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1.
Cancer Res ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33472890

RESUMO

Lung cancer is the leading cause of cancer death globally. An improved risk stratification strategy can increase efficiency of low-dose computed tomography (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. Based on 13,119 lung cancer patients and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK biobank data (N=335,931). Absolute risk was estimated based on age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial, N=50,772 participants). The lung cancer odds ratio (ORs) for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 (95%CI=1.92-3.00, P=1.80x10-14) in the validation set (trend p-value of 5.26 x 10-20). The OR per standard deviation of PRS increase was 1.26 (95%CI=1.20-1.32, P=9.69x10-23) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status and family history. Collectively, these results suggest that Individual's genetic background may inform the optimal lung cancer LDCT screening strategy.

2.
Physiol Rep ; 9(1): e14657, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33369886

RESUMO

Airway luminal area (Ai ) influences respiratory mechanics during dynamic exercise; however, previous studies have investigated the relationship between airway anatomy and physiological function in different groups of individuals. The purpose of this study was to determine the effect of Ai on respiratory mechanics by making in vivo measures of airway dimensions and work of breathing (Wb) in the same individuals. Healthy participants (3F/2M; 23-45 years) completed a cycle exercise test to exhaustion. During exercise, Wb was assessed using an esophageal balloon catheter, while simultaneously assessing minute ventilation ( V ˙ E ). On a separate day, subjects underwent a bronchoscopy procedure to capture optical coherence tomography (OCT) measures of three airways in the right lung. Each participant's Wb- V ˙ E data were fit to a non-linear regression equation (Wb = a V ˙ E 3  + b V ˙ E 2 ) that partitions Wb into its turbulent resistive (a) and viscoelastic (b) components. Measures of Ai and luminal diameter were made for the 4th-6th airway generations. A composite index of airway size was calculated as the sum of the Ai for each generation and the total area of the 4th-6th generation was calculated based on Weibel's model. Constant a was significantly correlated to the Weibel model total airway area (r = -0.94, p = 0.017) and index of airway size (r = -0.929, p = 0.023), whereas constant b was not associated with either measure (both p > 0.05). We found that individuals who had the smallest Ai had the highest resistive Wb and our findings provide the basis for further study of the relationship between airway size and respiratory mechanics during exercise.

3.
Am J Med Genet A ; 185(3): 675-686, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33314698

RESUMO

Kabuki syndrome (OMIM #147920 and 300867) is a rare genetic disorder characterized by a distinctive facial gestalt, intellectual disability and multiple congenital anomalies. We summarized the clinical features and molecular findings of the Kabuki syndrome (KS) patients diagnosed in Hong Kong between January 1991 and December 2019. There were 21 molecularly confirmed KS. Twenty of them were due to pathogenic KMT2D variants and one patient had KDM6A deletion. Nine KMT2D variants were novel. The clinical phenotype of our Chinese KS patients was largely comparable with that reported in patients of other ethnicities. This study expands the mutation spectrum but also provide important natural history information of Chinese KS in literature.

4.
Lancet Digit Health ; 2(5): e259-e267, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-33328058

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in the community. Thoracic CT scans are widely used for diagnostic and screening purposes for lung cancer. In this proof-of-concept study, we aimed to evaluate a software pipeline for the automated detection of COPD, based on deep learning and a dataset of low-dose CTs that were performed for early detection of lung cancer. METHODS: We examined the use of deep residual networks, a type of artificial residual network, for the automated detection of COPD. Three versions of the residual networks were independently trained to perform COPD diagnosis using random subsets of CT scans collected from the PanCan study, which enrolled ex-smokers and current smokers at high risk of lung cancer, and evaluated the networks using three-fold cross-validation experiments. External validation was performed using 2153 CT scans acquired from a separate cohort of individuals with COPD in the ECLIPSE study. Spirometric data were used to define COPD, with stages defined according to the GOLD criteria. FINDINGS: The best performing networks achieved an area under the receiver operating characteristic curve (AUC) of 0·889 (SD 0·017) in three-fold cross-validation experiments. When the same set of networks was applied to the ECLIPSE cohort without any modifications to the trained models, they achieved an AUC of 0·886 (0·017), a positive predictive value of 0·847 (0·056), and a negative predictive value of 0·755 (0·097), which is a greater performance than the best quantitative CT measure, the percentage of lung volumes of less than or equal to -950 Hounsfield units (AUC 0·742). INTERPRETATION: Our proposed approach could identify patients with COPD among ex-smokers and current smokers without a previous diagnosis of COPD, with clinically acceptable performance. The use of deep residual networks on chest CT scans could be an effective case-finding tool for COPD detection and diagnosis, particularly in ex-smokers and current smokers who are being screened for lung cancer. FUNDING: Data Science Institute, University of British Columbia; Canadian Institutes of Health Research.


Assuntos
Inteligência Artificial , Processamento de Imagem Assistida por Computador/métodos , Pulmão/patologia , Programas de Rastreamento/métodos , Modelos Biológicos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Fumar/efeitos adversos , Idoso , Área Sob a Curva , Canadá , Estudos de Coortes , Análise de Dados , Progressão da Doença , Ex-Fumantes , Feminino , Humanos , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Redes Neurais de Computação , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Curva ROC , Medição de Risco , Fumantes , Tomografia Computadorizada por Raios X/métodos
5.
Carcinogenesis ; 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33319219

RESUMO

Although it is well established that human cytochrome P450 1 (CYP1) family enzymes are induced by cigarette smoking through activation of the Ah receptor (AhR), it is not known whether this leads to increased metabolic activation or detoxification of carcinogenic polycyclic aromatic hydrocarbons (PAH), which are present in cigarette smoke and the general environment. We gave oral doses of deuterated phenanthrene ([D10]Phe), a non-carcinogenic surrogate of carcinogenic PAH such as benzo[a]pyrene, to smokers (N=170, 1 or 10 µg doses) and non-smokers (N=57, 1 µg dose). Bioactivation products (dihydrodiol and tetraol) and detoxification products (phenols) of [D10]Phe were determined in 6-hour urine to obtain a comprehensive metabolic profile. Cigarette smoking increased the bioactivation of [D10]Phe, and decreased its detoxification resulting in significantly different metabolic patterns between smokers and non-smokers (p<0.01), consistent with increased cancer risk in smokers. The phenanthrene bioactivation ratios ( [D10]PheT/total [D9]OHPhe) were significantly higher (2.3 (p<0.01) to 4.8 (p<0.001) fold) in smokers than non-smokers. With solid human in vivo evidence, our results for the first time demonstrate that cigarette smoking enhances the metabolic activation of phenanthrene, structurally representative of carcinogenic PAH, in humans, strongly supporting their causal role in cancers caused by smoking. The results suggest potential new methods for identifying smokers who could be at particularly high risk for cancer.

6.
Sci Rep ; 10(1): 19480, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33173057

RESUMO

Smoking is the number one risk factor for cancer mortality but only 15-20% of heavy smokers develop lung cancer. It would, therefore, be of great benefit to identify those at high risk early on so that preventative measures can be initiated. To investigate this, we evaluated the effects of smoking on inflammatory markers, innate and adaptive immune responses to bacterial and viral challenges and blood cell composition. We found that plasma samples from 30 heavy smokers (16 men and 14 women) had significantly higher CRP, fibrinogen, IL-6 and CEA levels than 36 non-smoking controls. Whole blood samples from smokers, incubated for 7 h at 37 °C in the absence of any exogenous stimuli, secreted significantly higher levels of IL-8 and a number of other cytokines/chemokines than non-smokers. When challenged for 7 h with E. coli, whole blood samples from smokers secreted significantly lower levels of many inflammatory cytokines/chemokines. However, when stimulated with HSV-1, significantly higher levels of both PGE2 and many cytokines/chemokines were secreted from smokers' blood samples than from controls. In terms of blood cell composition, red blood cells, hematocrits, hemoglobin levels, MCV, MCH, MCHC, Pct and RDW levels were all elevated in smokers, in keeping with their compromised lung capacity. As well, total leukocytes were significantly higher, driven by increases in granulocytes and monocytes. In addition, smokers had lower NK cells and higher Tregs than controls, suggesting that smoking may reduce the ability to kill nascent tumor cells. Importantly, there was substantial person-to person variation amongst smokers with some showing markedly different values from controls and others showing normal levels of many parameters measured, indicating the former may be at significantly higher risk of developing lung cancer.

7.
BMC Pulm Med ; 20(1): 300, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33198781

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an underdiagnosed condition sharing risk factors with lung cancer. Lung cancer screening may provide an opportunity to improve COPD diagnosis. Using Pan-Canadian Early Detection of Lung Cancer (PanCan) study data, the present study sought to determine the following: 1) What is the prevalence of COPD in a lung cancer screening population? 2) Can a model based on clinical and screening low-dose CT scan data predict the likelihood of COPD? METHODS: The single arm PanCan study recruited current or former smokers age 50-75 who had a calculated risk of lung cancer of at least 2% over 6 years. A baseline health questionnaire, spirometry, and low-dose CT scan were performed. CT scans were assessed by a radiologist for extent and distribution of emphysema. With spirometry as the gold standard, logistic regression was used to assess factors associated with COPD. RESULTS: Among 2514 recruited subjects, 1136 (45.2%) met spirometry criteria for COPD, including 833 of 1987 (41.9%) of those with no prior diagnosis, 53.8% of whom had moderate or worse disease. In a multivariate model, age, current smoking status, number of pack-years, presence of dyspnea, wheeze, participation in a high-risk occupation, and emphysema extent on LDCT were all statistically associated with COPD, while the overall model had poor discrimination (c-statistic = 0.627 (95% CI of 0.607 to 0.650). The lowest and the highest risk decile in the model predicted COPD risk of 27.4 and 65.3%. CONCLUSIONS: COPD had a high prevalence in a lung cancer screening population. While a risk model had poor discrimination, all deciles of risk had a high prevalence of COPD, and spirometry could be considered as an additional test in lung cancer screening programs. TRIAL REGISTRATION: (Clinical Trial Registration: ClinicalTrials.gov, number NCT00751660 , registered September 12, 2008).

9.
ERJ Open Res ; 6(4)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33083442

RESUMO

Background: Percutaneous microwave ablation is clinically used for inoperable lung tumour treatment. Delivery of microwave ablation applicators to tumour sites within lung parenchyma under virtual bronchoscopy guidance may enable ablation with reduced risk of pneumothorax, providing a minimally invasive treatment of early-stage tumours, which are increasingly detected with computed tomography (CT) screening. The objective of this study was to integrate a custom microwave ablation platform, incorporating a flexible applicator, with a clinically established virtual bronchoscopy guidance system, and to assess technical feasibility for safely creating localised thermal ablations in porcine lungs in vivo. Methods: Pre-ablation CTs of normal pigs were acquired to create a virtual model of the lungs, including airways and significant blood vessels. Virtual bronchoscopy-guided microwave ablation procedures were performed with 24-32 W power (at the applicator distal tip) delivered for 5-10 mins. A total of eight ablations were performed in three pigs. Post-treatment CT images were acquired to assess the extent of damage and ablation zones were further evaluated with viability stains and histopathologic analysis. Results: The flexible microwave applicators were delivered to ablation sites within lung parenchyma 5-24 mm from the airway wall via a tunnel created under virtual bronchoscopy guidance. No pneumothorax or significant airway bleeding was observed. The ablation short axis observed on gross pathology ranged 16.5-23.5 mm and 14-26 mm on CT imaging. Conclusion: We have demonstrated the technical feasibility for safely delivering microwave ablation in the lung parenchyma under virtual bronchoscopic guidance in an in vivo porcine lung model.

10.
J Biomed Opt ; 25(10)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33084256

RESUMO

SIGNIFICANCE: Diagnosis of suspicious lung nodules requires precise collection of relevant biopsies for histopathological analysis. Using optical coherence tomography and autofluorescence imaging (OCT-AFI) to improve diagnostic yield in parts of the lung inaccessible to larger imaging methods may allow for reducing complications related to the alternative of computed tomography-guided biopsy. AIM: Feasibility of OCT-AFI combined with a commercially available lung biopsy needle was demonstrated for visualization of needle puncture sites in airways with diameters as small as 1.9 mm. APPROACH: A miniaturized OCT-AFI imaging stylet was developed to be inserted through an 18G biopsy needle. We present design considerations and procedure development for image-guided biopsy. Ex vivo and in vivo porcine studies were performed to demonstrate the feasibility of the procedure and the device. RESULTS: OCT-AFI scans were obtained ex vivo and in vivo. Discrimination of pullback site is clear. CONCLUSIONS: Use of the device is shown to be feasible in vivo. Images obtained show the stylet is effective at providing structural information at the puncture site that can be used to assess the diagnostic potential of the sample prior to collection.

12.
Front Med ; 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32889700

RESUMO

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

13.
Genet Epidemiol ; 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32924180

RESUMO

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1ß pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.

14.
Int J Cancer ; 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32914876

RESUMO

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10-4 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (ORMVMR = 1.28, 95% CI = 1.06-1.55, PMVMR = .011), and an inverse effect on lung adenocarcinoma (ORMVMR = 0.86, 95% CI = 0.77-0.96, PMVMR = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (ORUVMR = 1.19, 95% CI = 1.01-1.40, PUVMR = .036), but this effect disappeared after adjustment of smoking (ORMVMR = 1.02, 95% CI = 0.90-1.16, PMVMR = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.

18.
Lung Cancer ; 146: 134-144, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32535225

RESUMO

The low nonadherence rates reported by large low-dose computed tomography (LDCT) lung cancer screening trials were not necessarily replicated outside of trial conditions. This systematic review and meta-analysis identified predictors of participant nonadherence to returning for annual LDCT screening. The systematic review protocol was registered at PROSPERO (CRD42019118347). MEDLINE, EMBASE, CINAHL, AgeLine, grey literature sources, and reference lists of included studies were searched until March 1st, 2020. Primary research articles were eligible for inclusion if they screened current or former smokers using LDCT as their primary screening modality and reported on participant demographics or programmatic interventions that predicted nonadherence. Risk of bias assessment was performed at both study and outcome levels. The primary outcome was predictors of nonadherence. The secondary outcomes were relative risks (RR) of second round nonadherence based on identified predictors, which were calculated using random-effects meta-analyses. Across 13 included studies (total n = 15,790; range: 157-3642), the overall rate of nonadherence was 28% (95% CI: 20-37%). Studies identified greater nonadherence in participants younger than 60 or older than 74, with longer travel distances to screening centers, and having a low risk perception of lung cancer. Meta-analyses identified higher nonadherence in community-based compared to academic-based programs, but this did not reach significance (32% versus 27%; p = 0.32). Current smokers were more likely to be nonadherent compared to former smokers (RR 1.23, 95% CI: 1.09-1.40; p < 0.01) while white participants were less likely nonadherent compared to non-white participants (RR 0.69, 95% CI: 0.60-0.81; p < 0.0001). No differences existed between male and female participants (RR 0.99, 95% CI: 0.85-1.15; p = 0.85). Programmatic interventions, including dedicated program coordinators, reminder calls/letters, and mobile LDCT scanners reduced nonadherence in lung cancer screening programs. These interventions should be targeted/tailored toward the subpopulations with the highest nonadherence rates.

19.
Nat Commun ; 11(1): 2220, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393777

RESUMO

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.


Assuntos
Adenocarcinoma/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias Pulmonares/genética , Idoso , Alelos , Bases de Dados Genéticas , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Técnicas de Genotipagem , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Judeus/genética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Razão de Chances , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , RNA-Seq , Fatores de Risco
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