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1.
Br J Cancer ; 2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-35999269

RESUMO

BACKGROUND: Malignant pleural mesothelioma (MPM) is a lung pleural cancer with very poor disease outcome. With limited curative MPM treatment available, it is vital to study prognostic biomarkers to categorise different patient risk groups. METHODS: We defined gene signatures to separately characterise intrinsic and extrinsic features, and investigated their interactions in MPM tumour samples. Specifically, we calculated gene signature scores to capture the downstream pathways of major mutated driver genes (BAP1, NF2, SETD2 and TP53) as tumour-intrinsic features. Similarly, we inferred the infiltration levels for major immune cells in the tumour microenvironment to characterise tumour-extrinsic features. Lastly, we integrated these features with clinical factors to predict prognosis in MPM. RESULTS: The gene signature scores were more prognostic than the corresponding genomic mutations, mRNA and protein expression. High immune infiltration levels were associated with prolonged survival. The integrative model indicated that tumour features provided independent prognostic values than clinical factors and were complementary with each other in survival prediction. CONCLUSIONS: By using an integrative model that combines intrinsic and extrinsic features, we can more correctly predict the clinical outcomes of patients with MPM.

2.
Genet Med ; 2022 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-35997715

RESUMO

PURPOSE: Models used to predict the probability of an individual having a pathogenic homozygous or heterozygous variant in a mismatch repair gene, such as MMRpro, are widely used. Recently, MMRpro was updated with new colorectal cancer penetrance estimates. The purpose of this study was to evaluate the predictive performance of MMRpro and other models for individuals with a family history of colorectal cancer. METHODS: We performed a validation study of 4 models, Leiden, MMRpredict, PREMM5, and MMRpro, using 784 members of clinic-based families from the United States. Predicted probabilities were compared with germline testing results and evaluated for discrimination, calibration, and predictive accuracy. We analyzed several strategies to combine models and improve predictive performance. RESULTS: MMRpro with additional tumor information (MMRpro+) and PREMM5 outperformed the other models in discrimination and predictive accuracy. MMRpro+ was the best calibrated with an observed to expected ratio of 0.98 (95% CI = 0.89-1.08). The combination models showed improvement over PREMM5 and performed similar to MMRpro+. CONCLUSION: MMRpro+ and PREMM5 performed well in predicting the probability of having a pathogenic homozygous or heterozygous variant in a mismatch repair gene. They serve as useful clinical decision tools for identifying individuals who would benefit greatly from screening and prevention strategies.

3.
Hum Mol Genet ; 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35776125

RESUMO

Fourteen years after the first genome-wide association study (GWAS) of lung cancer was published, approximately forty-five genomic loci have now been significantly associated with lung cancer risk. While functional characterization was performed for several of these loci, a comprehensive summary of current molecular understanding of lung cancer risk has been lacking. Further, many novel computational and experimental tools now became available to accelerate the functional assessment of disease-associated variants, moving beyond locus-by-locus approaches. In this review, we first highlight the heterogeneity of lung cancer GWAS findings across histological subtypes, ancestries, and smoking status, which poses unique challenges to follow-up studies. We then summarize the published lung cancer post-GWAS studies for each risk-associated locus to assess the current understanding of biological mechanisms beyond the initial statistical association. We further summarize strategies for GWAS functional follow-up studies considering cutting-edge functional genomics tools and providing a catalog of available resources relevant to lung cancer. Overall, we aim to highlight the importance of integrating computational and experimental approaches to draw biological insights from the lung cancer GWAS results beyond association.

4.
Neuro Oncol ; 2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35868246

RESUMO

PURPOSE: Glioma incidence is 25% lower in Hispanics than White non-Hispanics. The U.S. Hispanic population is diverse, and registry-based analyses may mask incidence differences associated with geographic/ancestral origins. METHODS: County-level glioma incidence data in Hispanics were retrieved from the Central Brain Tumor Registry of the United States (CBTRUS). American Community Survey data were used to determine county-level proportion of the Hispanic population of Mexican/Central-American origin and of Caribbean origin. Age-adjusted incidence rate-ratios and incidence rate ratios (IRRs) quantified the glioma incidence differences across groups. State-level estimates of admixture in Hispanics were obtained from published 23andMe data. RESULTS: Compared to predominantly Caribbean-origin counties, predominantly Mexican/Central-American-origin counties had lower age-adjusted risks of glioma (IRR=0.83; P<0.0001), glioblastoma (IRR=0.86; P<0.0001), diffuse/anaplastic astrocytoma (IRR=0.78; P<0.0001), oligodendroglioma (IRR=0.82; P<0.0001), ependymoma (IRR=0.88; P=0.012), and pilocytic astrocytoma (IRR=0.76; P<0.0001). Associations were consistent in children and adults, and using more granular geographic regions. Despite having lower glioma incidence, Hispanic glioblastoma patients from predominantly Mexican/Central-American-origin counties had poorer survival than Hispanics living in predominantly Caribbean-origin counties. Incidence and survival differences could be partially explained by state-level estimates of European admixture in Hispanics, with European admixture associated with higher incidence and improved survival. CONCLUSIONS: Glioma incidence and outcomes differ in association with the geographic origins of Hispanic communities, with counties of predominantly Mexican/Central-American-origin at significantly reduced risk and those of Caribbean-origin at comparatively greater risk. Although typically classified as a single ethnic group, appreciating the cultural, socioeconomic, and genetic diversity of Hispanics can advance cancer disparities research.

5.
Healthcare (Basel) ; 10(7)2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35885771

RESUMO

The role of smoking in the risk of SARS-CoV-2 infection is unclear. We used a retrospective cohort design to study data from veterans' Electronic Medical Record to assess the impact of smoking on the risk of SARS-CoV-2 infection. Veterans tested for the SARS-CoV-2 virus from 02/01/2020 to 02/28/2021 were classified as: Never Smokers (NS), Former Smokers (FS), and Current Smokers (CS). We report the adjusted odds ratios (aOR) for potential confounders obtained from a cascade machine learning algorithm. We found a 19.6% positivity rate among 1,176,306 veterans tested for SARS-CoV-2 infection. The positivity proportion among NS (22.0%) was higher compared with FS (19.2%) and CS (11.5%). The adjusted odds of testing positive for CS (aOR:0.51; 95%CI: 0.50, 0.52) and FS (aOR:0.89; 95%CI:0.88, 0.90) were significantly lower compared with NS. Four pre-existing conditions, including dementia, lower respiratory infections, pneumonia, and septic shock, were associated with a higher risk of testing positive, whereas the use of the decongestant drug phenylephrine or having a history of cancer were associated with a lower risk. CS and FS compared with NS had lower risks of testing positive for SARS-CoV-2. These findings highlight our evolving understanding of the role of smoking status on the risk of SARS-CoV-2 infection.

6.
Vaccines (Basel) ; 10(7)2022 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-35891163

RESUMO

This cross-sectional ecological study examined the relationship between neighborhood-level standard occupational groups in the USA and COVID-19 vaccine uptake using 774 census tract data, each consisting of approximately 1600 housing units. The neighborhood-level COVID-19 vaccination uptake data were retrieved from Harris County Public Health, Harris County, Texas. The standard occupational group data were from the US Census Bureau. We calculated the incidence rate ratios (IRRs) for vaccine uptake using bivariate and multivariable Poisson regression models. In the adjusted models, we found that the healthcare practitioner/technician (IRR: 1.008; 95% CI: 1.003-1.014; p = 0.001), business/management/legal (IRR: 1.011; 95% CI: 1.008-1.013; p < 0.001), computer/engineering/life/physical/social science (IRR: 1.018; 95% CI: 1.013-1.023; p < 0.001), and arts/design/entertainment/sports/media (IRR: 1.031; 95% CI: 1.018-1.044; p < 0.001) occupational groups were more likely to have received the full regimen of a COVID-19 vaccine. On the contrary, the building/installation/maintenance/repair (IRR: 0.991; 95% CI: 0.987-0.995; p < 0.001), construction/extraction/production (IRR: 0.991; 95% CI: 0.988-0.995; p < 0.001), transportation/material moving (IRR: 0.992; 95% CI: 0.987-0.997; p = 0.002), food preparation/serving related (IRR: 0.995; 95% CI: 0.990-0.999; p = 0.023), and personal care/services (IRR: 0.991; 95% CI: 0.985-0.998; p = 0.017) groups were less likely to have received the complete dose of a COVID-19 vaccine. White-collar workers were more likely to be vaccinated than blue-collar workers. We adjusted for age, sex, and race/ethnicity in the multivariable analysis. The low vaccine uptake among certain occupational groups remains a barrier to pandemic control. Engaging labor-centered stakeholders in the development of vaccination interventions may increase uptake.

7.
Artigo em Inglês | MEDLINE | ID: mdl-35839461

RESUMO

BACKGROUND: Tobacco exposure causes 8 of 10 lung cancers, and identifying additional risk factors is challenging due to confounding introduced by smoking in traditional observational studies. MATERIALS AND METHODS: We used Mendelian randomization (MR) to screen 207 metabolites for their role in lung cancer predisposition using independent genome-wide-association studies (GWAS) of blood metabolite levels (n =7,824) and lung cancer risk (n=29,266 cases / 56,450 controls). A nested case control study (656 cases and 1,309 matched controls) was subsequently performed using pre-diagnostic blood samples to validate MR association with lung cancer incidence data from population-based cohorts (EPIC and NSHDS). RESULTS: An MR-based scan of 207 circulating metabolites for lung cancer risk identified that blood isovalerylcarnitine (IVC) was associated with a decreased odds of lung cancer after accounting for multiple testing (Log10-OR = 0.43, 95% CI: 0.29-0.63). Molar measurement of IVC in pre-diagnostic blood found similar results (Log10-OR = 0.39, 95% CI: 0.21-0.72). Results were consistent across lung cancer sub-types. CONCLUSIONS: Independent lines of evidence support an inverse association of elevated circulating IVC with lung cancer risk through a novel methodological approach that integrates genetic and traditional epidemiology to efficiently identify novel cancer biomarkers. IMPACT: Our results find compelling evidence in favor of a protective role for a circulating metabolite, IVC, in lung cancer aetiology. From the treatment of a Mendelian disease, isovaleric acidemia, we know that circulating IVC is modifiable through a restricted protein diet or glycine and L-carnatine supplementation. IVC may represent a modifiable and inversely associated biomarker for lung cancer.

8.
Res Pract Thromb Haemost ; 6(4): e12733, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35647478

RESUMO

Background: Research on venous thromboembolism (VTE) that relies only on the International Classification of Diseases (ICD) can misclassify outcomes. Our study aims to discover and validate an improved VTE computable phenotype for people with cancer. Methods: We used a cancer registry electronic health record (EHR)-linked longitudinal database. We derived three algorithms that were ICD/medication based, natural language processing (NLP) based, or all combined. We then randomly sampled 400 patients from patients with VTE codes (n = 1111) and 400 from those without VTE codes (n = 7396). Weighted sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated on the entire sample using inverse probability weighting, followed by bootstrapped receiver operating curve analysis to calculate the concordance statistic (c statistic). Results: Among 800 patients sampled, 280 had a confirmed acute VTE during the first year after cancer diagnosis. The ICD/medication algorithm had a weighted PPV of 95% and a weighted sensitivity of 81%, with a c statistic of 0.90 (95% confidence interval [CI], 0.89-0.91). Adding Current Procedural Terminology codes for inferior vena cava filter removal or early death did not improve the performance. The NLP algorithm had a weighted PPV of 80% and a weighted sensitivity of 90%, with a c statistic of 0.93 (95% CI, 0.92-0.94). The combined algorithm had a weighted PPV of 98% at the higher cutoff and a weighted sensitivity of 96% at the lower cutoff, with a c statistic of 0.98 (95% CI, 0.97-0.98). Conclusions: Our ICD/medication-based algorithm can accurately identify VTE phenotype among patients with cancer with a high PPV of 95%. The combined algorithm should be considered in EHR databases that have access to such capabilities.

9.
Int J Cancer ; 2022 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-35747941

RESUMO

Deucravacitinib, a novel, selective inhibitor of TYK2 is currently under review at the FDA and EMA for treatment of moderate-to-severe plaque psoriasis. It is unclear whether recent safety concerns (ie, elevated rates of lung cancer and lymphoma) related to similar medications (ie, other JAK inhibitors) are shared with this novel TYK2 inhibitor. We used a partial loss-of-function variant in TYK2 (rs34536443), previously shown to protect against psoriasis and other autoimmune diseases, to evaluate the potential effect of therapeutic TYK2 inhibition on risk of lung cancer and non-Hodgkin lymphoma. Summary genetic association data on lung cancer risk were obtained from a GWAS meta-analysis of 29 266 cases and 56 450 controls in the Integrative Analysis of Lung Cancer Risk and Aetiology (INTEGRAL) consortium. Summary genetic association data on non-Hodgkin lymphoma risk were obtained from a GWAS meta-analysis of 8489 cases and 374 506 controls in the UK Biobank and InterLymph consortium. In the primary analysis, each copy of the minor allele of rs34536443, representing partial TYK2 inhibition, was associated with an increased risk of lung cancer (OR 1.15, 95% CI 1.09-1.23, P = 2.29 × 10-6 ) and non-Hodgkin lymphoma (OR 1.18, 95% CI 1.05-1.33, P = 5.25 × 10-3 ). Our analyses using an established partial loss-of-function mutation to mimic TYK2 inhibition provide genetic evidence that therapeutic TYK2 inhibition may increase risk of lung cancer and non-Hodgkin lymphoma. These findings, consistent with recent reports from postmarketing trials of similar JAK inhibitors, could have important implications for future safety assessment of deucravacitinib and other TYK2 inhibitors in development.

10.
Artigo em Inglês | MEDLINE | ID: mdl-35654360

RESUMO

BACKGROUND: Though germline TP53 pathogenic/likely pathogenic variants (PV) are associated with Li-Fraumeni syndrome, many detected by multigene panels represent aberrant clonal expansion (ACE), most due to clonal hematopoiesis (CH). Discerning ACE/CH from germline variants and post-zygotic mosaicism (PZM) is critically needed for risk assessment and management. METHODS: Participants in the Li Fraumeni & TP53 Understanding & Progress (LiFT UP) study with a TP53 PV were eligible. Demographics, personal/family cancer history and clinical laboratory test reports were obtained. DNA from multiple tissues was analyzed using a custom QIAseq® assay (ACE panel) that included TP53 and other CH-associated genes; the ACE panel and eyebrow follicles were assessed in a workflow to discern TP53 PV clinical categories. RESULTS: Among 134 participants there was a significant difference for the age at diagnosis (p=<0.001), component cancers (p=0.007), and clinical testing criteria (p=<0.001), comparing germline vs PZM or ACE. ACE panel analysis of DNA from 55 sets of eyebrow follicles (mean 1.4 ug) and 36 formalin-fixed paraffin imbedded tissues demonstrated low variance (standard error 3%; p = 0.993) for TP53 variant allele fraction, with no significant difference (p=0.965) between tissue types, and detected CH gene PVs. Of 55 multi-tissue cases, germline status was confirmed for 20, PZM in 7, ACE for 25 and 3 were indeterminate. Additional CH variants were detected in 6 ACE and 2 germline cases. CONCLUSIONS: We demonstrated an effective approach and tools for discerning germline TP53 status. IMPACT: Discernment of PZM and TP53-driven CH increases diagnostic accuracy and enables risk-appropriate care.

11.
12.
NPJ Precis Oncol ; 6(1): 48, 2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35773316

RESUMO

Limited efforts have been made in assessing the effect of genome-wide profiling of RNA splicing-related variation on lung cancer risk. In the present study, we first identified RNA splicing-related genetic variants linked to lung cancer in a genome-wide profiling analysis and then conducted a two-stage (discovery and replication) association study in populations of European ancestry. Discovery and validation were conducted sequentially with a total of 29,266 cases and 56,450 controls from both the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium as well as the OncoArray database. For those variants identified as significant in the two datasets, we further performed stratified analyses by smoking status and histological type and investigated their effects on gene expression and potential regulatory mechanisms. We identified three genetic variants significantly associated with lung cancer risk: rs329118 in JADE2 (P = 8.80E-09), rs2285521 in GGA2 (P = 4.43E-08), and rs198459 in MYRF (P = 1.60E-06). The combined effects of all three SNPs were more evident in lung squamous cell carcinomas (P = 1.81E-08, P = 6.21E-08, and P = 7.93E-04, respectively) than in lung adenocarcinomas and in ever smokers (P = 9.80E-05, P = 2.70E-04, and P = 2.90E-05, respectively) than in never smokers. Gene expression quantitative trait analysis suggested a role for the SNPs in regulating transcriptional expression of the corresponding target genes. In conclusion, we report that three RNA splicing-related genetic variants contribute to lung cancer susceptibility in European populations. However, additional validation is needed, and specific splicing mechanisms of the target genes underlying the observed associations also warrants further exploration.

13.
14.
Artigo em Inglês | MEDLINE | ID: mdl-35680035

RESUMO

BACKGROUND & AIMS: Cirrhosis is the main predisposing condition for hepatocellular carcinoma. Host genetic risk factors have been reported for cirrhosis; however, whether there is a genetic contribution to racial disparities in cirrhosis requires further investigation. METHODS: We used an affected-only mapping by admixture linkage disequilibrium analysis to characterize the genetic risk of cirrhosis in 227 African American patients with cirrhosis genotyped at 19,804 ancestry-informative marker single nucleotide polymorphisms. We additionally performed analyses stratified by hepatitis C virus (HCV) infection status. To replicate our findings, we conducted a case-control analysis in an external study population (452 cases and 196 controls). RESULTS: The mean age of patients was 63.3 years and 98.2% were male. Risk factors for cirrhosis included HCV infection (83.7%) and alcohol abuse (56.4%). In the admixture mapping analysis, we found that European ancestry on chromosome 2q21.1 and African ancestry on chromosome 6p21.2 were associated with increased risk of cirrhosis in African Americans. In the fine-mapping analysis, we identified regions near POTEKP on 2q21.1 (P = .0001) and DNAH8 on 6p21.2 (P = .0017) that were associated with cirrhosis. As the admixture peaks in the HCV-positive patients were the same as those in the overall group, findings in the analysis are reflective of the HCV-positive group. In the replication analysis, the results on chromosome 2 were not significant after adjusting for multiple comparisons, and we could not replicate the results on chromosome 6. CONCLUSIONS: We used admixture mapping to identify novel genomic regions on 2q21.1 and 6p21.2 that may be associated with HCV-related cirrhosis risk in African Americans.

15.
Am J Hematol ; 97(8): 1044-1054, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35638475

RESUMO

The epidemiology of cancer-associated thrombosis (CAT) among uninsured and vulnerable populations in the US is not well-characterized. We performed a retrospective cohort study for patients with newly diagnosed cancer from 2011 to 2020 at Harris Health System, which cares for uninsured residents in the Houston metropolitan area. Patient demographics, NCI comorbidity index, area of deprivation index (ADI), cancer histology, staging, and systemic therapy data were extracted. CAT included overall venous thromboembolism (VTE) or pulmonary embolism +/- lower extremity deep vein thrombosis (PE/LE-DVT) within 1 year of diagnosis. We used multivariable Fine-Gray models to assess the associations with CAT accounting for death as a competing risk. Among 15 342 patients, 74% were uninsured and 84% lived in socioeconomically disadvantaged neighborhoods. There were 16% Non-Hispanic White (NHW), 28% Non-Hispanic Black (NHB), 50% Hispanic (27% Mexican), and 6% Asian/Pacific Islanders (API). The 1-year CAT incidence rate was 14.6%. Overall VTE was lower for Hispanics versus NHW (SHR 0.87 [0.76-0.99]) and API versus NHW (SHR 0.58 [0.44-0.77]). PE/LE-DVT was higher for NHB versus NHW (SHR 1.18 [1.01-1.39]). CAT was also associated with chemotherapy-based regimens (+/- immunotherapy), age, obesity, cancer type/staging, VTE history, and recent hospitalization. NCI comorbidity and ADI scores were associated with mortality but not CAT. In a large cohort of underserved patients with cancer, we identified an elevated incidence of CAT with known and novel risk predictors. Hispanics had lower adjusted rates of CAT and mortality. Our findings highlight the need to investigate and incorporate vulnerable populations in clinical trials.


Assuntos
Neoplasias , Embolia Pulmonar , Tromboembolia Venosa , Humanos , Incidência , Pessoas sem Cobertura de Seguro de Saúde , Neoplasias/complicações , Neoplasias/epidemiologia , Neoplasias/terapia , Embolia Pulmonar/etiologia , Estudos Retrospectivos , Fatores de Risco , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Populações Vulneráveis
16.
Oncotarget ; 13: 756-767, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35634240

RESUMO

Largely, cancer development is driven by acquisition and positive selection of somatic mutations that increase proliferation and survival of tumor cells. As a result, genes related to cancer development tend to have an excess of somatic mutations in them. An excess of missense and/or nonsense mutations in a gene is an indicator of its cancer relevance. To identify genes with an excess of potentially functional missense or nonsense mutations one needs to compare the observed and expected numbers of mutations in the gene. We estimated the expected numbers of missense and nonsense mutations in individual human genes using (i) the number of potential sites for missense and nonsense mutations in individual transcripts and (ii) histology-specific nucleotide context-dependent mutation rates. To estimate mutation rates defined as the number of mutations per site per tumor we used silent mutations reported in the Catalog Of Somatic Mutations In Cancer (COSMIC). The estimates were nucleotide context dependent. We have identified 26 genes with an excess of missense and/or nonsense mutations for lung adenocarcinoma, 18 genes for small cell lung cancer, and 26 genes for squamous cell carcinoma of the lung. These genes include known genes and novel lung cancer gene candidates.


Assuntos
Códon sem Sentido , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Mutação de Sentido Incorreto , Nucleotídeos , Oncogenes
17.
J Thorac Oncol ; 17(8): 974-990, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35500836

RESUMO

INTRODUCTION: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC). METHODS: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms (SNPs). Then, the top interactions were further tested by demographically adjusted logistic regression models. Finally, we used the selected interactions to build lung cancer screening models of NSCLC, separately, for never and ever smokers. RESULTS: With the Bonferroni correction, we identified eight statistically significant pairs of SNPs, which predominantly appeared in the 6p21.32 and 5p15.33 regions (e.g., rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.17, p = 6.57 × 10-13; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.17, p = 2.43 × 10-13; rs2858859HLA-DQA1 and rs9275572HLA-DQA2, ORinteraction = 1.15, p = 2.84 × 10-13; rs2853668TERT and rs62329694CLPTM1L, ORinteraction = 0.73, p = 2.70 × 10-13). Notably, even with much genetic heterogeneity across ethnicities, three pairs of SNPs in the 6p21.32 region identified from the European-ancestry population remained significant among an Asian population from the Nanjing Medical University Global Screening Array project (rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.13, p = 0.008; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.11, p = 5.23 × 10-4; rs3135369BTNL2 and rs9271300HLA-DQA1, ORinteraction = 0.89, p = 0.006). The interaction-empowered polygenetic risk score that integrated classical polygenetic risk score and G × G information score was remarkable in lung cancer risk stratification. CONCLUSIONS: Important G × G interactions were identified and enriched in the 5p15.33 and 6p21.32 regions, which may enhance lung cancer screening models.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos de Casos e Controles , Detecção Precoce de Câncer , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único
18.
J Natl Cancer Inst ; 114(8): 1159-1166, 2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35511172

RESUMO

BACKGROUND: Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking behaviors and DNA repair genes, but further work is required to identify susceptibility variants. METHODS: To identify LC susceptibility loci, a family history-based genome-wide association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387 controls) was combined with a previous LC GWAS (29 266 patients, 56 450 controls) by meta-analysis. Colocalization was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic risk scores (PRS) were tested within an independent validation cohort (1 666 LC patients vs 6 664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumor resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided. RESULTS: The GWAx-GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1), and smoking propensity genes (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as subgenome-wide significant variants related to expression quantitative trait loci and/or smoking propensity, assisted in LC genetic risk prediction (odds ratio = 1.37, 95% confidence interval = 1.29 to 1.45; P < .001). Patients with higher genetic PRS loads of smoking-related variants tended to have higher mutation burdens in their lung tumors. CONCLUSIONS: This study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development.


Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Pulmonares , Predisposição Genética para Doença , Células Germinativas/patologia , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Polimorfismo de Nucleotídeo Único
19.
Autophagy ; : 1-18, 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35383530

RESUMO

At a time when complex diseases affect globally 280 million people and claim 14 million lives every year, there is an urgent need to rapidly increase our knowledge into their underlying etiologies. Though critical in identifying the people at risk, the causal environmental factors (microbiome and/or pollutants) and the affected pathophysiological mechanisms are not well understood. Herein, we consider the variations of autophagy-related (ATG) genes at the heart of mechanisms of increased susceptibility to environmental stress. A comprehensive autophagy genomic resource is presented with 263 single nucleotide polymorphisms (SNPs) for 69 autophagy-related genes associated with 117 autoimmune, inflammatory, infectious, cardiovascular, neurological, respiratory, and endocrine diseases. We thus propose the term 'autophagopathies' to group together a class of complex human diseases the etiology of which lies in a genetic defect of the autophagy machinery, whether directly related or not to an abnormal flux in autophagy, LC3-associated phagocytosis, or any associated trafficking. The future of precision medicine for common diseases will lie in our ability to exploit these ATG SNP x environment relationships to develop new polygenetic risk scores, new management guidelines, and optimal therapies for afflicted patients.Abbreviations: ATG, autophagy-related; ALS-FTD, amyotrophic lateral sclerosis-frontotemporal dementia; ccRCC, clear cell renal cell carcinoma; CD, Crohn disease; COPD, chronic obstructive pulmonary disease; eQTL, expression quantitative trait loci; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; GTEx, genotype-tissue expression; GWAS, genome-wide association studies; LAP, LC3-associated phagocytosis; LC3-II, phosphatidylethanolamine conjugated form of LC3; LD, linkage disequilibrium; LUAD, lung adenocarcinoma; MAF, minor allele frequency; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NSCLC, non-small cell lung cancer; OS, overall survival; PtdIns3K CIII, class III phosphatidylinositol 3 kinase; PtdIns3P, phosphatidylinositol-3-phosphate; SLE, systemic lupus erythematosus; SNPs, single-nucleotide polymorphisms; mQTL, methylation quantitative trait loci; ULK, unc-51 like autophagy activating kinase; UTRs, untranslated regions; WHO, World Health Organization.

20.
J Infect Public Health ; 15(5): 508-514, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35429789

RESUMO

BACKGROUND: The COVID-19 pandemic during lockdown has highlighted the importance of identifying individuals most at risk of infection with SARS-CoV-2, underscoring the need to assess factors contributing to susceptibility to disease. With the rapidly evolving nature of the pandemic and its new variants, there is an inadequate understanding on whether there are certain factors such as a specific symptom or collection of symptoms that combined with life-style behaviors may be useful to predict susceptibility. The study aims to explore such factors from pre-vaccination data to guide public health response to potential new waves. METHODS: An anonymous electronic survey was distributed through social media during the lockdown period in the United States from April to June 2020. Respondents were questioned regarding COVID testing, presenting symptoms, demographic information, comorbidities, and confirmation of COVID-19 test results. Stepwise logistic regression was used to identify predictors for COVID-19 perceived susceptibility. Selected classifiers were assessed for prediction performance using area under receiver operating characteristic (AUROC) curve analysis. RESULTS: A total of 130 participants deemed as susceptible because they self-reported their perception of having COVID-19 (but without the evidence of positive test) were compared with 130 individuals with documented negative test results. Participants had a mean age of 45 years, and 165 (63%) were female. Final multivariable model showed significant associations with perceived susceptibility for the following variables: fever (OR:33.5; 95%CI: 3.9,85.9), body ache (OR:3.0; 95%CI:1.1,6.4), contact history (OR:2.7; 95%CI:1.1,6.4), age> 50 (OR:2.7; 95%CI:1.1, 6.6) and smoking (OR:3.3; 95%CI: 1.2,9.1) after adjusting for other symptoms and presence of comorbid conditions. The AUROC ranged from poor to fair (0.65-0.76) for cluster of symptoms but improved to a good model (AUROC = 0.803) after inclusion of sociodemographic and lifestyle behaviors e.g., age and smoking tobacco. CONCLUSIONS: Fever and body aches suggest association with perceived COVID-19 susceptibility in the presence of demographic and lifestyle behaviors. Using other constitutional and respiratory symptoms with fever and body aches, the parsimonious classifier correctly predicts 80.3% of COVID-19 perceived susceptibility. A larger cohort of respondents will be needed to study and refine classifier performance in future lockdowns and with expected surge of new variants of COVID-19 pandemic.


Assuntos
COVID-19 , COVID-19/epidemiologia , Teste para COVID-19 , Controle de Doenças Transmissíveis , Feminino , Febre , Humanos , Masculino , Pessoa de Meia-Idade , Dor , Pandemias , SARS-CoV-2 , Autorrelato , Estados Unidos/epidemiologia
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