Search Results (2,860)

Cervical cancer is associated with persistent human papillomavirus (HPV) infections. The early detection of HPV is one of the key strategies for the effective treatment of cervical cancer. Current HPV molecular detection methods use enzyme-based nucleic acid amplification strategies that, although specific and sensitive, involve extensive workflows. Enzyme-free isothermal amplification detection strategies with the potential to adapt to low-resource settings for HPV oncogenic transcripts remain limited. This study aimed to validate a fluorescence-based branched hybridization chain reaction (bHCR) assay for the targeted detection of HPV 16/35 E6 oncogenic transcripts. Analytical performance was evaluated using a synthetic target and a negative clinical matrix, whereas the diagnostic performance of the bHCR assay was evaluated using clinically characterized samples (n = 67). The study demonstrated assay linearity over an analyte concentration range of 0.625–40 µM, with a statistically significant correlation between the fluorescence signal and target concentration (r² = 0.928, p < 0.0001). Analytical accuracy was assessed by pre-extraction spike recovery; achieved recoveries ranged from 70% to 86%, indicating potential RNA loss during the assay workflow. Analytical sensitivity determined the background signal threshold limit of blank (LoB) as 16,251.6 RFU, with detection and quantification at concentrations of 0.0625 µM (≈2.6 × 10¹¹ copies per reaction, limit of detection (LoD) and 0.125 µM (≈5.3 × 10¹¹ copies per reaction, limit of quantification (LoQ). The assay exhibited high diagnostic performance, with a diagnostic cut-off of 16,481 RFU and an area under the curve (AUC) of 0.9194. Specificity and sensitivity of the assay were 94% and 86%, respectively, with a Negative Predictive Value (NPV) of 85% and a Positive Predictive Value (PPV) of 94%. These findings demonstrate a reliable analytical assay with excellent diagnostic discrimination and warrant further optimization and expanded clinical validation. Full article

Background/Objectives: The androgen receptor (AR)-driven transcriptional program plays a pivotal role in the development and progression of prostate cancer. The binding of androgen dihydrotestosterone (DHT) to AR initiates transcriptional activation, thereby altering the transcriptional landscape. DHT-induced long non-coding RNAs (lncRNAs) have been recognized as crucial players in prostate cancer pathogenesis. This study aims to identify and explore the important role of such lncRNAs in prostate cancer. Methods: This study first analyzed transcriptome data from an androgen-dependent cell line, LNCaP, treated with different DHT concentrations and found a batch of lncRNAs exhibiting DHT concentration dependence. TCGA data suggested a correlation between the DHT-induced lncRNA and prostate cancer. Finally, a series of in vivo and in vitro experiments confirmed the effect and mechanism of lncRNA in prostate cancer. Results: AC092718.4 was highly expressed in AR-positive prostate cancer cell lines and tissues, and its expression in patients with Gleason scores 6–9 was significantly higher than in a normal control group. Notably, the expression level of AC092718.4 was upregulated in a concentration-dependent manner with DHT. In vitro experiments revealed that overexpression of AC092718.4 promoted cell proliferation and inhibited cell apoptosis. Conversely, knockdown of AC092718.4 suppressed tumorigenesis in vivo. Furthermore, our investigation into the pathogenetic mechanism demonstrated that AC092718.4 could act as an miRNA sponge for miR-138-5p, attenuating its inhibitory effect on downstream oncogenes, such as FERMT2, RHOC, and HIF1A. These AC092718.4/miR-138-5p/mRNA axes, in turn, facilitated the progression of prostate cancer. Conclusions: For the first time, we demonstrate that AC092718.4 may function as an oncogenic factor in prostate cancer. The AC0927.8.4/miR-138-5p/mRNA axes potentially offer promising diagnostic and therapeutic targets for prostate cancer. Full article

Nuclear factor kappa B (NF-κB) signaling plays a central role in inflammation, immunity, cell survival, and cancer progression. Its constitutive activation is frequently observed in breast cancer, contributing to tumor growth, treatment resistance, and metastasis. MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression and may modulate NF-κB signaling in a subtype-specific or -independent manner. The aim of the study was to identify miRNAs that may potentially regulate the activity of genes associated with NF-κB signaling across five molecular subtypes of breast cancer in Polish women. Tumor and matched normal tissue samples were collected from 405 patients with five breast cancer subtypes: luminal A (n = 130), HER2-negative luminal B (n = 100), HER2-positive luminal B (n = 96), non-luminal HER2-positive (n = 36), and triple-negative breast cancer (TNBC, n = 43). Expression profile of selected NF-κB-related genes were evaluated using mRNA microarrays and RT-qPCR. Protein levels were assessed by ELISA. Candidate regulatory miRNAs were identified via miRNA microarrays and validated using the miRDB database. A consistent upregulation of MAP3K7, TAB2, TNFAIP3, CSNK2A1, BCL2L1, XIAP, CXCL2, and PLAU was observed across all subtypes, suggesting activation of canonical NF-κB signaling. Downregulation of specific miRNAs, miR-1297 and miR-30a (targeting MAP3K7), miR-134 (TAB2), miR-125b (TNFAIP3), and miR-4329 (XIAP), may contribute to this deregulation. For CSNK2A1, BCL2L1, CXCL2, and PLAU, no regulatory miRNAs meeting our criteria were identified. Our study reveals a subtype-independent activation of the canonical NF-κB signaling pathway in breast cancer, underpinned by consistent upregulation of key components (at both the transcript and protein levels. Dysregulation of specific miRNAs likely contributes to this altered gene expression. These findings suggest the presence of a common NF-κB-driven oncogenic program across molecular subtypes, with potential implications for developing miRNA-based therapeutic strategies targeting inflammation, survival signaling, and treatment resistance in breast cancer. Full article

Renal cell carcinoma (RCC) is acknowledged as a heterogeneous malignancy underlined by complex genetic, metabolic, and immune dysregulation. In particular, molecular studies have revealed distinct oncogenic mechanisms that have been exploited and studied as therapeutic intervention targets. These include hypoxia-driven signaling, chromosomal translocations, and gene fusion events that affect tumor progression. This review provides a comprehensive overview of these targets and rethinks RCC management. Therapeutic concepts include the targeting of genomic fusion biology with emerging cell-based immunotherapies or targeted molecular inhibition, and orthomolecular therapeutic strategies are presented. Two clinical and pathological features are highlighted—namely, the TFE3 fusion proteins in translocation RCC and the growing role of hypoxia-inducible factor-2α (HIF-2α) inhibitors in clear-cell RCC. We also present recent data on novel immunotherapeutic approaches, including autologous hematopoietic stem and progenitor cell-based interferon-α gene therapy, as well as chimeric antigen receptor T-cell therapy. These therapies are discussed in light of their mechanistic rationale, translational potential, and existing clinical challenges due to unwanted side effects. At last, orthomolecular and natural product-based therapies are reviewed for their potential as adjunctive therapies that might be used for oxidative stress management, the targeting of tumor metabolism and immune effects, and to increase standard treatment tolerance. This review points to a multidimensional framework that might support further research and studies in precision-guided RCC management, as integrative approaches may enhance therapeutic efficacy, reduce toxicity, and support the development of personalized interventions for advanced or treatment-resistant RCC. Full article

Oncogenic driver mutations in non-small cell lung cancer (NSCLC) activate defined signaling pathways that sustain tumor growth and influence the immune landscape. Yet, how coordinated interactions among diverse cell populations within the tumor immune microenvironment (TIME) contribute to this process remains largely unresolved. To address this, we profiled approximately 200,000 single cells from 45 treatment-naïve NSCLC patients representing seven major driver mutations. This analysis uncovered five multicellular modules (CM1–5) with distinct functional properties, each linked to specific malignant regulatory programs. Among them, CM2 and CM5 exhibited pronounced invasive features and were associated with unfavorable clinical outcomes. CM2 was predominantly observed in EGFR- and MET-driven brain metastases and was defined by strong crosstalk between astrocytes and myofibroblasts. Factors such as SPP1, PTN, and PSAP, together with metabolic alterations, contributed to a microenvironment supportive of metastatic colonization in the brain. By contrast, CM5 was enriched in ROS1-, KRAS-, and EGFR-mutant tumors and consisted of diverse myeloid and endothelial subsets characterized by immunosuppressive and pro-angiogenic signaling, including MIF, GALECTIN, and RETN, collectively facilitating immune escape and vascular remodeling. We further constructed and validated a driver mutation-specific prognostic signature (DMSP.sig) model integrating receptor–ligand interactions and core transcription factors, which effectively stratified patient survival. Leveraging this model, we also identified potential therapeutic candidates linked to these prognostic features, highlighting opportunities for clinical intervention. In summary, our study delineates how oncogenic drivers give rise to distinct TIME architectures, providing a framework for prognostic assessment and precision immunotherapy in high-risk NSCLC. Full article

Cervical cancer (CC) is an alarming global health problem, with predominantly higher incidence, lethal progression, and mortality among women of African ancestry (AA) than women of European ancestry (EA). Although persistent high-risk human papillomavirus (HPV) integration and infection are the key etiological factors, currently available evidence implicates epigenetic reprogramming as a prime contributor to ancestry-associated differences in CC pathogenesis. To address these disparities, we performed genome-wide DNA methylation profiling of HPV-positive cervical intraepithelial neoplasia (CIN) lesions from AA (n = 15) and EA (n = 15) women. Differential methylation analysis identified a distinct epigenomic landscape in AA-CIN lesions, with widespread hypermethylation and hypomethylation at promoter-associated and regulatory CpG sites. Pathway enrichment analyses highlighted dysregulation of ECM-receptor interaction, focal adhesion, PI3K-Akt, MAPK, Ras, Rap1, and RUNX-dependent transcriptional networks. Comparative analysis across CIN grades (CIN1–CIN3) revealed progressive epigenetic reprogramming affecting cell cycles, cytoskeletal dynamics, signaling, and metabolic pathways. Among hypermethylated tumor suppressor genes, SH3GL2 and ARHGAP25 showed significantly higher methylation in AA lesions, accompanied by concomitant loss of their protein expression. MBD1, a methylation-binding regulator, was upregulated in AA-CIN lesions, coinciding with global loss of 5-hydroxymethylcytosine (5hmC), suggesting enhanced transcriptional repression. In contrast, EA lesions retained protein expression and 5hmC levels. Collectively, these findings indicate that early, ancestry-specific epigenetic modifications target tumor suppressor pathways and converge on oncogenic signaling, cytoskeletal remodeling, and cell–cell adhesion. Our study provides mechanistic insight into CC health disparities, identifying SH3GL2 and ARHGAP25 hypermethylation as potential biomarkers, and highlighting epigenetic regulation as a contributor to disparate CC progression in AA women. Full article

Anaplastic lymphoma kinase (ALK) rearrangement is a well-established oncogenic driver alteration in non-small cell lung cancer (NSCLC), and ALK tyrosine kinase inhibitors (TKIs), particularly lorlatinib, have significantly improved the prognosis of ALK-positive NSCLC patients. Although high programmed death-ligand 1 (PD-L1) expression (≥50%) is generally associated with favorable responses to immune checkpoint inhibitors (ICIs), PD-L1 has not been shown to reliably predict ICI benefit in ALK-rearranged disease, and optimal management after ALK TKI resistance remains challenging. Herein, we report a case of an elderly patient with ALK-rearrangement and exceptionally high PD-L1 expression (TPS ≥ 95%) NSCLC who experienced disease progression following first-line lorlatinib with genetically confirmed MET amplification. The patient subsequently received an exploratory combination of continued lorlatinib plus envafolimab and achieved partial response (PR) with manageable tolerability after 4 months, highlighting a potential sequential strategy that may warrant further investigation in select ALK-positive NSCLC patients exhibiting both bypass pathway activation and exceptionally high PD-L1 expression. Full article

The increasing global burden of cancer, together with the need for more sustainable resource management, has stimulated growing interest in the valorization of agro-industrial plant residues as sources of bioactive compounds with therapeutic potential. This review highlights the potential of plant by-products—including citrus peels, olive leaves, date palm residues, and tea and coffee processing wastes—as sustainable reservoirs of polyphenols and other phytochemicals with significant anticancer activity. Key compounds such as hesperidin and naringenin from citrus peels, oleuropein and hydroxytyrosol from olive leaves, quercetin and syringic acid from date palm residues, and chlorogenic acid and epigallocatechin gallate from tea and coffee by-products have demonstrated promising antitumor effects in both in vitro and in vivo studies. These molecules exert their activity through multiple mechanisms, including the inhibition of cancer cell proliferation, induction of apoptosis, regulation of the cell cycle, and modulation of major oncogenic signaling pathways such as PI3K/AKT, MAPK, NF-κB, and EGFR. For instance, hydroxytyrosol induces apoptosis and cell cycle arrest while inhibiting the PI3K/AKT and MAPK pathways. Quercetin limits metastasis and glycolysis and suppresses VEGF, PKM2, and AKT signaling. Ferulic acid suppresses tumor growth by inhibiting the PI3K/AKT and JAK2/STAT6 pathways, thereby promoting apoptosis (in vitro and in vivo). In addition to their pharmacological potential, the recovery of these compounds from plant waste supports circular economy strategies by reducing environmental impact and promoting the development of value-added products. Future research should focus on optimizing extraction methods, improving bioavailability and stability, and validating safety and efficacy through well-designed preclinical and clinical studies. Full article

Background: Thymic epithelial tumors (TETs) are rare neoplasms of the anterior mediastinum, ranging from indolent thymomas to aggressive thymic carcinomas. Increasing evidence suggests that genetic alterations contribute to their pathogenesis and biological behavior. GTF2I, TP53, and NOTCH1 are particularly interesting among the potential genes due to their central roles in transcriptional regulation, cell-cycle control, and oncogenic signaling. Methods: In this study, 150 TET samples from Vietnamese patients were classified according to WHO guidelines and the Masaoka–Koga staging system. Genotyping was conducted on 139 high-quality samples using Sanger sequencing targeting exon 15 of GTF2I, exon 7 of TP53, and exon 34 of NOTCH1. The potential impact of these variants was predicted using the in silico MutationTaster2025 and CADD v1.7 tools. Statistical analyses were also conducted to assess associations between variants and tumor subtypes. Results: Our study identified a total of 17 variants across GTF2I, TP53, and NOTCH1, in which the c.1271T>A variant in the GTF2I hotspot, predicted to be deleterious, was identified in 14.1% of indolent thymomas and showed a significant association with this subtype group (odds ratio: 0.048, adjusted p-value = 0.014). In contrast, previously unreported variants in TP53 (c.772G>A) and NOTCH1 (c.7546T>G) were also computationally predicted to be deleterious and were significantly enriched in aggressive subtypes, with ORs of 15.1 (adjusted p-value = 0.01) and 18.4 (adjusted p-value = 0.026), respectively. Conclusion: These hypothesis-generating findings suggest that variations in GTF2I, TP53, and NOTCH1 may serve as candidate molecular markers for distinguishing thymoma subtypes and assessing patient risk. To date, this is the first targeted hotspot screening study of GTF2I, TP53, and NOTCH1 variants in TETs within the Vietnamese population. Full article

Background/Objectives: Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1), also known as protein tyrosine phosphatase non-receptor type 6, functions as a tumor suppressor in breast, hepatocellular, and prostate cancers and an oncogene in glioblastoma and cervical cancer. A previous analysis of The Cancer Genome Atlas (TCGA) dataset revealed that lower SHP-1 transcript levels in bladder tumors were associated with poorer overall survival. Methods: This study aimed to evaluate the role of SHP-1 in bladder cancer and to assess the functional impact of its forced expression and knockdown in bladder carcinoma cell lines. SHP-1 expression was assessed in 19 bladder cancer cell lines and 26 bladder tissues. Lentiviral transduction was used to knock down or overexpress SHP-1 in four cell lines, followed by Western blot analysis of SHP-1 and pAkt/Akt protein expression. Results: SHP-1 protein levels were significantly lower in highly invasive cell lines (p < 0.001) and muscle-invasive tumors (p < 0.05). Functional studies demonstrated that SHP-1 modulation influenced the epithelial–mesenchymal transition (EMT) phenotype. SHP-1 expression was positively correlated with E-cadherin expression (p < 0.001) and negatively correlated with N-cadherin (p < 0.01) and Vimentin (p < 0.05) expression. Alteration of SHP-1 expression in bladder cancer cell lines affected proliferation, invasion, and migration (p < 0.05). RNA-seq analysis of the transduced cell lines revealed enrichment of gene sets related to EMT and signaling pathways involving MYC, PI3K, Akt, and mTOR. Furthermore, SHP-1 alteration impacted pAkt/Akt ratios (p < 0.05). Conclusions: Collectively, lower SHP-1 protein expression correlated with more aggressive phenotypes in bladder cancer cell lines and bladder tumors. In our limited dataset, reduced SHP-1 expression correlated with muscle-invasive disease, suggesting a potential link to more advanced tumor biology, consistent with TCGA associating reduced SHP-1 transcript expression to poorer survival rates. Our data provide preliminary functional evidence that SHP-1 may modulate Akt signaling in bladder cancer. Together, these results support further investigation of SHP-1 as a possible tumor suppressor, candidate prognostic biomarker, and potential therapeutic target in bladder cancer. Full article

Background/Objectives: Retinoblastoma treatment remains limited by therapeutic resistance and toxicity. While melphalan is a key chemotherapeutic agent, its efficacy is constrained by adverse effects. Curcumin has emerged as a potential adjunct owing to its capacity to regulate oxidative stress and oncogenic signaling pathways, including STAT3. This study aimed to assess the synergistic tumor-inhibitory effects of melphalan–curcumin combined treatment and to investigate the roles of ROS, apoptosis, and STAT3-associated signaling, including validation in a three-dimensional (3D) tumor spheroid model. Materials and Methods: Human retinoblastoma (WERI-Rb-1) and normal keratinocyte (HaCaT) cells were exposed to melphalan, curcumin and the combined treatment regimen. Cell viability was analyzed by MTT assay, and drug interactions were analyzed using the Chou–Talalay method. Migration was evaluated by scratch assay. Intracellular ROS levels were quantified using the DCFH-DA assay and confirmed by flow cytometry. Apoptosis was quantified by Annexin V/PI staining, and caspase activity was assessed colorimetrically and by immunocytochemistry. Cytokine levels were determined by ELISA, and gene expression profiling of STAT3 and apoptosis-associated genes were performed using qRT-PCR. Three-dimensional tumor spheroids were established to evaluate treatment responses in a physiologically relevant model. The contribution of ROS was further investigated using N-acetyl-L-cysteine (NAC) pretreatment. Results: The combination of melphalan and curcumin notably reduced WERI-Rb-1 cell viability in a synergistic manner (CI < 1) while exhibiting lower cytotoxicity in HaCaT cells, indicating selective antitumor activity. Co-treatment markedly inhibited cell migration and increased intracellular ROS levels. Cells pretreated with NAC significantly reduced ROS levels accumulation and moderately restored cellular viability, supporting a contributory role of oxidative stress. The combination treatment induced pronounced apoptosis, with increased early and late apoptotic cell populations, enhanced caspase-7 and caspase-9 activity, and elevated caspase-9 protein expression. These effects were associated with upregulation of pro-apoptotic genes (BAX, CASP3, CASP7, CASP9), downregulation of anti-apoptotic genes (BCL2, SURVIVIN), and reduction in STAT3 mRNA expression. In addition, the combination reduced pro-inflammatory cytokine levels. Importantly, these effects were recapitulated in 3D tumor spheroids, where the combination treatment reduced spheroid size and viability and induced structural disruption. NAC-mediated rescue experiments in 3D models further supported the notion that ROS contributes to, but is not solely responsible for, the observed effects. Conclusions: Overall, these results suggest that melphalan and curcumin exert synergistic and selective antitumor effects in retinoblastoma cells, associated with changes consistent with ROS-related effects, mitochondrial apoptotic processes, and STAT3-related transcriptional alterations rather than definitive pathway activation. The validation of these effects in a 3D tumor spheroid model provides additional support for the potential clinical significance of this combined treatment; however, additional protein-level and functional validation is required. Full article

Background: Microfibrillar-associated protein 2 (MFAP2) is implicated in various malignancies, yet its specific role and molecular mechanisms in glioblastoma (GBM) progression remain poorly understood. Methods: We analyzed MFAP2 expression in human clinical specimens and murine models. Functional impacts were assessed in U251 cells via gain- and loss-of-function assays. Mechanistic studies explored the interplay between autophagic flux and Wnt/β-catenin signaling. An orthotopic GL261 syngeneic orthotopic model validated these findings in vivo. Results: MFAP2 was significantly overexpressed in GBM, correlating with poor patient prognosis. In vitro, MFAP2 markedly enhanced U251 viability, migration, and invasion while suppressing apoptosis. Mechanistically, MFAP2 triggered autophagic flux, subsequently activating the Wnt/β-catenin cascade and its downstream targets (MMP9, c-Myc, Cyclin D1). Pharmacological inhibition of either autophagy or Wnt signaling effectively abrogated these oncogenic phenotypes. In vivo, MFAP2 knockdown reduced tumor volume by 62.4% and suppressed the autophagy–Wnt axis. Conclusions: MFAP2 is an oncogenic regulator in glioblastoma models that links autophagy activity to Wnt/β-catenin signaling. Our findings support MFAP2 as a candidate prognostic biomarker and a potential therapeutic target; however, additional validation in larger molecularly annotated clinical cohorts and multiple GBM models is warranted. Full article

Objectives: This study aimed to investigate the biological role and molecular mechanism of the RNA m⁵C methyltransferase NSUN4 in cervical cancer progression, with a focus on its involvement in ferroptosis regulation. Methods: Differential expression and survival analyses were performed using TCGA and GEPIA datasets. Functional enrichment and GSEA identified pathways associated with NSUN4 dysregulation. NSUN4 expression was validated in clinical tissues by qRT-PCR, Western blot, and immunohistochemistry. Gain- and loss-of-function assays, including CCK-8, colony formation, and Transwell assays, were conducted to assess cell proliferation and invasion. Furthermore, a nude mouse subcutaneous xenograft model was established to validate the oncogenic role of NSUN4 in vivo. Ferroptosis was evaluated using specific inhibitors and measurement of GSH and ferroptosis-related proteins. RIP, m⁵C-RIP, RNA stability, and dual-luciferase assays were performed to explore the underlying mechanism. Results: NSUN4 was markedly upregulated in cervical cancer tissues and correlated with poor prognosis. Functionally, NSUN4 enhanced tumor cell growth, migration, and invasion while inhibiting ferroptosis. Mechanistically, NSUN4 bound to and stabilized C-MYC mRNA via m⁵C methylation, activating the PI3K/Akt signaling pathway and promoting ferroptosis resistance. Conclusions: NSUN4 promotes cervical cancer progression by stabilizing C-MYC mRNA through m⁵C modification, leading to PI3K/Akt activation and suppression of ferroptosis. These findings identify NSUN4 as a novel oncogenic regulator and potential therapeutic target in cervical cancer. Full article

Background: High-grade serous ovarian carcinoma (HG-SOC) remains the most lethal gynecological malignancy, largely due to intrinsic or acquired resistance to platinum-based chemotherapy. Although large-scale sequencing studies have delineated the genomic landscape of HG-SOC, clinically actionable biomarkers predictive of platinum response and outcome are still lacking. This study aimed to identify genomic alterations associated with platinum sensitivity, resistance, or refractoriness, and to assess their prognostic relevance. Methods: Tumor DNA from 24 HG-SOC patients with optimal cytoreductive resection, classified as platinum-sensitive (n = 9), platinum-resistant (n = 8), or platinum-refractory (n = 7) underwent targeted next-generation sequencing of 409 cancer-associated genes. Somatic variants were filtered and classified for oncogenicity using established criteria incorporating predicted functional impact, REVEL scores, and population allele frequencies. Associations between mutational profiles, platinum response, and overall survival (OS) were evaluated using Kaplan–Meier and Cox regression analyses. Key findings were validated in the TCGA ovarian serous carcinoma (TCGA-OV) dataset using survival analyses. Results: A total of 1367 protein-altering somatic variants across 301 genes were identified. While TP53 mutations were ubiquitous, platinum-resistant and platinum-refractory tumors showed enrichment of pathogenic alterations affecting DNA repair, transcriptional regulation, epigenetic modification, and oncogenic signaling, including FANCA, ATF1, MAF, NCOA2, PIK3CA, and TET1. Mutations in these genes were associated with reduced overall survival in exploratory analyses (median 2.5–9 months vs. 27.5–45 months). Multivariate analysis identified FANCA and ATF1 as potential independent predictors in exploratory modeling. In the TCGA-OV cohort, patients harboring pathogenic variants in a multi-gene panel derived from this study (excluding BRCA1/2) exhibited significantly worse survival compared with both BRCA1/2-mutated cases and the overall cohort. Conclusions: This exploratory study identifies a set of genomic alterations converging on transcriptional and epigenetic regulation, DNA repair, and oncogenic signaling that are associated with platinum resistance and adverse prognosis in HG-SOC. Independent validation in TCGA supports the potential clinical relevance of this mutational signature. These findings warrant further validation in larger prospective cohorts and functional studies to clarify their role as biomarkers of aggressive disease and therapeutic vulnerability. Full article

Background: Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with distinct clinical and biological features compared to rarer entities such as primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECTCL). Although recurrent genomic alterations in CTCL have been described, comparative analyses at the pathway level across biologically divergent subtypes remain limited. Here, we leveraged a conversational artificial intelligence (AI) platform for precision oncology to enable rapid, integrative, and hypothesis-driven interrogation of publicly available genomic datasets. Methods: We conducted a secondary analysis of somatic mutation and clinical data from the Columbia University CTCL cohort accessed via cBioPortal. Cases were stratified into SS (n = 26) and PCAECTCL (n = 13). High-confidence coding variants were curated and mapped to biologically relevant signaling pathways and functional gene categories implicated in CTCL pathogenesis. Pathway-level mutation frequencies were compared using Fisher’s exact tests, with effect sizes quantified as odds ratios. Tumor mutational burden (TMB) was compared using the Wilcoxon rank-sum test. Subtype-specific co-mutation patterns were evaluated using pairwise association analyses and visualized through oncoplots and network heatmaps. A conversational AI agent, AI-HOPE, was used to iteratively refine cohort definitions, prioritize pathway-level signals, and contextualize findings. Results: TMB was comparable between SS and PCAECTCL (p = 0.96), indicating no significant difference in global mutational load. In contrast, pathway-centric analyses revealed marked qualitative differences. SS demonstrated enrichment of alterations in epigenetic regulators, tumor suppressor and cell-cycle control pathways, NFAT signaling, and DNA damage response mechanisms, consistent with transcriptional dysregulation and immune modulation. PCAECTCL exhibited relatively higher frequencies of alterations involving epigenetic regulators and MAPK pathway signaling, suggesting distinct oncogenic dependencies. Co-mutation analysis revealed a more constrained and focused interaction landscape in SS, whereas PCAECTCL displayed broader and more heterogeneous co-mutation networks, indicative of divergent evolutionary trajectories. Notably, ERBB2 mutations were significantly enriched between subtypes (p = 0.031), highlighting a potential subtype-specific therapeutic vulnerability. Conclusions: This study demonstrates that SS is distinguished from PCAECTCL not by increased mutational burden but by distinct pathway-level architectures, particularly involving epigenetic regulation, immune signaling, and transcriptional control. These findings generate biologically grounded, testable hypotheses for subtype-specific therapeutic targeting and underscore the value of conversational AI as a scalable framework for accelerating discovery in translational cancer genomics. Full article