK2 may represent a promising therapeutic strategy for androgen-independent prostate cancer.

The purpose of this study was to compare the perioperative efficacy and safety of neoadjuvant chemoradiotherapy (NCRT) alone versus short-course radiotherapy combined with immunochemotherapy (SCRT + ICT) in patients with proficient mismatch repair (pMMR) rectal cancer.

Pleural effusion (PE) is a common clinical manifestation associated with advanced stages of both malignant and non-malignant diseases. PE frequently occurs in advanced non-small cell lung cancer (NSCLC) and contributes to tumor progression. NSCLC accounts for more than 85% of the lung cancers and remains a problem worldwide due to its late diagnosis and low rate of response to treatment. Extracellular vesicles (EVs) present in PE are emerging as key mediators of intercellular communication, capable of transferring oncogenic signals through their molecular cargo. Among these molecules, microRNAs (miRNAs) are increasingly recognized as important drivers of cancer progression. miR-21 is a representative onco-miRNA, involved in lung cancer progression; moreover EV-miR-21 upregulation at the pre-dissemination stage promotes cancer cell survival in the pleural cavity. This study compares, for the first time, the functional role of EVs isolated from malignant PE in NSCLC patients (NSCLC-PE-EVs) with those isolated from PE in patients with congestive heart failure (CHF-PE-EVs), focusing on their ability to modulate lung cancer cell behavior. The effects of these EVs were evaluated on COLO699 lung adenocarcinoma cells with proliferation, migration, and gene expression assays. NSCLC-PE was found to contain approximately twice the amount of EVs compared to CHF-PE. NSCLC-PE-EVs were enriched in the oncogenic miR-21-5p, while CHF-PE-EVs had higher levels of the tumor-suppressive miR-126-3p. Only NSCLC-PE-EVs induced dose-dependent increases in COLO699 cell proliferation and migration, consistent with elevated miR-21-5p expression. Functional studies confirmed that miR-21-5p mediates these effects by downregulating PTEN and PDCD4, and by upregulating MMP9 expression. Our findings show that NSCLC-PE-EVs promote malignant phenotypes in lung cancer cells via the transfer of miR-21-5p.

Hemangioblastoma is an uncommon tumor of uncertain histogenesis, primarily found in the central nervous system. However, extraneural cases have been reported in visceral organs such as the kidneys, pancreas, peritoneum, and liver. Hemangioblastoma occurring in the gastrointestinal tract is extremely rare, with only 4 cases can be retrieved. Here, we presented a case of rectal hemangioblastoma.

Tumor tissues are composed of malignant subclones with diverse genetic profiles. Reconstructing the evolutionary trajectory of these subclones is crucial for understanding how tumors acquire malignant traits. However, current approaches to subclonal tree reconstruction are limited either by their reliance on single-cell DNA sequencing (scDNA-seq) that involve a small number of cells and thus yield low-resolution results, or using single-cell RNA sequencing (scRNA-seq) data, which despite including larger cell populations, remain susceptible to bias from high dropout rates and technical noise. Here, we introduce CluVar, an autoencoder-based framework for inferring the phylogeny of cancer subclones from scRNA-seq data using mutation profile analysis. To address the extensive missing variant information inherent in scRNA-seq datasets, CluVar incorporates a customized loss function and multiple hidden layers optimized for clustering. CluVar demonstrated superior performance in reconstructing phylogenetic trees of cancer subclones under a range of erroneous conditions. When applied to cancer scRNA-seq data, the phylogenetic tree predicted using CluVar aligned well with the transcriptomic profiles. These findings highlight its utility for tracing evolutionary trajectories and identifying novel variants associated with cancer progression.

Chronic obstructive pulmonary disease (COPD) commonly co-occurs with lung cancer, particularly lung adenocarcinoma (LUAD), suggesting a potential shared molecular mechanism and risk factors between the 2 conditions. This study aimed to explore the causal relationship between COPD and LUAD mediated by immune cells using a 2-step, 2-sample Mendelian randomization (MR) analysis. The random-effect inverse variance weighted method, which combines the Wald ratio of individual single-nucleotide polymorphisms, was employed as the primary approach for causal inference, with random-effects models utilized in the presence of heterogeneity. Mediation analysis was conducted to assess indirect effects in the pathway from COPD to LUAD. The MR analysis demonstrated that COPD increased the risk of LUAD (odds ratio = 1.180, 95% confidence interval [CI]: 1.004-1.387, P = .045). Furthermore, among 40 immune cell traits examined, 5 were associated with an elevated risk of LUAD, while 6 exhibited a detrimental effect. Importantly, the mediation MR analysis revealed that the indirect impact of COPD on LUAD was partially mediated by Activated & resting Treg cells (mediation effect: 0.010, 95% CI: 0.001-0.021; P = .047) and Activated & secreting Treg cells (mediation effect: 0.004, 95% CI: 0.001-0.008; P = .044). These findings suggest a positive association between COPD and LUAD, with a partial mediation effect through Activated & resting Treg cells and Activated & secreting Treg cells.

Pneumonic-type lung carcinoma is a rare radiological lung cancer subtype. Its clinical and imaging manifestations are easily confused with pneumonia, leading to frequent misdiagnosis and mistreatment in clinical practice.

Subhealth status (SHS), an intermediate state between health and disease, is increasingly prevalent, yet its potential causal role in cancer remains unclear. Leveraging publicly available genome-wide association data from the Integrative Epidemiology Unit, we conducted a two-sample Mendelian randomization (MR) study to estimate the causal effects of 4 SHS proxies - heart rate variability (HRV), health satisfaction, irritability, and mood swings - on risk of lung, breast, colorectal, prostate, cervical, pancreatic, and basal-cell carcinoma. Inverse variance-weighted (IVW) regression was the primary analysis, supplemented by sensitivity analyses (weighted median, MR-Egger, radial IVW, maximum likelihood). Genetically predicted higher HRV (standard deviation of normal-to-normal interbeat intervals and peak-to-valley respiratory sinus arrhythmia or high-frequency power) was associated with lower colorectal cancer risk. Higher irritability was causally linked to increased lung cancer risk. Mood swings showed a modest positive association with basal-cell carcinoma. Greater health satisfaction was associated with higher risks of cervical and pancreatic cancer. No directional pleiotropy or heterogeneity was detected for these associations. These findings suggest that selected SHS indicators may causally influence site-specific cancer risk, supporting early intervention on autonomic dysfunction and emotional dysregulation as plausible cancer-prevention strategies.