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Molecular diagnostics in gastric cancer.
Despite recent advances in individualised targeted therapy, gastric cancer remains one of the most challenging diseases in gastrointestinal oncology. Modern imaging techniques using endoscopic filter devices and in vivo molecular imaging are designed to enable early detection of the cancer and surveillance of patients at risk. Molecular characterisation of the tumour itself as well as of the surrounding inflammatory environment is more sophisticated in the view of tailored therapies and individual prognostic assessment. The broad application of high throughput techniques for the description of genome wide patterns of structural (copy number aberrations, single nucleotide polymorphisms, methylation pattern) and functional (gene expression profiling, proteomics, miRNA) alterations in the cancer tissue lead not only to a better understanding of the tumour biology but also to a description of gastric cancer subtypes independent from classical stratification systems. Biostatistical means are required for the interpretation of the massive amount of data generated by these approaches. In this review we give an overview on the current knowledge of diagnostic methods for detection, description and understanding of gastric cancer disease.
Clinical characteristics and time trends in etiology of hepatocellular cancer in Germany.
IntroductionThe incidence of hepatocellular cancer (HCC) continues to rise in Europe with a shift of the primary cause towards alcoholic and non-alcoholic fatty liver disease. Metabolic factors like diabetes mellitus and overweight have been identified as significant risk factors for HCC development.Patients and methodsA retrospective analysis in a large single-center cohort of 650 patients diagnosed with HCC was performed. Demographic characteristics, risk factors, tumor stage at diagnosis and survival were evaluated.ResultsAmong 650 patients (aged 17-87 years, with a male: female ratio of 4:1), 80.8% had underlying liver cirrhosis. Alcohol abuse was identified as the only risk factor for liver cirrhosis in 52.2% of patients. Viral infection with hepatitis C and hepatitis B was present in 13.7 and 3.6% of patients, respectively. 66.1% of patients with HCC were overweight with a body mass index exceeding 25, 25.5% even exceeding 30; 52% of patients had diabetes mellitus.ConclusionStrategies aiming at prevention and surveillance of patients at risk to develop HCC in the future need to widen the focus from patients with chronic viral hepatitis and a history of alcohol abuse to patients with metabolic risk factors.
Functional and topological properties in hepatocellular carcinoma transcriptome.
Hepatocellular carcinoma (HCC) is a leading cause of global cancer mortality. However, little is known about the precise molecular mechanisms involved in tumor formation and pathogenesis. The primary goal of this study was to elucidate genome-wide molecular networks involved in development of HCC with multiple etiologies by exploring high quality microarray data. We undertook a comparative network analysis across 264 human microarray profiles monitoring transcript changes in healthy liver, liver cirrhosis, and HCC with viral and alcoholic etiologies. Gene co-expression profiling was used to derive a consensus gene relevance network of HCC progression that consisted of 798 genes and 2,012 links. The HCC interactome was further confirmed to be phenotype-specific and non-random. Additionally, we confirmed that co-expressed genes are more likely to share biological function, but not sub-cellular localization. Analysis of individual HCC genes revealed that they are topologically central in a human protein-protein interaction network. We used quantitative RT-PCR in a cohort of normal liver tissue (n = 8), hepatitis C virus (HCV)-induced chronic liver disease (n = 9), and HCC (n = 7) to validate co-expressions of several well-connected genes, namely ASPM, CDKN3, NEK2, RACGAP1, and TOP2A. We show that HCC is a heterogeneous disorder, underpinned by complex cross talk between immune response, cell cycle, and mRNA translation pathways. Our work provides a systems-wide resource for deeper understanding of molecular mechanisms in HCC progression and may be used further to define novel targets for efficient treatment or diagnosis of this disease.
Serological assessment of gastric mucosal atrophy in gastric cancer.
BackgroundNon-invasive tools for gastric cancer screening and diagnosis are lacking. Serological testing with the detection of pepsinogen 1 (PG1), pepsinogen 2 (PG2) and gastrin 17 (G17) offers the possibility to detect preneoplastic gastric mucosal conditions. Aim of this study was to assess the performance of these serological tests in the presence of gastric neoplasia.MethodsHistological and serological samples of 118 patients with gastric cancer have been assessed for tumor specific characteristics (Laurén type, localisation), degree of mucosal abnormalities (intestinal metaplasia, atrophy) and serological parameters (PG1, PG2, PG1/2-ratio, G17, H. pylori IgG, CagA status). Association of the general factors to the different serological values have been statistically analyzed.ResultsPatients with intestinal type gastric cancer had lower PG1 levels and a lower PG1/2-ratio compared to those with diffuse type cancer (p = 0.003). The serum levels of PG2 itself and G17 were not significantly altered. H. pylori infection in general had no influence on the levels of PG1, PG2 and G17 in the serum of gastric cancer patients. There was a trend towards lower PG1 levels in case of positive CagA-status (p = 0.058). The degree of both intestinal metaplasia and atrophy correlated inversely with serum levels for PG1 and the PG1/2-ratio (p < 0.01). Laurén-specific analysis revealed that this is only true for intestinal type tumors. Univariate ANOVA revealed atrophy and CagA-status as the only independent factors for low PG1 and a low PG1/2-ratio.ConclusionsGlandular atrophy and a positive CagA status are determinant factors for decreased pepsinogen 1 levels in the serum of patients with gastric cancer. The serological assessment of gastric atrophy by analysis of serum pepsinogen is only adequate for patients with intestinal type cancer.
Low-cost and clinically applicable copy number profiling using repeat DNA
Large-scale cancer genome studies suggest that tumors are driven by somatic copy number alterations (SCNAs) or single-nucleotide variants (SNVs). Due to the low-cost, the clinical use of genomics assays is biased towards targeted gene panels, which identify SNVs. There is a need for a comparably low-cost and simple assay for high-resolution SCNA profiling. Here we present our method, conliga, which infers SCNA profiles from a low-cost and simple assay.
Identification of Prognostic Phenotypes of Esophageal Adenocarcinoma in 2 Independent Cohorts.
BACKGROUND & AIMS: Most patients with esophageal adenocarcinoma (EAC) present with de novo tumors. Although this could be due to inadequate screening strategies, the precise reason for this observation is not clear. We compared survival of patients with prevalent EAC with and without synchronous Barrett esophagus (BE) with intestinal metaplasia (IM) at the time of EAC diagnosis. METHODS: Clinical data were studied using Cox proportional hazards regression to evaluate the effect of synchronous BE-IM on EAC survival independent of age, sex, TNM stage, and tumor location. We analyzed data from a cohort of patients with EAC from the Mayo Clinic (n=411; 203 with BE and IM) and a multicenter cohort from the United Kingdom (n=1417; 638 with BE and IM). RESULTS: In the Mayo cohort, BE with IM had a reduced risk of death compared to patients without BE and IM (hazard ratio [HR] 0.44; 95% CI, 0.34-0.57; P
Immunogenicity of MVA-BN vaccine deployed as mpox prophylaxis: a prospective cohort study and analysis of transcriptomic predictors of response
Background: Since 2022, mpox has emerged as a global health threat, with two clades (I and II) causing outbreaks of international public health concern. The third generation smallpox vaccine modified vaccinia Ankara, manufactured by Bavarian Nordic (MVA-BN), has emerged as a key component of mpox prevention. To date, the immunogenicity of this vaccine, including determinants of response has been incompletely described, especially when MVA-BN has been administered intradermally at 1/5th the registered dose (‘fractionated dosing’), as recommended as a dose-sparing strategy. The aim of this study was to explore the immunogenicity of MVA-BN, and baseline determinants of vaccine response in an observational public-health response setting. Methods: We conducted a prospective cohort study and immunological analysis of responses to MVA-BN in patients attending a sexual health vaccination clinic in Oxford, UK. Blood samples were taken at baseline, day 14, and day 28 after first vaccine, and 28 and 90 days following a second vaccine. A sub-cohort had additional blood samples collected day 1 following their first vaccine (optional timepoint). We assessed IgG responses to mpox/vaccinia antigens using Luminex assay (‘MpoxPlex’) via generalised linear mixed modelling, and T-cell responses using interferon- enzyme linked immunospot and activation induced marker assay. Associations between blood transcriptomic signatures (baseline, day 1) and immunogenicity were assessed using differential expression analysis and gene set enrichment methods. Findings: We recruited 34 participants of whom 33 received fractionated dosing. Of those without prior smallpox vaccination (n=30), 50% seroconverted by day 28, and while this increased to 89% by day 90 post second vaccination, individuals seronegative on day 28 demonstrated persistently lower responses compared to day 28 seropositive individuals. Serological response on day 28 positively associated with type I and II interferon signatures day one post-vaccination (n=18 samples) but negatively associated with these signatures at baseline. Interpretation: Baseline inflammatory states may inhibit MVA-BN serological immunogenicity by inhibiting the upregulation of MVA-induced innate immune signalling. If confirmed mechanistically these insights may inform improved vaccination strategies against mpox in diverse geographic and demographic settings. Given the likelihood of vaccine supply limitations in the current context and in future outbreak settings, the utility of dose-sparing vaccine strategies as a general approach to maximising population benefit warrants further study
Altered IL-6 signalling and risk of tuberculosis: a multi-ancestry mendelian randomisation study.
BACKGROUND: The role of IL-6 responses in human tuberculosis risk is unknown. IL-6 signalling inhibitors, such as tocilizumab, are thought to increase the risk of progression to tuberculosis, and screening for latent Mycobacterium tuberculosis infection before using these drugs is widely recommended. We used single nucleotide polymorphisms (SNPs) in and near the IL-6 receptor gene (IL6R), including the non-synonymous variant, rs2228145, for which the C allele contributes to reduced classic (cis) IL-6 signalling activity, to test the hypothesis that altered IL-6 signalling is causally associated with the risk of developing tuberculosis. METHODS: We performed a meta-analysis of genome-wide association studies (GWAS) published in English from database inception to Jan 1, 2024. GWAS were identified from the European Bioinformatics Institute, MRC Integrative Epidemiology Unit catalogues, and MEDLINE, selecting publicly available studies for which tuberculosis was an outcome and that included the IL6R rs2228145 SNP. Using each study's population-level summary statistics, effect estimates were extracted for each additional copy of the C allele of rs2228145. We used these estimates to perform multi-ancestry, two-sample mendelian randomisation analyses to estimate the causal effect of reduced IL-6 signalling on tuberculosis. Our primary analyses used rs2228145-C as a genetic instrument, weighted on C-reactive protein (CRP) reduction as a measure of the effect on IL-6 signalling. We also took an alternative, ancestry-specific, multiple SNP approach using IL-6 receptor plasma protein as an exposure. Additionally, we compared the effects of rs2228145 in tuberculosis with those in critical COVID-19, rheumatoid arthritis, Crohn's disease, and coronary artery disease using the summary statistics extracted from GWAS. FINDINGS: 17 GWAS were included, collating data for 19 302 individuals with tuberculosis (cases) and 1 019 821 population controls across multiple ancestries. For each additional rs2228145-C allele, the odds of tuberculosis reduced (odds ratio [OR] 0·94 [95% CI 0·92-0·97]; p=6·8 × 10-6). Multi-ancestry mendelian randomisation analyses supported these findings, with decreased odds of tuberculosis associated with readouts of reduced IL-6 signalling (0·52 [0·39-0·69] for each natural log CRP decrease; p=6·8 × 10-6), with weak evidence of heterogeneity (I2=0·315; p=0·11). Ancestry-specific, multiple SNP mendelian randomisation using increase in IL-6 receptor plasma protein as an exposure revealed a similar reduced risk of tuberculosis (OR 0·94 [95% CI 0·93-0·96]; p=2·4 × 10-10). The protective effects on tuberculosis seen with rs2228145-C were similar in size and direction to those observed in critical COVID-19 (0·66 [0·50-0·86]), Crohn's disease (0·57 [0·44-0·74]), and rheumatoid arthritis (0·45 [0·36-0·58]), all of which benefit from the therapeutic effects of IL-6 antagonism. INTERPRETATION: Our findings propose a causal relationship between reduced IL-6 signalling and lower risk of tuberculosis, akin to the effect seen in other IL-6 mediated diseases. This study suggests that IL-6 antagonists do not increase the risk of tuberculosis but rather should be investigated as therapeutic adjuncts in its treatment. FUNDING: UK National Institute for Health and Care Research, Wellcome Trust, EU European Regional Development Fund, the Welsh Government, and UK Research and Innovation.
Incidence of diabetes mellitus following hospitalisation for COVID-19 in the United Kingdom: A prospective observational study.
BACKGROUND: People hospitalised for coronavirus disease 2019 (COVID-19) have elevated incidence of diabetes. However, it is unclear whether this is due to shared risk factors, confounding or stress hyperglycaemia in response to acute illness. METHODS: We analysed a multicentre prospective cohort study (PHOSP-COVID) of people ≥18 years discharged from NHS hospitals across the United Kingdom following COVID-19. Individuals were included if they attended at least one research visit with a HbA1c measurement within 14 months of discharge and had no history of diabetes at baseline. The primary outcome was new onset diabetes (any type), as defined by a first glycated haemoglobin (HbA1c) measurement ≥6.5% (≥48 mmol/mol). Follow-up was censored at the last HbA1c measurement. Age-standardised incidence rates and incidence rate ratios (adjusted for age, sex, ethnicity, length of hospital stay, body mass index, smoking, physical activity, deprivation, hypertension, hyperlipidaemia/hypercholesterolaemia, intensive therapy unit admission, invasive mechanical ventilation, corticosteroid use and C-reactive protein score) were calculated using Poisson regression. Incidence rates were compared with the control groups of published clinical trials in the United Kingdom by applying the same inclusion and exclusion criteria, where possible. RESULTS: Incidence of diabetes was 91.4 per 1000 person-years and was higher in South Asian (incidence rate ratios [IRR] = 3.60; 1.77, 7.32; p
Assessing the Utility of ColabFold and AlphaMissense in Determining Missense Variant Pathogenicity for Congenital Myasthenic Syndromes.
BACKGROUND/OBJECTIVES: Congenital myasthenic syndromes (CMSs) are caused by variants in >30 genes with increasing numbers of variants of unknown significance (VUS) discovered by next-generation sequencing. Establishing VUS pathogenicity requires in vitro studies that slow diagnosis and treatment initiation. The recently developed protein structure prediction software AlphaFold2/ColabFold has revolutionized structural biology; such predictions have also been leveraged in AlphaMissense, which predicts ClinVar variant pathogenicity with 90% accuracy. Few reports, however, have tested these tools on rigorously characterized clinical data. We therefore assessed ColabFold and AlphaMissense as diagnostic aids for CMSs, using variants of the CHRN genes that encode the nicotinic acetylcholine receptor (nAChR). METHODS: Utilizing a dataset of 61 clinically validated CHRN variants, (1) we evaluated the possibility of a ColabFold metric (either predicted structural disruption, prediction confidence, or prediction quality) that distinguishes variant pathogenicity; (2) we assessed AlphaMissense's ability to differentiate variant pathogenicity; and (3) we compared AlphaMissense to the existing pathogenicity prediction programs AlamutVP and EVE. RESULTS: Analyzing the variant effects on ColabFold CHRN structure prediction, prediction confidence, and prediction quality did not yield any reliable pathogenicity indicative metric. However, AlphaMissense predicted variant pathogenicity with 63.93% accuracy in our dataset-a much greater proportion than AlamutVP (27.87%) and EVE (28.33%). CONCLUSIONS: Emerging in silico tools can revolutionize genetic disease diagnosis-however, improvement, refinement, and clinical validation are imperative prior to practical acquisition.
TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival.
DNA repair and autophagy are distinct biological processes vital for cell survival. Although autophagy helps maintain genome stability, there is no evidence of its direct role in the repair of DNA lesions. We discovered that lysosomes process topoisomerase 1 cleavage complexes (TOP1cc) DNA lesions in vertebrates. Selective degradation of TOP1cc by autophagy directs DNA damage repair and cell survival at clinically relevant doses of topoisomerase 1 inhibitors. TOP1cc are exported from the nucleus to lysosomes through a transient alteration of the nuclear envelope and independent of the proteasome. Mechanistically, the autophagy receptor TEX264 acts as a TOP1cc sensor at DNA replication forks, triggering TOP1cc processing by the p97 ATPase and mediating the delivery of TOP1cc to lysosomes in an MRE11-nuclease- and ATR-kinase-dependent manner. We found an evolutionarily conserved role for selective autophagy in DNA repair that enables cell survival, protects genome stability, and is clinically relevant for colorectal cancer patients.
BLM and BRCA1-BARD1 coordinate complementary mechanisms of joint DNA molecule resolution.
The Bloom syndrome helicase BLM interacts with topoisomerase IIIα (TOP3A), RMI1, and RMI2 to form the BTR complex, which dissolves double Holliday junctions and DNA replication intermediates to promote sister chromatid disjunction before cell division. In its absence, structure-specific nucleases like the SMX complex (comprising SLX1-SLX4, MUS81-EME1, and XPF-ERCC1) can cleave joint DNA molecules instead, but cells deficient in both BTR and SMX are not viable. Here, we identify a negative genetic interaction between BLM loss and deficiency in the BRCA1-BARD1 tumor suppressor complex. We show that this is due to a previously overlooked role for BARD1 in recruiting SLX4 to resolve DNA intermediates left unprocessed by BLM in the preceding interphase. Consequently, cells with defective BLM and BRCA1-BARD1 accumulate catastrophic levels of chromosome breakage and micronucleation, leading to cell death. Thus, we reveal mechanistic insights into SLX4 recruitment to DNA lesions, with potential clinical implications for treating BRCA1-deficient tumors.