Gene methylation biomarkers in sputum as a classifier for lung cancer risk

CT screening for lung cancer reduces mortality, but will cost Medicare ∼2 billion dollars due in part to high false positive rates. Molecular biomarkers could augment current risk stratification used to select smokers for screening. Gene methylation in sputum reflects lung field cancerization that remains in lung cancer patients post-resection. This population was used in conjunction with cancer-free smokers to evaluate classification accuracy of a validated eight-gene methylation panel in sputum for cancer risk. Sputum from resected lung cancer patients (n=487) and smokers from Lovelace (n=1380) and PLuSS (n=718) cohorts was studied for methylation of an 8-gene panel. Area under a receiver operating characteristic curve was calculated to assess the prediction performance in logistic regressions with different sets of variables. The prevalence for methylation of all genes was significantly increased in the ECOG-ACRIN patients compared to cancer-free smokers as evident by elevated odds ratios that ranged from 1.6 to 8.9. The gene methylation panel showed lung cancer prediction accuracy of 82–86% and with addition of clinical variables improved to 87–90%. With sensitivity at 95%, specificity increased from 25% to 54% comparing clinical variables alone to their inclusion with methylation. The addition of methylation biomarkers to clinical variables would reduce false positive screens by ruling out one-third of smokers eligible for CT screening and could increase cancer detection rates through expanding risk assessment criteria

Differential Epigenetic Regulation of TOX Subfamily High Mobility Group Box Genes in Lung and Breast Cancers

Aberrant cytosine methylation affects regulation of hundreds of genes during cancer development. In this study, a novel aberrantly hypermethylated CpG island in cancer was discovered within the TOX2 promoter. TOX2 was unmethylated in normal cells but 28% lung (n = 190) and 23% breast (n = 80) tumors were methylated. Expression of two novel TOX2 transcripts identified was significantly reduced in primary lung tumors than distant normal lung (p<0.05). These transcripts were silenced in methylated lung and breast cancer cells and 5-Aza-2-deoxycytidine treatment re-expressed both. Extension of these assays to TOX, TOX3, and TOX4 genes that share similar genomic structure and protein homology with TOX2 revealed distinct methylation profiles by smoking status, histology, and cancer type. TOX was almost exclusively methylated in breast (43%) than lung (5%) cancer, whereas TOX3 was frequently methylated in lung (58%) than breast (30%) tumors. TOX4 was unmethylated in all samples and showed the highest expression in normal lung. Compared to TOX4, expression of TOX, TOX2 and TOX3 in normal lung was 25, 44, and 88% lower, respectively, supporting the premise that reduced promoter activity confers increased susceptibility to methylation during lung carcinogenesis. Genome-wide assays revealed that siRNA-mediated TOX2 knockdown modulated multiple pathways while TOX3 inactivation targeted neuronal development and function. Although these knockdowns did not result in further phenotypic changes of lung cancer cells in vitro, the impact on tissue remodeling, inflammatory response, and cell differentiation pathways suggest a potential role for TOX2 in modulating tumor microenvironment

Implication of a Chromosome 15q15.2 Locus in Regulating UBR1 and Predisposing Smokers to MGMT Methylation in Lung

O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that protects cells from carcinogenic effects of alkylating agents; however, MGMT is silenced by promoter hypermethylation during carcinogenesis. A single nucleotide polymorphism (SNP) in an enhancer in the MGMT promoter was previously identified to be highly significantly associated with risk for MGMT methylation in lung cancer and sputum from smokers. To further genetic investigations, a genome-wide association and replication study was conducted in two smoker cohorts to identify novel loci for MGMT methylation in sputum that were independent of the MGMT enhancer polymorphism. Two novel trans-acting loci (15q15.2 and 17q24.3) that were identified acted together with the enhancer SNP to empower risk prediction for MGMT methylation. We found that the predisposition to MGMT methylation arising from the 15q15.2 locus involved regulation of the ubiquitin protein ligase E3 component UBR1. UBR1 attenuation reduced turnover of MGMT protein and increased repair of O6-methylguanine in nitrosomethylurea-treated human bronchial epithelial cells (HBEC), while also reducing MGMT promoter activity and abolishing MGMT induction. Overall, our results substantiate reduced gene transcription as a major mechanism for predisposition to MGMT methylation in the lungs of smokers, and support the importance of UBR1 in regulating MGMT homeostasis and DNA repair of alkylated DNA adducts in cells

Genetic Associations and Architecture of Asthma-COPD Overlap

BACKGROUND: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 x 10(-6)) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2). RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 x 10(-8)) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.Peer reviewe

Genetic Associations and Architecture of Asthma-COPD Overlap

BackgroundSome people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.Research QuestionWhat is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?Study Design and MethodsWe conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P –6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2).ResultsWe selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P –8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent.InterpretationWe identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.</p

Potential Micronutrients and Phytochemicals against the Pathogenesis of Chronic Obstructive Pulmonary Disease and Lung Cancer

Lung cancer and chronic obstructive pulmonary disease have shared etiology, including key etiological changes (e.g., DNA damage and epigenetics change) and lung function impairment. Focusing on those shared targets may help in the prevention of both. Certain micronutrients (vitamins and minerals) and phytochemicals (carotenoids and phenols) have potent antioxidant or methyl-donating properties and thus have received considerable interest. We reviewed recent papers probing into the potential of nutrients with respect to lung function preservation and prevention of lung cancer risk, and suggest several hypothetical intervention patterns. Intakes of vitamins (i.e., A, C, D, E, B12), carotenoids, flavonoids, curcumins, resveratrol, magnesium, and omega-3 fatty acids all show protective effects against lung function loss, some mainly by improving average lung function and others through reducing decline rate. Dietary interventions early in life may help lung function reserve over the lifespan. Protective nutrient interventions among smokers are likely to mitigate the effects of cigarettes on lung health. We also discuss their underlying mechanisms and some possible causes for the inconsistent results in observational studies and supplementation trials. The role of the lung microbiome on lung health and its potential utility in identifying protective nutrients are discussed as well. More prospective cohorts and well-designed clinical trials are needed to promote the transition of individualized nutrient interventions into health policy

Softwares and methods for estimating genetic ancestry in human populations

Abstract The estimation of genetic ancestry in human populations has important applications in medical genetic studies. Genetic ancestry is used to control for population stratification in genetic association studies, and is used to understand the genetic basis for ethnic differences in disease susceptibility. In this review, we present an overview of genetic ancestry estimation in human disease studies, followed by a review of popular softwares and methods used for this estimation.</p

Thermodynamic case study of boundary layer viscous nanofluid flow via a riga surface by means of finite difference method

The Riga plate is an electromagnetic actuator made out of permanent magnets and alternating electrodes on a flat surface. In the boundary layer flow across the Riga Plate, viscous dissipation is surveyed in this paper. The suitable boundary conditions have been assigned to the governing model for mass and heat convection phenomenon. A governing equation can be converted into non-dimensional form using similarity transformations. To create numerical solutions to physical phenomena, the finite difference approach can be utilized. Extensive graphical illustrations are provided for the effects of the buoyancy coefficient parameter, modified Hartmann number, parameter related to electrode and magnet width, Prandtl number, slip parameter, thermophoretic parameter, thermal radiation parameter, Schmidt number, chemical reaction rate parameter, suction parameter, Brownian motion parameter, volume fraction, Biot number, and Eckert parameter on velocity, temperature, and concentration distributions. By varying the Eckert number, the viscous dissipation effects can be obtained. Suction and slip parameters increase the velocity while decrease the temperature in both nanofluid cases. The high temperature and velocity of equally distributed nanofluids rise as the volume fraction increases. Thermal radiation promotes heat transport. The concentration of nanoparticles in the region around the plate increases as the chemical reaction parameter increases. The research findings are useful for thermal engineers and practitioners involved in the design and optimization of systems where boundary layer fluxes and heat transfer are important factors. Understanding the effects of viscous dissipation can lead to more reliable heat transfer estimates and more effective thermal management in real-world structures