Epstein-Barr virus (EBV) is a widespread gamma-herpesvirus associated with a number of malignancies, including nasopharyngeal carcinoma and gastric cancer (GC/EBV+). The primary oncogenic protein of EBV is latent membrane protein 1 (LMP1). Genetic variability of the LMP1 protein affects its oncogenic activity and clinical manifestations.

Osteosarcoma (OS) is an aggressive primary bone tumour with high metastatic potential. Current treatments including surgery and chemotherapy are limited by side effects and chemoresistance, underscoring the need for novel therapies. This study aimed to investigate the antitumor potential of resveratrol (RSV), a natural polyphenol, as a novel treatment for OS. The effects of RSV were evaluated in two osteosarcoma cell lines (SAOS-2 and U2-OS). A viability assay established 100 μM as the effective concentration, and hyperspectral imaging confirmed cellular uptake. Apoptosis was measured via caspase-3/7 activity and Annexin V/PI staining, while qRT-PCR assessed pro-apoptotic gene expression. Flow cytometry evaluated cell-cycle progression, and a wound-healing assay measured migration. Gene expression analyses (qRT-PCR) examined markers of cell adhesion, tumour progression and epithelial-mesenchymal transition. Finally, RSV's impact on the Wnt/β-catenin pathway was determined by quantifying nuclear β-catenin accumulation and the expression of its downstream oncogenic targets. RSV inhibited cell proliferation and induced apoptosis, increasing caspase-3/7 activity and modulating apoptotic gene expression. RSV also caused cell cycle arrest in S-phase. It reduced the cells' migration and altered the expression of cell adhesion and tumour progression genes, promoting a less invasive phenotype. Notably, RSV decreased nuclear β-catenin accumulation, downregulated oncogenic targets like c-Myc and MMPs, and upregulated E-cadherin while reducing vimentin levels, suggesting a reversal of epithelial-mesenchymal transition. These results suggest that RSV may offer a promising therapeutic approach for osteosarcoma, modulating key pathways involved in tumour progression, metastasis and chemoresistance. Further studies are required to assess its clinical applicability.

We report a case of hereditary bilateral retinoblastoma due to a de novo germline inversion on chromosome 13, resulting in disruption of the RB1 gene. The patient is a 22-month-old female who initially presented to the emergency room at 11 months of age with an erythematous left eye and leukocoria of the right eye. Computed tomography (CT) of the brain and orbits showed solid internal calcifications arising from the posterior globes concerning for bilateral retinoblastoma. Magnetic resonance imaging (MRI) of the brain and orbits confirmed bilateral retinoblastoma without associated pineal region or suprasellar mass. On initial examination under anesthesia, the right eye showed one tumor in the macula and two tumors in the inferior mid-periphery. Sub-retinal seeding extended to the inferior periphery. The left eye was enucleated and pathology showed leptomeningeal extension along the optic nerve extending to the surgical margin. The patient was treated on a non-protocol treatment plan with five cycles of vincristine, carboplatin, etoposide, cyclophosphamide, and weekly intraventricular topotecan via Ommaya reservoir, followed by autologous stem cell rescue. Tumor analysis showed loss of pRB protein expression by immunohistochemistry and methylation copy number profiling showed several segmental gains and losses, including focal loss of RB1 on 13q. A 123-gene cancer predisposition germline panel using genome and exome sequencing initially did not identify any RB1 single nucleotide variants or insertion/deletions. Subsequent constitutional chromosome analysis for RB1 showed a paracentric inversion between bands 13q14.2 and 13q31. Optical genome mapping (OGM) showed that the proximal breakpoint of the balanced inversion at 13q14.2 was within intron 17 of RB1, while the distal breakpoint at 13q31.3 did not interrupt any known genes of clinical significance. We review the various molecular techniques that aided in diagnosis of this patient and provide a summary of similar RB1-disrupting structural variants reported in the literature.

Hepatitis B virus (HBV) and hepatocellular carcinoma (HCC) are serious medical problems worldwide. Today, many researchers believe that genetic variations play a major role in how easily someone gets infected and how the disease progresses over time. Although many genetic association studies have suggested various susceptibility loci, lack of consistent results across studies has limited clinical utility. We performed a comprehensive meta-analysis primarily involving East Asian cohorts. We analysed eight SNPs related to HBV infection and 11 SNPs related to HCC across multiple etiologic subgroups. We found that CD40 rs1883832 and C2 rs9267665 exhibited the strongest associations with susceptibility to HBV infection, with no heterogeneity. We found that HLA-DPA1 rs3077 and HLA-DQB1 rs2856718 were significantly associated with HBV infection susceptibility, though with considerable heterogeneity. In our HCC analyses, we found that certain risk variants are linked to specific causes. These include HBV, HCV, alcohol-related disease, and non-alcoholic fatty liver disease (NAFLD). Each cause seems to have its own genetic factors. Based on these results, our meta-analysis brings together many studies to give a clearer picture of the genetic factors that influence HBV infection and HCC in different etiologic pathways. We found that immune-related genes and HLA class II variants seem to have roles in HBV persistence, while metabolic gene variants are major contributors to HCC risk.

Hepatocellular carcinoma (HCC) is a malignant tumor worldwide with a high mortality rate and recurrence rate. Numerous miRNAs are being applied to the healing and prognosis of HCC. A prior investigation predicted that miR-5003-3p was linked to HCC, but the relevant molecular mechanisms were not clear.

NOL1/NOP2/SUN domain family member 2 (NSUN2), a member of the RNA methyltransferase family responsible for catalysing 5-methylcytosine (m5 C) modifications, has been increasingly recognized as a key regulatory factor in the initiation and progression of cancer. A growing body of evidence indicates that NSUN2 is aberrantly expressed in multiple malignancies, such as hepatocellular carcinoma, breast cancer, and gastric cancer, where its overexpression is frequently associated with unfavourable clinical outcomes, increased tumour aggressiveness, and resistance to therapy. Through its m5C modification activity, NSUN2 influences RNA stability, translational efficiency, and molecular interaction networks, thereby modulating critical oncogenic signalling pathways, including Wnt/β-catenin, PI3K/AKT, and epithelial-mesenchymal transition (EMT). Moreover, NSUN2 has been shown to interact with non-coding RNAs and epigenetic regulatory factors, contributing to the remodelling of the tumour microenvironment and facilitating immune evasion. Although NSUN2 is predominantly characterized by its tumour-promoting functions, emerging studies also suggest context-specific tumour-suppressive roles, highlighting its functional complexity in cancer biology. This review aims to summarize recent advances in understanding the molecular mechanisms underlying NSUN2 function, its clinical significance, and its potential as a biomarker or therapeutic target, while also discussing the challenges in translating these findings into clinical practice. A deeper understanding of NSUN2's diverse roles in carcinogenesis may provide novel insights into RNA epigenetics and inform the development of innovative strategies for cancer diagnosis and treatment.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies because of its typically late diagnosis and limited treatment options, with surgical resection being the primary intervention. Emerging studies have consistently reported associations between PDAC and metabolic dysfunctions, including obesity, chronic inflammation, and diabetes. In this study, we investigated the molecular interplay between PDAC-associated genes and metabolic disorder pathways.

Despite initial success, cancer therapies often fail due to the emergence of drug-resistant cells. In this study, we use a mathematical model to investigate how cancer evolves over time, specifically focusing on the state of the tumor when it recurs after treatment. We use a two-type birth-death process to capture the dynamics of both drug-sensitive and drug-resistant cells. Assuming resistant cells have equal fitness, we analyze the clonal diversity of drug-resistant cells at the time of cancer recurrence, which is defined as the first time the population size of drug-resistant cells exceeds a specified proportion of the initial population size of drug-sensitive cells. We examine two clonal diversity indices: the number of clones and the Simpson's Index. We calculate the expected values of these indices at the time of cancer recurrence. Additionally, we examine these two indices conditioned on early recurrence in the special case of a deterministically decaying sensitive population, with the aim of addressing the question of whether early recurrence is driven by a single mutation that generates an unusually large family of drug-resistant cells (corresponding to a low clonal diversity), or if it is due to the presence of an unusually large number of mutations causing drug resistance (corresponding to a high clonal diversity). Our findings, based on both indices, support the latter possibility. Furthermore, we demonstrate that the time of cancer recurrence can serve as a valuable indicator of clonal diversity, providing new insights into the evolutionary dynamics of recurrent cancers.

Giant Cell Lesions exhibit variable aggressive clinical behavior. Understanding the molecular mechanisms of these lesions can facilitate a more personalized and effective therapeutic approach.

Oncocytic adrenal neoplasms are rare adrenocortical tumors characterized by abundant eosinophilic cytoplasm due to massive mitochondrial accumulation. Their biological behavior is often difficult to predict, and various diagnostic systems-including the Lin-Weiss-Bisceglia system, the Helsinki score, and the reticulin algorithm-are used to assess their malignant potential. We report a case of an oncocytic adrenocortical carcinoma associated with Cushing's syndrome and hyperandrogenemia in a 34-year-old woman. Histologically, the tumor showed diffuse growth of eosinophilic cells with marked pleomorphism and focal capsular invasion. Immunohistochemistry confirmed adrenocortical origin and cortisol production, with a Ki-67 labeling index of 25%. Ultrastructural examination revealed densely packed mitochondria with lamellar and tubulovesicular cristae, accompanied by numerous whorled smooth endoplasmic reticulum formations, suggesting active remodeling of the endoplasmic reticulum. Whole-exome sequencing identified a pathogenic GNAS R201S mutation, together with copy number losses of ARID1A, CDKN2A, and ZNRF3 with widespread copy number alteration. Despite multiple adverse prognostic indicators, the patient has remained disease-free for over 5 years following adrenalectomy and adjuvant low-dose mitotane therapy. These findings suggest that GNAS activation may drive steroidogenesis while attenuating malignant progression, as demonstrated by integrated morphologic and genomic assessment in this case.

Retinoblastoma (RB) is typically associated with highly penetrant pathogenic sequence variants (PSVs) in the RB1 gene; however, some families exhibit low penetrance RB (LPRB). We aimed to determine the penetrance rate and identify genetic and clinical characteristics of LPRB. To that end two cohorts were analyzed: 250 genetically confirmed LPRB cases identified through systematic literature review and 78 classical germline RB (CGRB) from three international centers- Thailand, Korea, and Israel. Penetrance rate was estimated as the proportion of affected individuals among RB1 PSV carriers. Multivariate models assessed parent-of-origin effects and predictors of penetrance. PSVs were annotated with Combined Annotation Dependent Depletion (CADD) scores and mapped to pRB structural domains. LPRB penetrance ranged from 50% (125/250, non-age-adjusted, CI [43.8%-56.2%]) to 64% (125/196, age-adjusted, CI [56.8%-70.2%]). Paternal inheritance of RB1 PSV was associated with a significantly increased risk of LPRB in offspring (OR = 6.24; P < 0.0001). Clinically, LPRB were significantly more likely than CGRB to present with unilateral disease (OR = 9.3, P < 0.0001), diagnosed at an older age (13 Vs 6.5 months, P = 0.01), and affect males (OR = 2.4, P = 0.03). LPRB-associated PSVs showed lower CADD scores (OR = 1.5; P = 0.0008), indicating lower predicted pathogenicity, and were enriched in pRB's N- or C-terminal domains (OR = 3.2; P = 0.007), consistent with hypomorphic effects. In conclusion, LPRB shows a 50-64% penetrance rate, more likely to be paternally inherited, have unilateral presentation, and associated with hypomorphic RB1 PSVs in the terminal pRB regions. These findings support retitling 'low penetrance RB' to 'medium penetrance RB'.

Background and objectives Diffuse large B-cell lymphoma presents a significant challenge due to its high rate of treatment failure in 40% of patients. In this study we screened microRNAs as biomarkers in chemotherapy non-responding patients, to allow their early prognostication. Methods In the exploratory phase, whole transcriptome microRNA profiling was conducted on 10 diffuse large B-cell lymphoma cases. Three patients achieved complete remission, while seven had refractory or relapsed disease. The differentially expressed miRNAs were validated in 41 retrospective, treatment-naive diffuse large B-cell lymphoma biopsies, including the original 10 cases. Additionally, 33 cases with paired biopsy and plasma samples were prospectively evaluated using qRT-PCR to correlate miRNA expression with clinical outcomes. Functional validation to identify downstream pathways was done by knocking down identified miRNAs in JM-1 cells by semi-quantitative proteomics. Results miR-193b-5p, miR-1307-5p, and miR-671-5p expression were downregulated in refractory/relapsed diffuse large B-cell lymphoma biopsies. Plasma miRNA levels did not reflect prognosis. In vitro proteomics showed their impact on key oncogenic pathways, revealing significant enrichment of replication and transcription-related proteins. Interpretation and conclusions The expression of miR-193b-5p, miR-1307-5p, and miR-671-5p miRNAs in diffuse large B-cell lymphoma tissues may serve as predictive biomarkers.

Background and objectives Ovarian carcinoma is one of the most lethal carcinomas among females. Its high prevalence and shorter 5-year survival rate is due to the fact that most of the cases are diagnosed at later stages. This highlights the importance of early diagnosis through reliable biomarkers. We studied the diagnostic role of SOX9 protein in ovarian carcinoma and its diagnostic ability. The primary objective was to compare the level and clinical relevance of SOX9 protein in the tissues of patients with ovarian carcinoma with non-malignant ovarian tissues. Methods Tissue levels of SOX9 protein were estimated in the study and control groups (60 each group). SOX9 levels were compared between the study vs. control groups and also between high grade and low-grade ovarian cancer. SK-OV3 ovarian adenocarcinoma cell line was used as supportive evidence to prove the presence of SOX9 in malignant ovarian cells. Results Levels of SOX 9 protein (3.9±2.7 ng/mL) were high in tissue of ovarian cancer patients when compared to non-malignant (1.5 ±1.1 ng/mL) ovarian tissues. Higher levels of SOX 9 protein were found in tissues of ovarian cancer patients when compared to non-malignant ovarian tissues. The mean of SOX 9 levels in tissues of high-grade serous carcinoma was 3.5±2.5 ng/mL as compared to 1.0±0.9 ng/mL in low-grade serous carcinoma. Interpretation and conclusions SOX9 appears to be an important player in the molecular tumourigenesis of ovarian cancer, particularly in high grade tumours.

Background and objectives Genomic studies are essential for identifying mutations that may influence key aspects of breast tumours, such as susceptibility, aggressiveness, and response to treatment. There are deficient molecular and genomic data from Indian breast cancer patients. Methods mRNA from primary breast cancer samples were subjected to next-generation transcriptome (mRNA) sequencing on an Illumina platform, in duplicates and triplicates to generate 30-60 M reads/sample. PAM50, and absolute intrinsic molecular subtyping (AIMS) gene expression-based classifiers were used for intrinsic subtyping. Variants were called using, GATK, MuTect2, VarScan2, and VarDict, followed by filtering for somatic and non-synonymous changes. Germline variants were excluded using public databases. ClinVar annotations prioritised pathogenic variants, and the STRING algorithm was used for network analysis. Results A total of 207 RNA-Seq datasets from 97 breast cancer patients were analysed. There was good concordance between the immunohistochemical receptor and AIMS classification for all subtypes, but there was discordance between immunohistochemical and PAM50 subtypes within the ER-positive/HER2-positive subgroup, wherein only 38.5% (n= 5) were classified as HER2-like by gene expression classification. Variant analysis identified 145 high-confidence somatic mutations, with TP53 (n=46, 47%) and PIK3CA (n=33, 34%) being the most frequent. Additional actionable mutations in BRCA1, BRCA2, FGFR2, PTEN, AKT1, and mTOR pathways were identified. At least one actionable mutation was found in 52% of patients. Fusion transcript analysis identified 91 recurrent fusions, including novel partners with ERBB2, MED1, and CDK12, suggesting the possibility of unique molecular events. Interpretation and conclusions This study demonstrates that Indian breast cancer patients exhibit molecular subtypes and actionable mutations comparable to Caucasian cohorts.

Hyperandrogenism and elevated thioredoxin-interacting protein (TXNIP) are potential causes of infertility in women with polycystic ovary syndrome (PCOS). Epigenetic regulation of TXNIP mediates oxidative stress and inflammatory activation. However, the precise mechanisms including epigenetic regulation in PCOS are poorly understood. In this study, aberrant TXNIP in dehydroepiandrosterone (DHEA)-induced rat PCOS ovaries and dihydrotestosterone (DHT)-induced PCOS primary granulosa cells (GCs) coincided with a marked increase of DNA methyltransferases (DNMTs); this aberrant TXNIP triggers the release of pro-fibrotic factors, such as collagen I, α-SMA, and TGF-β, from GCs. Administration of the DNMT inhibitor 5-Aza downregulated TXNIP expression and improved the aberrant expression of the pro-fibrotic factors in PCOS-like ovaries and DHT-treated GCs. Furthermore, MG132, a proteasome inhibitor, attenuated the inhibitory effect of 5-Aza on DHT-induced TXNIP upregulation. Our data suggest that DNMT activation, by suppressing proteasome activity, contributes to increases in TXNIP expression, resulting in ovarian fibrosis and GC dysfunction in PCOS-like ovaries after exposure to hyperandrogenism.

Glioblastoma (GBM) is an aggressive CNS malignancy with extensive tumor growth and invasion. Highly proliferating cells require an increased intracellular iron concentration to maintain cell metabolism. We assessed the expression of transferrin receptor 1 (TFR1), the principal iron transporter, in GBM and ascertained its clinicopathological significance, implication in pathobiology, and therapeutic potential. Ninety-four cases of adult-type hemispheric GBM were included, along with 60 cases of IDH-mutant astrocytic and oligodendroglial tumors (grade 2-4) for comparison. The protein and mRNA expression were assessed by immunohistochemistry and qRT-PCR, respectively. We used U87MG and LN229 cell lines for in vitro analysis. TFR1 expression was significantly higher in GBM than in other IDH-mutant/lower-grade diffuse gliomas at mRNA and protein level. The non-tumor brain was negative on immunohistochemistry, and strong immunoreactivity was present only in GBM, indicating its diagnostic significance. SiRNA-mediated knockdown of TFR1 was associated with reduced cell survival, proliferation, migration, invasion, and increased apoptosis in vitro. Ferroptosis induction by RSL3/FIN56 led to increased TFR1 expression and ROS generation. The pro-ferroptotic effect of these drugs could be reversed by TFR1 knockdown. Hence, TFR1 appears to be crucially implicated in the cell survival and proliferation and ferroptosis sensitivity of malignant cells. Temozolomide in combination with siRNA-mediated gene silencing showed a significantly higher antitumor effect than the drug or silencing alone. This may be one of the important therapeutic vulnerabilities of GBM. High TFR1 expression was associated with shorter overall survival in all gliomas together but not in GBM separately.

Renal tumours account for one in twenty paediatric cancers, with Wilms tumour (WT) the most common in young children and renal cell carcinoma (RCC) predominating in adolescents and young adults. Diagnostic work-up has traditionally focused on clinical features, radiology, and histology, with a limited role for molecular analysis. However, it is estimated that up to one-third of children with WT have underlying cancer predisposition, which could necessitate prolonged treatment and intensive follow-up.

Ferroptosis is an iron-dependent form of cell death converging on lipid peroxidation first identified by examining compounds with enhanced lethality to KRAS mutant cells. Despite over 90% of pancreatic ductal adenocarcinoma (PDAC) tumors harboring KRAS mutations, PDAC exhibits relative resistance to ferroptosis compared with other tumor types, and the mechanisms behind this resistance remain unclear. Here, we report that exposure to pancreatic tumor interstitial fluid in synergy with hypoxia induced robust protection against ferroptosis in a manner dependent on the hypoxia-inducible transcription factor 2 (HIF-2). HIF-2 upregulates the expression of both components of the system Xc- cystine transporter and transsulfuration pathway enzymes CBS and CTH to increase intracellular cysteine levels, enabling anti-ferroptotic glutathione production. HIF-2 also induces the Parkin mitophagy factor and suppresses mitochondrial function and reactive oxygen species (ROS) generation. Altogether, our findings uncover an unforeseen role of the HIF-2 transcription factor as a coordinator of anti-ferroptotic mechanisms in pancreatic cancer.

Homologous recombination deficiency (HRD) is a key determinant of sensitivity to DNA-damaging agents; however, its genomic characterization in colorectal cancer (CRC) remains limited. This study investigated whether low RNA expression of homologous recombination (HR) genes identifies patients with metastatic CRC who derive survival benefit from oxaliplatin- or irinotecan-based therapy.

Tumor-agnostic therapies represent a transformative shift in oncology, targeting molecular alterations irrespective of cancer histology. These therapies offer new hope for patients with rare and difficult-to-treat malignancies, yet their integration into clinical practice remains inconsistent because of the absence of guidelines. Traditional organ-based classifications hinder timely access to precision treatments, despite evidence supporting molecular-driven approaches. Living guidelines, continuously updated frameworks based on emerging data, are essential to bridge this gap. They enable just-in-time incorporation of new therapies, streamline biomarker-driven care, and address the unique needs of rare and ultrarare cancers. Regulatory approvals for tumor-agnostic agents, such as NTRK inhibitors and immunotherapies for microsatellite instability-high/mismatch repair-deficient tumors, underscore the urgency for unified guidance. Trials like TAPUR, TRACK, and NCI-MATCH demonstrate the feasibility and benefit of molecular profiling across diverse cancer types. Tools like ESMO's ETAC-S provide structured criteria for evaluating tumor-agnostic potential, yet real-world implementation lags. Living guidelines can harmonize testing practices, improve access, and educate clinicians on cross-tumor applicability. They also facilitate proactive biomarker testing, reduce treatment delays, and enhance patient safety through tailored toxicity management. As oncology evolves toward molecular precision, living tumor-agnostic guidelines are critical for ensuring equitable, evidence-informed care for all patients, particularly those with rare cancers. National organizations must prioritize their development to fully realize the promise of precision medicine.