Search Results (9)

Background/Objectives: Response to immune checkpoint inhibitors (ICIs) is associated with several biological pathways, including tumor immunogenicity and antitumor immunity. Identifying host factors involved in these pathways may guide personalized ICI treatment. Methods: We describe the application of chromatin conformation assays to blood from patients with advanced urothelial carcinoma from the phase 3 JAVELIN Bladder 100 trial (NCT02603432). This trial demonstrated a significant survival benefit with avelumab maintenance plus best supportive care (BSC) vs. BSC alone following non-progression with platinum-based chemotherapy as first-line therapy. Blood-based chromatin conformation markers (CCMs) were screened for associations with high/low immune effector gene expression in tumors and for interactions with outcomes and tumor mutation burden. Results: Candidate CCMs included genes involved in several immune response pathways, such as POU2F2, which encodes a transcription factor that regulates B-cell maturation. Conclusions: Our findings suggest that polygenic host factors may affect response to ICIs and support further investigation of chromatin conformation assays. Full article

Background/Objectives: Prostate cancer (PCa) remains a major contributor to cancer-related morbidity and mortality worldwide. Current diagnostic strategies, largely based on PSA screening, lack specificity and sensitivity, leading to unnecessary invasive procedures and elevated healthcare costs. This real-world study evaluated the EpiSwitch^® PSE assay, a blood-based test analyzing 3D genome conformation signatures, ability to avoid unnecessary biopsies and the resulting clinical and economical benefits. Methods: 187 patients undergoing evaluation for PCa were tested with the EpiSwitch^® PSE assay. Biopsy confirmation was available for 53 patients, while predictive modeling assessed 134 patients using EpiSwitch PSE results and clinical variables. Results: Among the 187 patients evaluated, predictive modeling showed that up to 79.1% (106/134) of patients could safely defer biopsy based on a low-likelihood EpiSwitch PSE result, while an alternative model showed a 66.4% (89/134) biopsy avoidance rate. The PSE result demonstrated strong concordance with biopsy-confirmed diagnoses and was the most influential predictor in multivariate analysis, followed by PI-RADS score. The test achieved a 100% technical success rate, with an average turnaround time of 4.4 days. Conclusions: Incorporating the EpiSwitch PSE assay into clinical workflows enhances decision-making efficiency, reduces unnecessary biopsies, and improves healthcare resource utilization. These findings support the assay’s strong clinical utility and economic value, highlighting its potential for broader adoption as a minimally invasive reflex test and a pre-biopsy triage tool for the early and accurate detection of prostate cancer. Future studies should include prospective, multicenter trials to confirm these results across broader populations and evaluate longitudinal outcomes of patients managed with PSE-guided care. Full article

Background/Objectives: The 3-dimensional (3D) architecture of the genome in the nucleus of a living cell plays an unexpected yet fundamental regulatory role in cell biology. As an imprint of the cellular genetic, epigenetic and metabolic status, it discriminates pathological conditions through conditional changes to long-range 3D interactions (up to 300 kb) and thus could act as a powerful molecular biomarker linked closely to clinical outcomes. Methods: Here an assessment is made of the latest paradigm shift in molecular biology from a supply chain where information flows from DNA to RNA to protein, to the concept of heritable 3D folding of the genome reflecting the epigenetic and metabolic state of the cell, and which serves as a molecular biomarker for complex clinical outcome. Results: While biomarkers based on individual components of the supply chain fail to accurately reflect clinical outcomes, 3D genomics offers highly informative insights, exemplified for immuno-oncology and prostate cancer diagnosis by clinical tests of superior performance, already in practice in the US and UK. Conclusions: A more complete understanding of human biology will require models that account for the flow of information to and from the 3D genomic architecture in living cells, together with its regulation and logic. Integrating these principles into biomarker discovery and therapeutic design, along with other frontline approaches in precision medicine, including multi-omics and other system-level tools, will be essential for advancing precision medicine beyond its current limitations. Full article

Background/Objectives: Colorectal cancer (CRC) arises from the epithelial lining of the colon or rectum, often following a progression from benign adenomatous polyps to malignant carcinoma. Screening modalities such as colonoscopy, faecal immunochemical tests (FIT), and FIT-DNA are critical for early detection and prevention, but non-invasive methods lack sensitivity to polyps and early CRC. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression. We have previously developed an epigenetic assay, EpiSwitch^®®, that employs an algorithmic-based CCs analysis. Using EpiSwitch^®® technology, we have shown the presence of cancer-specific CCs in peripheral blood mononuclear cells (PBMCs) and primary tumours of patients with melanoma and prostate cancer. EpiSwitch^®®-based commercial tests are now available to diagnose prostate cancer with 94% accuracy (PSE test) and response to immune checkpoint inhibitors across 14 cancers with 85% accuracy (CiRT test). Methods/Results/Conclusions: Using blood samples collected from n = 171 patients with CRC, n = 44 patients with colorectal polyps and n = 110 patients with a ‘clear’ colonoscopy we performed whole Genome DNA screening for CCs correlating to CRC diagnosis. Our findings suggest the presence of two eight-marker CC signatures (EpiSwitch^®® NST) in whole blood that allow diagnosis of CRC and precancerous polyps, respectively. Independent validation cohort testing demonstrated high accuracy in identifying colorectal polyps and early versus late stages of CRC with an exceptionally high sensitivity of 79–90% and a high positive prediction value of 60–84%. Linking the top diagnostic CCs to nearby genes, we have built pathways maps that likely underline processes contributing to the pathology of polyp and CRC progression, including TGFβ, cMYC, Rho GTPase, ROS, TNFa/NFκB, and APC. Full article

Background: Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICIs) remain limited to only a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetic and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint pathways reveal a highly prevalent molecular profile predictive of response to PD-1/PD-L1 ICIs. A clinical blood test based on a set of eight (8) 3D genomic biomarkers has been developed and validated on the basis of an observational trial to predict response to ICI therapy. Methods: The predictive eight biomarker set is derived from prospective observational clinical trials, representing 280 treatments with Pembrolizumab, Atezolizumab, Durvalumab, Nivolumab, and Avelumab in a broad range of indications: melanoma, lung, hepatocellular, renal, breast, bladder, colon, head and neck, bone, brain, lymphoma, prostate, vulvar, and cervical cancers. Results: The 3D genomic eight biomarker panel for response to immune checkpoint therapy achieved a high accuracy of 85%, sensitivity of 93%, and specificity of 82%. Conclusions: This study demonstrates that a 3D genomic approach can be used to develop a predictive clinical assay for response to PD-1/PD-L1 checkpoint inhibition in cancer patients. Full article

Background: Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of any prostate cancer, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance in some men with PCa. We have recently identified circulating chromosome conformation signatures (CCSs, Episwitch^® PCa test) allowing PCa detection and risk stratification in line with standards of clinical PCa staging. The purpose of this study was to determine whether combining the Episwitch PCa test with the PSA test will increase its diagnostic accuracy. Methods: n = 109 whole blood samples of men enrolled in the PROSTAGRAM screening pilot study and n = 38 samples of patients with established PCa diagnosis and cancer-negative controls from Imperial College NHS Trust were used. Samples were tested for PSA, and the presence of CCSs in the loci encoding for of DAPK1, HSD3B2, SRD5A3, MMP1, and miRNA98 associated with high-risk PCa identified in our previous work. Results: PSA > 3 ng/mL alone showed a low positive predicted value (PPV) of 0.14 and a high negative predicted value (NPV) of 0.93. EpiSwitch alone showed a PPV of 0.91 and a NPV of 0.32. Combining PSA and Episwitch tests has significantly increased the PPV to 0.81 although reducing the NPV to 0.78. Furthermore, integrating PSA, as a continuous variable (rather than a dichotomised 3 ng/mL cut-off), with EpiSwitch in a new multivariant stratification model, Prostate Screening EpiSwitch (PSE) test, has yielded a remarkable combined PPV of 0.93 and NPV of 0.95 when tested on the independent combined cohort. Conclusions: Our results demonstrate that combining the standard PSA readout with circulating chromosome conformations (PSE test) allows for significantly enhanced PSA PPV and overall accuracy for PCa detection. The PSE test is accurate, rapid, minimally invasive, and inexpensive, suggesting significant screening diagnostic potential to minimise unnecessary referrals for expensive and invasive MRI and/or biopsy testing. Further extended prospective blinded validation of the new combined signature in a screening cohort with low cancer prevalence would be the recommended step for PSE adoption in PCa screening. Full article

The definitive diagnosis and early treatment of many immune-mediated inflammatory diseases (IMIDs) is hindered by variable and overlapping clinical manifestations. Psoriatic arthritis (PsA), which develops in ~30% of people with psoriasis, is a key example. This mixed-pattern IMID is apparent in entheseal and synovial musculoskeletal structures, but a definitive diagnosis often can only be made by clinical experts or when an extensive progressive disease state is apparent. As with other IMIDs, the detection of multimodal molecular biomarkers offers some hope for the early diagnosis of PsA and the initiation of effective management and treatment strategies. However, specific biomarkers are not yet available for PsA. The assessment of new markers by genomic and epigenomic profiling, or the analysis of blood and synovial fluid/tissue samples using proteomics, metabolomics and lipidomics, provides hope that complex molecular biomarker profiles could be developed to diagnose PsA. Importantly, the integration of these markers with high-throughput histology, imaging and standardized clinical assessment data provides an important opportunity to develop molecular profiles that could improve the diagnosis of PsA, predict its occurrence in cohorts of individuals with psoriasis, differentiate PsA from other IMIDs, and improve therapeutic responses. In this review, we consider the technologies that are currently deployed in the EU IMI2 project HIPPOCRATES to define biomarker profiles specific for PsA and discuss the advantages of combining multi-omics data to improve the outcome of PsA patients. Full article

Recent large national and international cohorts describe the baseline characteristics and outcome of hospitalised patients with COVID-19, however there is limited granularity to these reports. We aimed to provide a detailed description of a UK COVID-19 cohort, focusing on management and outcome. We performed a retrospective single-centre analysis of clinical management and 28-day outcomes of consecutive adult inpatients with SARS-CoV-2 PCR-confirmed COVID-19 from 31 January to 16 April 2020 inclusive. In total, 316 cases were identified. Most patients were elderly (median age 75) with multiple comorbidities. One quarter were admitted from residential or nursing care. Mortality was 84 out of 316 (26.6%). Most deaths occurred in patients in whom a ceiling of inpatient treatment had been determined and for whom end of life care and specialist palliative care input was provided where appropriate. No deaths occurred in patients aged under 56 years. Decisions to initiate respiratory support were individualised after consideration of patient wishes, premorbid frailty and comorbidities. In total, 59 (18%) patients were admitted to intensive care, of which 31 (10% overall cohort) required intubation. Multiple logistic regression identified associations between death and age, frailty, and disease severity, with age as the most significant factor (odds ratio 1.07 [95% CI 1.03–1.10] per year increase, p < 0.001). These findings provide important clinical context to outcome data. Mortality was associated with increasing age. Most deaths were anticipated and occurred in patients with advance decisions on ceilings of treatment. Full article

The integration of genetic and environmental factors that regulate the gene expression patterns associated with exercise adaptation is mediated by epigenetic mechanisms. The organisation of the human genome within three-dimensional space, known as chromosome conformation, has recently been shown as a dynamic epigenetic regulator of gene expression, facilitating the interaction of distal genomic regions due to tight and regulated packaging of chromosomes in the cell nucleus. Technological advances in the study of chromosome conformation mean a new class of biomarker—the chromosome conformation signature (CCS)—can identify chromosomal interactions across several genomic loci as a collective marker of an epigenomic state. Investigative use of CCSs in biological and medical research shows promise in identifying the likelihood that a disease state is present or absent, as well as an ability to prospectively stratify individuals according to their likely response to medical intervention. The association of CCSs with gene expression patterns suggests that there are likely to be CCSs that respond, or regulate the response, to exercise and related stimuli. The present review provides a contextual background to CCS research and a theoretical framework discussing the potential uses of this novel epigenomic biomarker within sport and exercise science and medicine. Full article