The high prevalence of breast cancer is fairly frequent among women worldwide. In the current era of personalized medicine, understanding the molecular etiology of Breast Cancer is essential for better treatment options. Our investigation of the molecular alterations in tumors using next-generation sequencing targeted panels, specifically the Oncomine Precision Assay, has revealed clinically substantial somatic mutations. A total of 32 pretherapeutic invasive ductal carcinoma patients were enrolled in this study. The DNA extraction and quantification were carried out from tumor tissues and proceeded for the run and analyzed with genexus software. The analysis revealed a highly prevalent PIK3CA mutation which plays a significant role in tumorigenesis. PIK3CA mutation incorporated different single nucleotide variations including H1047R (COSMIC ID -775), E545K (COSMIC ID-763), E542K (COSMIC ID-760), H1047L (COSMIC ID-776) and N345K (COSMIC ID-754). While the most frequent copy number variations (CNV) were found for the ERBB2 gene. Apart from these frequent mutations, TP53 SNVs, FGFR, EGFR, CDKN2A, CD274, and PTEN Copy Number Variations were also present in the study cohort. The noteworthy observation is out of 7 Triple Negative Breast Cancer patients three patients were negative for any mutation. Hence, the association of genetic variation with clinicopathological parameters will be helpful in the selection of targeted treatment.

5-hydroxymethylcytosine (5hmC) is a stable epigenomic mark associated with gene regulation and tumorigenesis. To evaluate its potential for multi-cancer detection, epigenomic distribution of 5hmC was analyzed in tumor tissues (n = 217), normal tissues (n = 50), and cell-free DNA (cfDNA) from cancer (n = 1009) and non-cancer subjects (n = 1678) across breast, colon, lung, ovarian, and pancreatic cancers. Differential analysis revealed extensive redistribution of 5hmC in early-stage tumors that persisted into the late-stage, while global 5hmC abundance decreased in all tumors. Two distinct patterns of hydroxymethylation distribution were identified: one common across cancers and another tissue specific. Differential hydroxymethylation regions (DhmRs) that were tumor tissue specific had significantly improved cancer prediction in cfDNA. A multinomial logistic regression model was trained on tissue-specific DhmRs to predict Tissue of Tumor Origin (TOTO) of cfDNA with 85.2% accuracy. These findings demonstrate that stable, cancer-specific 5hmC signatures appear to be established early in tumorigenesis persist throughout disease progression, suggesting 5hmC as a potential pan-cancer marker for early and late-stage tumor detection via liquid biopsy.

Cancer cells rapidly induce PD-L1 expression in response to inflammatory cytokines such as IFNγ from cytotoxic T cells. Increased surface PD-L1 is a primary mechanism of cancer cells evading cytotoxic T-cell-mediated immune clearance. Identifying how cancer cells increase PD-L1 expression may yield clinically relevant immune checkpoint regulators. However, the key regulators and molecular mechanisms mediating rapid PD-L1 induction are yet to be understood entirely. To identify targetable mechanisms controlling cytokine-induced PD-L1 expression, we performed functional CRISPR gene KO screening with a custom-designed sgRNA library that targets "druggable" genes. We performed the screening in 6 different cancer lines: 3 ovarian (OVCAR4, CaOV3, and SKOV3) and three pancreatic cancer (MiaPaca2, ASPC1 and KP4) cell lines. The screening recovered the known regulators of PD-L1 expression and uncovered several novel regulators of PD-L1 that control its expression in all cell lines or in a cancer-type-specific fashion. For example, while genetic or pharmacological depletion of CSNK1A1 results in reduced PD-L1 expression in ovarian cancer cells, CDK1 depletion modulates PD-L1 in pancreatic cancer cell lines. Significantly, we discovered that KEAP1 depletion or pharmacological inhibition diminishes PD-L1 in all cell lines tested (n = 6). Mechanistically, KEAP1 depletion-mediated reduced PD-L1 is due to transcriptional repression of the PD-L1 gene by NRF2 activation. As such, depletion of NRF2 restores PD-L1 expression, while its overexpression leads to diminished PD-L1 expression. Supporting this, pharmacological NRF2 activation resulted in significant antitumor immunity with increased cytotoxic effector T cell infiltration and reduced exhausted T cells, resulting in smaller xenografted tumors. These findings establish the KEAP1/NRF2 axis as a novel and potentially druggable mechanism of IFNγ-meditated PD-L1 expression in cancer cells.

Lynch Syndrome (LS) carriers occasionally develop central nervous system (CNS) malignancies or tumors in organs not traditionally linked to the syndrome. These tumors are poorly characterized in the literature, and there is no sufficient consensus on guidelines and management recommendations for these tumors. Here we study LS from the tumor perspective and profile 238 pan-cancer specimens from 228 genetically confirmed LS carriers. Tumors are stratified into CNS LS-related, non-CNS LS-related, and non-CNS LS-unrelated groups according to anatomic site and established LS tumor spectrum. Comparative analyses against TCGA reveal significant alterations in LS incidence within endometrial and hepatic cancers. Across the three groups, we reveal marked heterogeneity in germline pathogenic-variant distribution, age at diagnosis, somatic mutation landscapes, tumor mutational burden, and microsatellite-instability status. This site- and spectrum-based stratification of a large, pan-cancer LS cohort underscores the heterogeneity of the LS and provides a data-driven foundation for refining future disease management strategies.

Cancers are complex diseases characterized by dynamic perturbations of regulatory networks across multiple hierarchical levels, which cannot be fully captured by alterations in a small number of genes. To this end, based on the concept of Hallmarks of Cancer, a whole genomic data-driven approach is proposed to capture the dynamic variation from normal to cancerous cells. This framework focuses on the characteristic functional modules of cancer via hallmarks of cancer by constructing a coarse-grained gene regulatory network of hallmarks. Through this framework, with stochastic differential equations, macroscopic dynamic changes in tumorigenesis are simulated and further explored. The analysis results reveal that network topology undergoes significant reconfiguration before shifts in hallmark levels, serving as an early indicator of malignancy. A pan-cancer examination across 15 cancer types uncovers universal patterns, for example, the "Tissue Invasion and Metastasis" hallmark exhibits the most significant difference between normal and cancer states, while "Reprogramming Energy Metabolism" shows the least pronounced differences. These findings reinforce the systemic nature of cancer evolution, highlighting the potential of network-based systems biology methods for understanding critical transitions in tumorigenesis.

Prostate cancer is the most common malignant tumor of the male genitourinary system, especially metastatic castration resistant prostate cancer (mCRPC), which currently lacks effective treatment methods. Immunotherapy has limited efficacy in prostate cancer, partly due to its immunosuppressive "cold" tumor microenvironment (TME). Oncolytic virus therapy, such as OH2 modified based on herpes simplex virus type 2, provides a new strategy for reshaping TME and enhancing immune activation. However, the complex regulatory mechanism of oncolytic viruses on TME has not been fully elucidated. This study used multi omics integrated analysis (transcriptomics, metabolomics, and single-cell RNA sequencing) to investigate the effect of OH2 intervention on prostate cancer TME. We systematically analyzed the gene expression changes, metabolic reprogramming, and immune cell dynamics after OH2 treatment using in vitro cell models and RM-1 mouse subcutaneous transplant tumor models. The dataset includes gene expression profiles, metabolic profiles, and single-cell transcriptomes, providing a resource for investigating OH2-induced changes in the prostate cancer TME.

Metastatic head and neck squamous cell carcinoma (mHNSCC) poses a significant threat to patient survival. Previous studies have identified cathepsin L (CTSL) as a key driver of tumourigenesis, metastasis and chemoresistance. However, the regulatory mechanisms underlying CTSL expression remain poorly understood.

Neoadjuvant chemoimmunotherapy (NACI) shows promise for locally advanced cervical cancer (LACC), but drug-tolerant persister (DTP) cells and immunosuppressive microenvironmental adaptations limit clinical efficacy. The underlying determinants governing heterogeneous responses to NACI regimens remain poorly understood, particularly regarding how dynamic tumor-immune interactions shape therapeutic outcomes.

Homologous recombination deficiency (HRD) is a critical biomarker for guiding targeted therapies, yet the full range of somatic alterations driving HRD across cancers remains incompletely characterized. Here, we present a tumor-agnostic machine learning framework that integrates somatic multi-omics data, including copy-number variations, single-nucleotide variants, DNA methylation, and gene expression from over 8,000 patients in The Cancer Genome Atlas. Using a genome-wide mutational signature-based HRD score as ground truth, our model achieved high predictive performance and leveraged SHAP-based explainability to uncover HRD regulators beyond BRCA1/2 Cross-tumor analysis revealed both shared and cancer type-specific molecular determinants, whereas functional enrichment highlighted key molecular and cellular processes. These findings expand the known repertoire of HRD-associated alterations, provide a resource for mechanistic investigation, and demonstrate the potential of integrative AI approaches to improve patient stratification for HR-targeted therapies across diverse malignancies.

Comparative analyses of normal esophageal tissue, Barrett's Esophagus (BE), and esophageal adenocarcinoma have identified distinctive molecular alterations in genomic DNA, epigenetics, non-coding RNA, and proteins that have shown promise as disease-specific biomarkers. Some of the best characterized and promising biomarkers for managing BE are multi-target esophageal cytology DNA assays based on methylated-DNA and immunohistochemical staining of Trefoil factor 3. Additional biomarkers including microRNA, measures of genomic instability, mixed-method panels, and other novel biomarkers (e.g. volatile organic compounds and saliva microbiome) remain in early development and will need further validation in large, prospective studies prior to clinical use.

This article seeks to provide updated information on the pathogenesis of Barrett's esophagus (BE) including the possible cellular origins of esophageal columnar cells and the impact of chronic esophageal inflammation. Other considerations include clinical exposures and the importance of risk factor modifications such as weight loss and tobacco cessation. The article summarizes genetic risk factors in the pathogenesis of BE and discusses how familial risk and exposures are considered in current guidelines to identify those who may benefit from BE screening. Finally, insights gleaned from postablative therapy are integrated into this article for both clinical providers and researchers.

Radiation therapy exerts its therapeutic effect by killing cells via the induction of DNA double-strand breaks (DSBs) in malignant tumors, but cancer cells can repair damaged DNA, leading to radiation resistance (radioresistance). Therefore, a radiosensitizing effect can be expected by suppressing mechanism(s) involved in DNA repair after irradiation. Here, we show that the P2Y12 receptor is involved in the radioresistance of mouse B16 melanoma cells, and that P2Y12 antagonist treatment decreases the radioresistance both in vitro and in vivo by inhibiting DNA repair after γ-irradiation. P2Y12 receptor antagonists Clopidogrel and PSB0739 increased cellular sites of unrepaired DNA by suppressing the DNA damage response (DDR) after γ-irradiation and enhanced radiation-induced proliferative death in B16 melanoma cells. On the other hand, ADP (a P2Y12 receptor agonist) enhanced DDR after γ-irradiation and increased radioresistance. Knockdown of the P2Y12 receptor resulted in an increase of unrepaired DNA damage and enhanced proliferative death after γ-irradiation. Suppression of the P2Y12 receptor also contributed to the enhancement of the cancer-killing effect of γ-irradiation, even in fractionated irradiation samples in which the cancer-killing effect decreased due to sublethal damage recovery. Finally, PSB0739 significantly enhanced the antitumor effect of γ-irradiation in vivo. Our results suggest that P2Y12 receptor antagonists are promising candidates as radiosensitizers to improve radiation therapy.

We performed a systematic review of the literature to better define the scope of MYB alterations in angiocentric glioma and their associated clinical characteristics, as well as to include a novel MYB mutation in an angiocentric glioma case. We also review MYB alterations in the context of oncologic disease. Following PRISMA guidelines, we searched PubMed and Web of Science for relevant literature from 2010 to October 2024. Included articles reported original data on human subjects with angiocentric glioma and a detected MYB mutation. We include one additional angiocentric glioma case showcasing a novel MYB mutation. A total of 14 studies met the inclusion criteria, with a total of 114 patients with individual data for pooled analysis. The mean age was 10.3 years (SD ±9.7 years); 60% of patients were male. MYB::QKI was the most common fusion in 68% of patients. Other MYB mutations included MYB rearrangements, MYB::ESR1, MYB::PCDHGA1, MYB::LOC105378099, and MYB::MMP16. The most common anatomical location was in the cerebral cortex in 68% of patients. MYB fusions in other relevant neuro-oncologic diseases highlight the importance of MYB fusions in adenoid cystic carcinomas, which frequently occur at the skull base, head and neck, and breast. In conclusion, we characterize the breadth of angiocentric glioma patterns in terms of demographics, anatomic location, and MYB fusion patterns. The updated molecular diagnosis of angiocentric glioma as of 2021 warrants continued exploration of the scope of MYB oncogene fusions as drivers of prognosis and targets for future therapies.

Estrogen receptor-positive breast cancer (ER+BC) accounts for ∼70% of all breast tumors, and 20%-40% of patients develop metastases. Everolimus is an mammalian target of rapamycin (mTOR) inhibitor used in combination with exemestane for metastatic ER+BC. However, resistance remains common and leads to poor survival outcomes. To uncover resistance mechanisms, we analyze transcriptomic profiles from everolimus-sensitive and -resistant ER+BC cell lines. Our study uncovers persistent activation of a growth-factor signaling meta-phenotype in resistant cells involving IGF1R, ESR1, and mitogen-activated protein kinase (MAPK) pathways. We identify SMARCD3 regulons linked to this meta-phenotype. Additionally, we find SMARCD3 regulon activity elevated in everolimus-refractory patient tumors. Importantly, we show that SMARCD3 regulon activation was correlated with sensitivity to several known MEK1/2 inhibitors, including trametinib. Combining trametinib with everolimus treatment significantly reduces resistant cell growth. Our results demonstrate that everolimus-resistant ER+BC cells evade therapy via alternate growth-factor signaling linked to activation of SMARCD3 regulons, which can be therapeutically targeted using MEK1/2 inhibitors.

[18F]-Fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) is essential for disease staging and treatment response evaluation in diffuse large B cell lymphoma (DLBCL). In this study, we analyze 18F-FDG-PET scans from 1,024 newly diagnosed DLBCL patients, integrating with DNA and RNA sequencing data. Using the nnUNet deep learning framework and training on both AutoPET public and in-house datasets, we identify key baseline biomarkers-including total metabolic tumor volume (TMTV), Max MTV, and the standardized tumor dissemination biomarker-that demonstrate significant prognostic value. Further integrating PET biomarkers with clinical factors and LymphPlex genetic subtypes, we develop high TMTV, elevated lactate dehydrogenase (LDH), and EZB-like MYC+, MCD-like, and TP53Mut subtypes as risk factors to form the ClinicalPET LymphPlex model, efficiently distinguishing patient outcomes across different treatments. Notably, high TMTV correlates with an immunosuppressive tumor microenvironment, while elevated LDH is linked to increased metabolic activity and tumor proliferation. Collectively, our findings necessitate multimodal integration to enhance prognostic precision and advance personalized therapy in DLBCL.

High-dose chemotherapy and consecutive autologous stem cell transplantation (ASCT) remain the backbone of treatment for transplant-eligible patients of Multiple Myeloma (MM). However, patients are still at high risk of relapse or treatment-related complications. Hence, by understanding the function of hematopoietic stem and progenitor cells (HSPCs) from MM patients in more detail, transplant outcomes in MM patients might be further improved. We combine in our study functional analyses of the potential of HSPCs from newly diagnosed (NDMM) and chemotherapy treated MM patients in a xenotransplant model system with in depth single cells sequencing analysis to provide novel data that might inform clinical routine to improve the outcome of ASCT in MM. Our data demonstrate that (i) HSPCs from treated MM patients are indeed significantly impaired in their overall reconstitution potential and provide a reduced level of B-cells in comparison to HSPCs from age-matched healthy donors and NDMM patients. (ii) We further demonstrate that CD34+ HSPCs acquire a high-risk MM expression profile signature upon induction treatment, which likely adds to the risk of relapse. This high-risk MM expression profile signature relies within CD34+ HSPCs primarily in granulocyte/macrophage progenitors (GMPs), megakaryocyte Erythroid Progenitors (MEPs) and monocytes, while hematopoietic stem cells (HSCs) stay unaffected by transcriptional changes. These data suggest that the elimination of myeloid progenitors and more mature monocytes (likely by purification for HSCs) in HSPCs harvests from treated MM patients for subsequent ASCT might improve transplant outcomes by avoiding re-infusion of cells with a dysregulated and disease-linked transcriptional program.

About one in three Black Africans carry the African-predominant allele variants CYP2D6*17 and/or CYP2D6*29, which confer a reduced enzymatic activity. CYP2D6 intermediate metabolizers (IM) have a reduced biotransformation rate of tamoxifen compared with its more active metabolite endoxifen.

The initiation and progression of multiple myeloma (MM) are intricate processes, and a critical challenge lies in understanding the mechanisms of malignant transformation in MM-initiating cells (MICs) and their driver genes. In this study, we used single-cell sequencing and genetic tracer analysis at each developmental stage, from hematopoietic stem cells to lymphoid lineage differentiation, to identify abnormal differentiation stages in patients with MM. We found that chromosome 1q amplification (1qAmp) originated from a specific subgroup of B cells, whereas chromosome 17p deletion occurred at the plasma cell stage. 1qAmp was present in CD24-FCRL5+ B cell subgroups and initiated B cell transformation into malignant plasma cells by enhancing B cell proliferation and promoting plasma cell differentiation in vitro and in vivo. FCRL5 facilitated B cell differentiation into malignant plasma cells through its interaction with the IRF4/SPI1 complex. The use of targeted FCRL5 CAR T cells in patients with relapsed or refractory MM (RRMM) showed promising safety and efficacy. Together, our work identified genetic events linked to the initiation and malignant transformation of MM along the B cell lineage. These findings form the foundation for identifying potential therapeutic strategies for patients with RRMM by targeting MICs and their driving oncogenes.

T-cell prolymphocytic leukemia is a rare and aggressive mature T-cell malignancy that usually presents with marked lymphocytosis, hepatosplenomegaly, lymphadenopathy, and B symptoms. However, a minority of patients present with an indolent, asymptomatic form. Case Report: A 44-year-old man was diagnosed with asymptomatic T-cell prolymphocytic leukemia after routine blood tests revealed persistent lymphocytosis. Immunophenotyping revealed a mature CD4-/CD8+ T-cell population. Cytogenetic analysis showed 14q11.2 abnormalities with TCRAD rearrangement by fluorescent in situ hybridization. A monoclonal T-cell population was confirmed by flow cytometry and polymerase chain reaction, and a STAT5B mutation was identified by next-generation sequencing. The patient had no cytopenia or organ involvement and a watch-and-wait strategy was adopted. The pathogenesis of T-cell prolymphocytic leukemia involves recurrent genetic alterations, including TCL1A rearrangements and ATM mutations, which promote genomic instability. Despite their aggressive nature, up to 30% of cases initially follow an indolent course, allowing for observation rather than immediate treatment. Standard therapies include alemtuzumab-based regimens and hematopoietic stem cell transplantation, although relapse rates remain high. Conclusion: This case underscores the need to recognize indolent presentations of T-cell prolymphocytic leukemia that may be managed conservatively. Further research is required to identify prognostic markers and optimize therapeutic strategies.