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© 2014 by The American Society of Human Genetics. All rights reserved.The extent of recent selection in admixed populations is currently an unresolved question. We scanned the genomes of 29,141 African Americans and failed to find any genome-wide-significa

Background Recent studies suggest that environmental exposures to pesticides, tobacco, and other xenobiotic chemicals may increase risk of childhood acute lymphoblastic leukemia (ALL). We sought to evaluate the role of genes involved in xenobiotic transpor

Background: Smoking tobacco reduces lung function. African Americans have both lower lung function and decreased metabolism of tobacco smoke compared to European Americans. African ancestry is also associated with lower pulmonary function in African Americ

Background: Few studies have examined the association between home use of solvents and paint and the risk of childhood leukemia. Objectives: In this caseDScontrol study, we examined whether the use of paint and petroleum solvents at home before birth and in early childhood influenced the risk of leukemia in children. Methods: We based our analyses on 550 cases of acute lymphoblastic leukemia (ALL) , 100 cases of acute myeloid leukemia (AML) , and one or two controls per case individually matched for sex, age, Hispanic status, and race. We conducted further analyses by cytogenetic subtype. We used conditional logistic regression techniques to adjust for income. Results: ALL risk was significantly associated with paint exposure [odds ratio (OR) = 1.65 ; 95% confidence interval (CI) , 1.26-2.15], with a higher risk observed when paint was used postnatally, by a person other than the mother, or frequently. The association was restricted to leukemia with translocations between chromosomes 12 and 21 (OR = 4.16 ; 95% CI, 1.66-10.4) . We found no significant association between solvent use and ALL risk overall (OR = 1.15 ; 95% CI, 0.87-1.51) or for various cytogenetic subtypes, but we observed a significant association in the 2.0- to 5.9-year age group (OR = 1.55 ; 95% CI, 1.07-2.25) . In contrast, a significant increased risk for AML was associated with solvent (OR = 2.54 ; 95% CI, 1.19-5.42) but not with paint exposure (OR = 0.64 ; 95% CI, 0.32-1.25). Conclusions: The association of ALL risk with paint exposure was strong, consistent with a causal relationship, but further studies are needed to confirm the association of ALL and AML risk with solvent exposure. [ABSTRACT FROM AUTHOR]

Background: Pathologic stage (pStage) IA and IB non-small-cell lung cancer (NSCLC) has a median survival time of 119 and 81 months, respectively. We describe the outcomes of veterans with pStage I NSCLC.Methods: A retrospective review of 78 patients with pStage I NSCLC who underwent cancer resection was performed at the Tennessee Valley Veterans Affairs Hospital between 2005 and 2010. All-cause 30-day, 90-day, and overall mortality were determined. Survival was assessed with the Kaplan-Meier and Cox proportional hazards methods.Results: There were 55 (71%) pStage IA and 23 (29%) IB patients. Thirty- and 90-day mortality was 3.8% (3 of 78) and 6.4% (5 of 78), respectively. Median survival was 59 and 28 months for pStage 1A and 1B, respectively. Postoperative events were associated with impaired survival on multivariable analysis (hazard ratio, 1.26, P = .03).Conclusions: Veterans with pStage I NSCLC at our institution have poorer survival than the general population. More research is needed to determine the etiology of this disparity. [ABSTRACT FROM AUTHOR]

Introduction: Self-reported household pesticide use has been associated with higher risk of childhood leukemia in a number of case-control studies. The aim of this study is to assess the reliability of self-reported household use of pesticides and potential differences in reliability by case-control status, and by socio-demographic characteristics.Methods: Analyses are based on a subset of the Northern California Childhood Leukemia Study population. Eligible households included those with children less than 8 years old who lived in the same residence since diagnosis (reference date for controls). The reliability was based on two repeated in-person interviews. Kappa, percent positive and negative agreements were used to assess reliability of responses to ever/never use of six pesticides categories.Results: Kappa statistics ranged from 0.31 to 0.61 (fair to substantial agreement), with 9 out of the 12 tests indicating moderate agreement. The percent positive agreement ranged from 46 to 80% and the percent negative agreement from 54 to 95%. Reliability for all pesticide types as assessed by the three reliability measures did not differ significantly for cases and controls as confirmed by bootstrap analysis. For most pesticide types, Kappa and percent positive agreement were higher for non-Hispanics than Hispanics and for households with higher income vs. lower income.Conclusions: Reproducibility of maternal-reported pesticide use was moderate to high and was similar among cases and controls suggesting that differential recall is not likely to be a major source of bias. [ABSTRACT FROM AUTHOR]

Polygenic risk scores (PRSs) are promising for risk stratification but have mainly been developed in European populations. This study developed single- and multi-ancestry PRSs for lung adenocarcinoma (LUAD) in East Asian (EAS) never-smokers using genome-wide association study summary statistics from EAS (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. A multi-ancestry PRS, developed using CT-SLEB, was strongly associated with LUAD risk (odds ratio=1.71, 95% confidence interval (CI):1.61,1.82), with an area under the receiver operating curve value of 0.640 (95% CI:0.629,0.653). Individuals in the highest 20% of the PRS had nearly four times the risk compared to the lowest 20%. Individuals in the 95 th percentile of the PRS had an estimated 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41. Our study underscores the potential of multi-ancestry PRS approaches to enhance LUAD risk stratification in EAS never-smokers.

Background: Despite recent advances in lung cancer therapeutics and improving overall survival, disparities persist among socially disadvantaged populations. This study aims to determine the effects of neighborhood deprivation indices (NDI) on lung cancer mortality. This is a multicenter retrospective cohort study assessing the relationship between NDI and overall survival adjusted for age, disease stage, and DNA methylation among biopsy-proven lung cancer patients. State-specific NDI for each year of sample collection were computed at the U.S. census tract level and dichotomized into low- and high-deprivation., Results: A total of 173 non small lung cancer patients were included, with n = 85 (49%) and n = 88 (51%) in the low and high-deprivation groups, respectively. NDI was significantly higher among Black patients when compared with White patients (p = 0.003). There was a significant correlation between DNA methylation and stage for HOXA7, SOX17, ZFP42, HOXA9, CDO1 and TAC1. Only HOXA7 DNA methylation was positively correlated with NDI. The high-deprivation group had a statistically significant shorter survival than the low-deprivation group (p = 0.02). After adjusting for age, race, stage, and DNA methylation status, belonging to the high-deprivation group was associated with higher mortality with a hazard ratio of 1.81 (95%CI: 1.03-3.19)., Conclusions: Increased neighborhood-level deprivation may be associated with liquid biopsy DNA methylation, shorter survival, and increased mortality. Changes in health care policies that consider neighborhood-level indices of socioeconomic deprivation may enable a more equitable increase in lung cancer survival., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: After accounting for smoking history, lung cancer incidence is greater in African Americans than Whites. In the multiethnic cohort, total nicotine equivalents (TNE) are higher in African Americans than Whites at similar reported cigarettes per day. Greater toxicant uptake per cigarette may contribute to the greater lung cancer risk of African Americans., Methods: In a nested case-control lung cancer study within the Southern Community Cohort, smoking-related biomarkers were measured in 259 cases and 503 controls (40% White; 56% African American). TNE, the trans-3-hydroxycotinine/cotinine ratio, 4-(methylnitrosamino)-1-3-(pyridyl)-1-butanol (NNAL), mercapturic acid metabolites of volatile organic compounds, phenanthrene metabolites, cadmium (Cd), and (Z)-7-(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopenyl]hept-5-enoic acid were quantified in urine. Unconditional logistic regression was used to estimate the ORs and 95% confidence intervals (CI) for each biomarker and lung cancer risk., Results: TNE, NNAL, and Cd were higher in cases than controls (adjusted for age, race, sex, body mass index, and cigarettes per day). Among cases, these levels were higher in African Americans compared with Whites. After accounting for age, sex, body mass index, and pack-years, a one-SD increase in log-TNE (OR = 1.30; 95% CI, 1.10-1.54) and log-NNAL (OR = 1.27; 95% CI, 1.03-1.58 with TNE adjustment) was associated with lung cancer risk. In this study, in which NNAL concentration is relatively high, the association for log-TNE was attenuated after adjustment for log-NNAL., Conclusions: Smoking-related biomarkers provide additional information for lung cancer risk in smokers beyond smoking pack-years., Impact: Urinary NNAL, TNE, and Cd concentrations in current smokers, particularly African American smokers, may be useful for predicting lung cancer risk., (©2024 American Association for Cancer Research.)

Background: Social determinants of health (SDoH) are associated with cardiovascular risk factors and outcomes; however, they are absent from risk prediction models. We aimed to assess if the addition of SDoH improves the predictive ability of the MESA (Multi-Ethnic Study of Atherosclerosis) Risk Score., Methods and Results: This was a community-based prospective population cohort study that enrolled 6286 men and women, ages 45-84 years, who were free of clinical coronary heart disease (CHD) at baseline. Data from 10-year follow-up were examined for CHD events, defined as myocardial infarction, fatal CHD, resuscitated cardiac arrest, and revascularization in cases of anginal symptoms. Participants included 53% women with average age of 62 years. When adjusting for traditional cardiovascular risk factors, SDoH, and coronary artery calcium, economic strain, specifically low family income, was associated with a greater risk of CHD events (hazard ratio [HR], 1.42 [95% CI, 1.17-1.71], P value<0.001). Area under the curve of risk prediction with SDoH was 0.822, compared with 0.816 without SDoH. The calibration slope was 0.860 with SDoH and 0.878 in the original model., Conclusions: Significant associations were found between economic/financial SDoH and CHD risk factors and outcomes. Incorporation of SDoH into the MESA Risk Score did not improve predictive ability of the model. Our findings do not support the incorporation of SDoH into current risk prediction algorithms.

Introduction: Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors but can also often lead to immune-related adverse events (irAEs). Predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Using data from 1,327 patients with lung cancer treated with ICIs between 2009 and 2022 at four academic medical centers, we evaluated the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs., Methods: Using Cox proportional hazards model, we assessed the association between a polygenic risk score for autoimmune disease (PRS AD ) and cessation of ICI therapy due to irAEs. All models were adjusted for age at diagnosis, sex, lung cancer histology, type of therapy, recruiting center, and the first 5 principal components. To further understand the differential effects of type of therapy and disease stage on the association between PRS AD and cessation of ICI due to irAEs, we conducted stratified logistic regression analysis by type of ICI therapy and disease stage., Results: We found an association between PRS AD and ICI cessation due to irAEs (HR per SD = 1.18, 95% CI = 1.02 - 1.37, P = 0.03). This association was particularly strong in patients who had ICI cessation due to irAEs within three months of therapy initiation (HR per SD = 1.38, 95% CI = 1.08 - 1.78, P = 0.01). Individuals in the top 20th percentile of PRS AD had 7.2% ICI discontinuation for irAEs by three months, compared to 3.9% discontinuation by three months among patients in the bottom 80th percentile (log-rank P = 0.02). In addition, among patients who received combination PD-1/PD-L1 and CTLA-4 inhibitor therapy, PRS AD had an OR per SD of 1.86 (95% CI = 1.08 - 3.51, P = 0.04)., Conclusions: We demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs, particularly among patients treated with combination ICI therapy. Our results suggest that germline genetics may be used as an adjunctive tool for risk stratification around ICI clinical decision-making in solid tumor oncology.

Importance: Screening for lung cancer using low-dose computed tomography is associated with reduced lung cancer-specific mortality, but uptake is low in the US; understanding how patients make decisions to engage with lung cancer screening is critical for increasing uptake. Prior research has focused on individual-level psychosocial factors, but environmental factors (eg, historical contexts that include experiencing racism) and modifying factors-those that can be changed to make it easier or harder to undergo screening-also likely affect screening decisions., Objective: To investigate environmental, psychosocial, and modifying factors influencing lung cancer screening decision-making and develop a conceptual framework depicting relationships between these factors., Design, Setting, and Participants: This multimethod qualitative study was conducted from December 2021 to June 2022 using virtual semistructured interviews and 4 focus groups (3-4 participants per group). All participants met US Preventive Services Task Force eligibility criteria for lung cancer screening (ie, age 50-80 years, at least a 20 pack-year smoking history, and either currently smoke or quit within the past 15 years). Screening-eligible US participants were recruited using an online panel., Main Outcomes and Measures: Key factors influencing screening decisions (eg, knowledge, beliefs, barriers, and facilitators) were the main outcome. A theory-informed, iterative inductive-deductive approach was applied to analyze data and develop a conceptual framework summarizing results., Results: Among 34 total participants (interviews, 20 [59%]; focus groups, 14 [41%]), mean (SD) age was 59.1 (4.8) years and 20 (59%) identified as female. Half had a household income below $20 000 (17 [50%]). Participants emphasized historical and present-day racism as critical factors contributing to mistrust of health care practitioners and avoidance of medical procedures like screening. Participants reported that other factors, such as public transportation availability, also influenced decisions. Additionally, participants described psychosocial processes involved in decisions, such as perceived screening benefits, lung cancer risk appraisal, and fear of a cancer diagnosis or harmful encounters with practitioners. In addition, participants identified modifying factors (eg, insurance coverage) that could make receiving screening easier or harder., Conclusions and Relevance: In this qualitative study of patient lung cancer screening decisions, environmental, psychosocial, and modifying factors influenced screening decisions. The findings suggest that systems-level interventions, such as those that help practitioners understand and discuss patients' prior negative health care experiences, are needed to promote effective screening decision-making.

Background: Lung cancer risk attributable to smoking is dose dependent, yet few studies examining a polygenic risk score (PRS) by smoking interaction have included comprehensive lifetime pack-years smoked., Methods: We analyzed data from participants of European ancestry in the Framingham Heart Study Original (n = 454) and Offspring (n = 2,470) cohorts enrolled in 1954 and 1971, respectively, and followed through 2018. We built a PRS for lung cancer using participant genotyping data and genome-wide association study summary statistics from a recent study in the OncoArray Consortium. We used Cox proportional hazards regression models to assess risk and the interaction between pack-years smoked and genetic risk for lung cancer adjusting for European ancestry, age, sex, and education., Results: We observed a significant submultiplicative interaction between pack-years and PRS on lung cancer risk (P = 0.09). Thus, the relative risk associated with each additional 10 pack-years smoked decreased with increasing genetic risk (HR = 1.56 at one SD below mean PRS, HR = 1.48 at mean PRS, and HR = 1.40 at one SD above mean PRS). Similarly, lung cancer risk per SD increase in the PRS was highest among those who had never smoked (HR = 1.55) and decreased with heavier smoking (HR = 1.32 at 30 pack-years)., Conclusions: These results suggest the presence of a submultiplicative interaction between pack-years and genetics on lung cancer risk, consistent with recent findings. Both smoking and genetics were significantly associated with lung cancer risk., Impact: These results underscore the contributions of genetics and smoking on lung cancer risk and highlight the negative impact of continued smoking regardless of genetic risk., (©2024 The Authors; Published by the American Association for Cancer Research.)

Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRS CD ) and UC (PRS UC ) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRS UC predicts all-grade IMC (OR meta =1.35 per standard deviation [SD], 95% CI = 1.12-1.64, P = 2×10 -03 ) and severe IMC (OR meta =1.49 per SD, 95% CI = 1.18-1.88, P = 9×10 -04 ). PRS CD is not associated with IMC. Furthermore, PRS UC predicts severe IMC among patients treated with combination ICIs (OR meta =2.20 per SD, 95% CI = 1.07-4.53, P = 0.03). Overall, PRS UC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes., (© 2024. The Author(s).)

Background: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non-small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated., Methods: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed-effect meta-analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi-omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways., Results: Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni-corrected p ≤ 1.67 × 10 -6 ) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni-corrected p ≤ 1.28 × 10 -3 ), including four novel CpGs. Multi-omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty-five genes within a 1-Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified., Conclusions: Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby., Plain Language Summary: The epigenetic consequences of DNA methylation in lung cancer development are still largely unknown. This study used summary data of large-scale genome-wide association studies to investigate the associations between genetically predicted levels of methylation biomarkers and non-small cell lung cancer risk at the first time. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. These findings will provide a unique insight into the epigenetic susceptibility mechanisms of lung cancer., (© 2023 American Cancer Society.)

The impact of tobacco exposure on health varies by race and ethnicity and is closely tied to internal nicotine dose, a marker of carcinogen uptake. DNA methylation is strongly responsive to smoking status and may mediate health effects, but study of associations with internal dose is limited. We performed a blood leukocyte epigenome-wide association study (EWAS) of urinary total nicotine equivalents (TNEs; a measure of nicotine uptake) and DNA methylation measured using the MethylationEPIC v1.0 BeadChip (EPIC) in six racial and ethnic groups across three cohort studies. In the Multiethnic Cohort Study (discovery, n = 1994), TNEs were associated with differential methylation at 408 CpG sites across >250 genomic regions (p < 9 × 10 -8 ). The top significant sites were annotated to AHRR, F2RL3, RARA, GPR15, PRSS23, and 2q37.1, all of which had decreasing methylation with increasing TNEs. We identified 45 novel CpG sites, of which 42 were unique to the EPIC array and eight annotated to genes not previously linked with smoking-related DNA methylation. The most significant signal in a novel gene was cg03748458 in MIR383;SGCZ. Fifty-one of the 408 discovery sites were validated in the Singapore Chinese Health Study (n = 340) and the Southern Community Cohort Study (n = 394) (Bonferroni corrected p < 1.23 × 10 -4 ). Significant heterogeneity by race and ethnicity was detected for CpG sites in MYO1G and CYTH1. Furthermore, TNEs significantly mediated the association between cigarettes per day and DNA methylation at 15 sites (average 22.5%-44.3% proportion mediated). Our multiethnic study highlights the transethnic and ethnic-specific methylation associations with internal nicotine dose, a strong predictor of smoking-related morbidities., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer., Methods: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer., Results: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 × 10-8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior., Conclusions: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies., Impact: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis. Single-variant and gene-based associations of 43 tobacco carcinogen-metabolizing genes with lung cancer were analyzed using summary statistics and individual-level genetic data, followed by causal inference of Mendelian randomization, mediation analysis, and structural equation modeling. Cigarette smoke-exposed cell models were used to detect gene expression patterns in relation to specific alleles. Data from the International Lung Cancer Consortium (29,266 cases and 56,450 controls) and UK Biobank (2,155 cases and 376,329 controls) indicated that the genetic variant rs56113850 C>T located in intron 4 of CYP2A6 was significantly associated with decreased lung cancer risk among smokers (OR = 0.88, 95% confidence interval = 0.85-0.91, P = 2.18 × 10-16), which might interact (Pinteraction = 0.028) with and partially be mediated (ORindirect = 0.987) by smoking status. Smoking intensity accounted for 82.3% of the effect of CYP2A6 activity on lung cancer risk but entirely mediated the genetic effect of rs56113850. Mechanistically, the rs56113850 T allele rescued the downregulation of CYP2A6 caused by cigarette smoke exposure, potentially through preferential recruitment of transcription factor helicase-like transcription factor. Together, this study provides additional insights into the interplay between host susceptibility and carcinogen exposure in smoking-related lung tumorigenesis., Significance: The causal pathway connecting CYP2A6 genetic variability and activity, cigarette consumption, and lung cancer susceptibility in smokers highlights the need for behavior modification interventions based on host susceptibility for cancer prevention., (©2023 American Association for Cancer Research.)

Background: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored., Methods: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold., Results: Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12-3.50, P-value = 4.13 × 10 -15 ) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99-2.49, P-value = 5.70 × 10 -46 ). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72-0.74)., Conclusions: Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS., (© 2024. The Author(s).)

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Appropriate risk stratification of indeterminate pulmonary nodules (IPNs) is necessary to direct diagnostic evaluation. Currently available models were developed in populations with lower cancer prevalence than that seen in thoracic surgery and pulmonology clinics and usually do not allow for missing data. We updated and expanded the Thoracic Research Evaluation and Treatment (TREAT) model into a more generalized, robust approach for lung cancer prediction in patients referred for specialty evaluation., Research Question: Can clinic-level differences in nodule evaluation be incorporated to improve lung cancer prediction accuracy in patients seeking immediate specialty evaluation compared with currently available models?, Study Design and Methods: Clinical and radiographic data on patients with IPNs from six sites (N = 1,401) were collected retrospectively and divided into groups by clinical setting: pulmonary nodule clinic (n = 374; cancer prevalence, 42%), outpatient thoracic surgery clinic (n = 553; cancer prevalence, 73%), or inpatient surgical resection (n = 474; cancer prevalence, 90%). A new prediction model was developed using a missing data-driven pattern submodel approach. Discrimination and calibration were estimated with cross-validation and were compared with the original TREAT, Mayo Clinic, Herder, and Brock models. Reclassification was assessed with bias-corrected clinical net reclassification index and reclassification plots., Results: Two-thirds of patients had missing data; nodule growth and fluorodeoxyglucose-PET scan avidity were missing most frequently. The TREAT version 2.0 mean area under the receiver operating characteristic curve across missingness patterns was 0.85 compared with that of the original TREAT (0.80), Herder (0.73), Mayo Clinic (0.72), and Brock (0.68) models with improved calibration. The bias-corrected clinical net reclassification index was 0.23., Interpretation: The TREAT 2.0 model is more accurate and better calibrated for predicting lung cancer in high-risk IPNs than the Mayo, Herder, or Brock models. Nodule calculators such as TREAT 2.0 that account for varied lung cancer prevalence and that consider missing data may provide more accurate risk stratification for patients seeking evaluation at specialty nodule evaluation clinics., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: J. M. I. discloses grants from Guardant Health and GRAIL, prior support for meeting attendance from Intuitive Surgical, planned or issued patents with AstraZeneca and Roche Genentech, and stock or stock options from LumaCyte, LLC. L. T. V. has received consulting fees from Ambu A/S. F. M. receives consulting fees from Medtronic, Johnson & Johnson, and Intuitive and additionally received research funding from Medtronic. The disclosures listed did not have any relation to the content of this manuscript. None declared (C. M. G., M. E. S., V. F. W., A. W. M., M. C. A., C. M., J. C., S. R., O. B. R., R. P., E. S. L., J. C. N., J. D. B., S. A. D., E. L. G.)., (Published by Elsevier Inc.)

Objective: To develop and validate an approach that identifies patients eligible for lung cancer screening (LCS) by combining structured and unstructured smoking data from the electronic health record (EHR)., Methods: We identified patients aged 50-80 years who had at least one encounter in a primary care clinic at Vanderbilt University Medical Center (VUMC) between 2019 and 2022. We fine-tuned an existing natural language processing (NLP) tool to extract quantitative smoking information using clinical notes collected from VUMC. Then, we developed an approach to identify patients who are eligible for LCS by combining smoking information from structured data and clinical narratives. We compared this method with two approaches to identify LCS eligibility only using smoking information from structured EHR. We used 50 patients with a documented history of tobacco use for comparison and validation., Results: 102,475 patients were included. The NLP-based approach achieved an F1-score of 0.909, and accuracy of 0.96. The baseline approach could identify 5,887 patients. Compared to the baseline approach, the number of identified patients using all structured data and the NLP-based algorithm was 7,194 (22.2 %) and 10,231 (73.8 %), respectively. The NLP-based approach identified 589 Black/African Americans, a significant increase of 119 %., Conclusion: We present a feasible NLP-based approach to identify LCS eligible patients. It provides a technical basis for the development of clinical decision support tools to potentially improve the utilization of LCS and diminish healthcare disparities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Mosaic chromosomal alterations (mCAs) detected in white blood cells represent a type of clonal hematopoiesis (CH) that is understudied compared with CH-related somatic mutations. A few recent studies indicated their potential link with nonhematological cancers, especially lung cancer., Methods: In this study, we investigated the association between mCAs and lung cancer using the high-density genotyping data from the OncoArray study of INTEGRAL-ILCCO, the largest single genetic study of lung cancer with 18,221 lung cancer cases and 14,825 cancer-free controls., Results: We identified a comprehensive list of autosomal mCAs, ChrX mCAs, and mosaic ChrY (mChrY) losses from these samples. Autosomal mCAs were detected in 4.3% of subjects, in addition to ChrX mCAs in 3.6% of females and mChrY losses in 9.6% of males. Multivariable logistic regression analysis indicated that the presence of autosomal mCAs in white blood cells was associated with an increased lung cancer risk after adjusting for key confounding factors, including age, sex, smoking status, and race. This association was mainly driven by a specific type of mCAs: copy-neutral loss of heterozygosity on autosomal chromosomes. The association between autosome copy-neutral loss of heterozygosity and increased risk of lung cancer was further confirmed in two major histologic subtypes, lung adenocarcinoma and squamous cell carcinoma. In addition, we observed a significant increase of ChrX mCAs and mChrY losses in smokers compared with nonsmokers and racial differences in certain types of mCA events., Conclusions: Our study established a link between mCAs in white blood cells and increased risk of lung cancer., (Copyright © 2023. Published by Elsevier Inc.)

Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility., Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry., Design, Setting, and Participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry., Outcome Measurements and Statistical Analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness., Results and Limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10 -4 )., Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry., Patient Summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci., Methods: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci., Results: We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci., Conclusions: Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Females with polycystic ovary syndrome (PCOS), the most common endocrine disorder in women, have an increased risk of developing cardiometabolic disorders such as insulin resistance, obesity, and type 2 diabetes (T2D). While only diagnosable in females, males with a family history of PCOS can also exhibit a poor cardiometabolic profile. Therefore, we aimed to elucidate the role of sex in the cardiometabolic comorbidities observed in PCOS by conducting bidirectional genetic risk score analyses in both sexes. We first conducted a phenome-wide association study (PheWAS) using PCOS polygenic risk scores (PCOSPRS) to identify potential pleiotropic effects of PCOSPRS across 1,380 medical conditions recorded in the Vanderbilt University Medical Center electronic health record (EHR) database, in females and males. After adjusting for age and genetic ancestry, we found that European (EUR)-ancestry males with higher PCOSPRS were significantly more likely to develop hypertensive diseases than females at the same level of genetic risk. We performed the same analysis in an African (AFR)-ancestry population, but observed no significant associations, likely due to poor trans-ancestry performance of the PRS. Based on observed significant associations in the EUR-ancestry population, we then tested whether the PRS for comorbid conditions (e.g., T2D, body mass index (BMI), hypertension, etc.) also increased the odds of a PCOS diagnosis. Only BMIPRS and T2DPRS were significantly associated with a PCOS diagnosis in EUR-ancestry females. We then further adjusted the T2DPRS for measured BMI and BMIresidual (regressed on the BMIPRS and enriched for the environmental contribution to BMI). Results demonstrated that genetically regulated BMI primarily accounted for the relationship between T2DPRS and PCOS. Overall, our findings show that the genetic architecture of PCOS has distinct sex differences in associations with genetically correlated cardiometabolic traits. It is possible that the cardiometabolic comorbidities observed in PCOS are primarily explained by their shared genetic risk factors, which can be further influenced by biological variables including sex and BMI., Competing Interests: The authors declare they have no competing interests., (Copyright: © 2023 Actkins et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction  = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Black Americans receive a diagnosis at later stage of lung cancer more often than White Americans. We undertook a population-based study to identify factors contributing to racial disparities in lung cancer stage of diagnosis among low-income adults., Research Question: Which multilevel factors contribute to racial disparities in stage of lung cancer at diagnosis?, Study Design and Methods: Cases of incident lung cancer from the prospective observational Southern Community Cohort Study were identified by linkage with state cancer registries in 12 southeastern states. Logistic regression shrinkage techniques were implemented to identify individual-level and area-level factors associated with distant stage diagnosis. A subset of participants who responded to psychosocial questions (eg, racial discrimination experiences) were evaluated to determine if model predictive power improved., Results: We identified 1,572 patients with incident lung cancer with available lung cancer stage (64% self-identified as Black and 36% self-identified as White). Overall, Black participants with lung cancer showed greater unadjusted odds of distant stage diagnosis compared with White participants (OR,1.29; 95% CI, 1.05-1.59). Greater neighborhood area deprivation was associated with distant stage diagnosis (OR, 1.58; 95% CI, 1.19-2.11). After controlling for individual- and area-level factors, no significant difference were found in distant stage disease for Black vs White participants. However, participants with COPD showed lower odds of distant stage diagnosis in the primary model (OR, 0.72; 95% CI, 0.53-0.98). Interesting and complex interactions were observed. The subset analysis model with additional variables for racial discrimination experiences showed slightly greater predictive power than the primary model., Interpretation: Reducing racial disparities in lung cancer stage at presentation will require interventions on both structural and individual-level factors., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Considerable evidence has been reported that tobacco use could cause alterations in gut microbiota composition. The microbiota-gut-brain axis also in turn hinted at a possible contribution of the gut microbiota to smoking. However, population-level studies with a higher evidence level for causality are lacking., Methods: This study utilized the summary-level data of respective genome-wide association study (GWAS) for 211 gut microbial taxa and five smoking phenotypes to reveal the causal association between the gut microbiota and tobacco smoking. Two-sample bidirectional Mendelian randomization (MR) design was deployed and comprehensively sensitive analyses were followed to validate the robustness of results. We further performed multivariable MR to evaluate the effect of neurotransmitter-associated metabolites on observed associations., Results: Our univariable MR results confirmed the effects of smoking on three taxa (Intestinimonas, Catenibacterium, and Ruminococcaceae, observed from previous studies) with boosted evidence level and identified another 13 taxa which may be causally affected by tobacco smoking. As for the other direction, we revealed that smoking behaviors could be potential consequence of specific taxa abundance. Combining with existing observational evidence, we provided novel insights regarding a positive feedback loop of smoking through Actinobacteria and indicated a potential mechanism for the link between parental smoking and early smoking initiation of their children driven by Bifidobacterium. The multivariable MR results suggested that neurotransmitter-associated metabolites (tryptophan and tyrosine, also supported by previous studies) probably played a role in the action pathway from the gut microbiota to smoking, especially for Actinobacteria and Peptococcus., Conclusions: In summary, the current study suggested the role of the specific gut microbes on the risk for cigarette smoking (likely involving alterations in metabolites) and in turn smoking on specific gut microbes. Our findings highlighted the hazards of tobacco use for gut flora dysbiosis and shed light on the potential role of specific gut microbiota for smoking behaviors., (© 2023. The Author(s).)

As precision medicine approaches are implemented, cancer treatment decisions have come to require comprehension of genetic tests and their role in risk stratification and treatment options. Acceptance and implementation of precision medicine requires patient understanding of numeracy, genetic literacy, health literacy, and medical trust. Implementing precision medicine in a US federally qualified community health center (FQCHC) setting has received little attention. Using a mixed-methods approach, we sought to identify patient-level factors influencing the understanding of cancer risk and precision medicine among FQCHC patients. We enrolled 26 English-speaking adults aged 40-79 years. Participants enrolled in focus groups and completed surveys to assess patient-level understanding of precision medicine, numeracy, and health literacy. The majority of participants were female (77%) and self-identified as African American (89%). Approximately one-third reported having a high school degree or less. While health literacy was generally high, 42% felt that genes or genetics had little impact on health and most (69%) reported little familiarity with precision medicine. Many participants reported that trust in their providers was extremely or very important when receiving genetic tests. Numeracy levels were moderate, with nearly half reporting some discomfort working with fractions and 38% finding numerical information only occasionally useful. Findings suggest that patients may lack familiarity with precision medicine concepts relevant for understanding cancer treatment decisions. Future educational efforts may help bridge the gap in patient understanding and facilitate equitable opportunities for precision medicine for all patients, including those seeking care from community health centers., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize low-dose CT (LDCT) lung cancer screening. Here, we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL. The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1161 proteins in a nested-case control study within 2 prospective cohorts (n = 252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n = 479 cases and 479 controls). Eligible participants had a current or former history of smoking and cases were diagnosed up to 3 years following blood draw. The Nodule Malignancy project measured 1078 proteins among participants with a heavy smoking history within four LDCT screening studies (n = 425 cases diagnosed up to 5 years following blood draw, 430 benign-nodule controls, and 398 nodule-free controls). The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n = 1696 cases and 2926 subcohort representatives), and in the Nodule Malignancy project within five LDCT screening studies (n = 675 cases, 680 benign-nodule controls, and 648 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies., (Copyright © 2022. Published by Elsevier Inc.)

Limited research has explored the mental health impact of coronavirus disease 2019 (COVID-19) in the U.S., especially among Black and low-income Americans who are disproportionately affected by COVID-19. To address this gap in the literature, we investigated factors associated with depressive and anxiety symptoms during the pandemic. From October to December 2020, over 4400 participants in the Southern Community Cohort Study (SCCS) completed a survey about the impact of the pandemic. The SCCS primarily enrolled adults with low income in 12 southeastern states. We used polytomous unconditional logistic regression to investigate factors associated with depressive and anxiety symptoms. About 28% of respondents reported mild or moderate/severe depressive symptoms and 30% reported mild or moderate/severe anxiety symptoms. Respondents in fair/poor health had significantly higher odds of moderate/severe depression and anxiety than those in very good/excellent health (depression: odds ratio (OR) = 4.72 [95% confidence interval (CI): 3.57-6.23]; anxiety: OR = 4.77 [95%CI: 3.63-6.28]). Similarly, living alone was associated with higher odds of moderate/severe depression and anxiety (depression: OR = 1.74 [95%CI: 1.38-2.18]; anxiety: OR = 1.57 [95%CI: 1.27-1.95]). Individuals whose physical activity or vegetable/fruit consumption decreased since the start of the pandemic also had higher odds of moderate/severe depression and anxiety. Results overall suggest that individuals in fair/poor health, living alone, and/or experiencing decreased physical activity and vegetable/fruit consumption have higher risk of depressive and anxiety symptoms. Clinical and public health interventions are needed to support individuals experiencing depression and anxiety during the pandemic., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10-8); rs79942605 (OR = 2.17, P = 2.81×10-8) and rs208908 (OR = 0.70, P = 4.54×10-8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development., (© The Author(s) 2022. Published by Oxford University Press.)