Neighbourhood deprivation and lung cancer risk: a nested case–control study in the USA

Objectives To examine the association between neighbourhood deprivation and lung cancer risk. Design Nested case–control study. Setting Southern Community Cohort Study of persons residing in 12 states in the southeastern USA. Participants 1334 cases of lung cancer and 5315 controls. Primary outcome measure Risk of lung cancer. Results After adjustment for smoking status and other confounders, and additional adjustment for individual-level measures of socioeconomic status (SES), there was no monotonic increase in risk with worsening deprivation score overall or within sex and race groups. There was an increase among current and shorter term former smokers (p=0.04) but not among never and longer term former smokers. There was evidence of statistically significant interaction by sex among whites, but not blacks, in which the effect of worsening deprivation on lung cancer existed in males but not in females. Conclusions Area-level measures of SES were associated with lung cancer risk in current and shorter term former smokers only in this population

Impact of Timing of Lung resection on Survival for Clinical Stage I and II Lung Cancer

Background: Lung cancer has the highest mortality among the leading cancers in the U.S. Surgical resection is considered as the most effective treatment for lung cancer in early stages, providing greater long-term survival. Clinical guidelines on delays in resection of early-stage lung cancer do not exist. This work aims to assess whether increasing time between diagnosis/first doctor visit and surgery for early stage non-small cell lung cancer (NSCLC) is associated with poorer survival. Methods: We identified a retrospective cohort of incident lung cancer cases who had surgical treatment for lung cancer at our institution between January 2009 and December 2017, and no prior radiation or chemotherapy. We assessed overall survival (OS) and predictors included a) time from first contact to surgery; and b) time from diagnosis to surgery. The association between time from diagnosis and time from first contact to surgery, and survival for patients with early stage NSCLC was assessed using multivariable Cox proportional hazard. We investigated four cut-off points: surgery within 15 days, 30 days, 60 days and 90 days. We controlled for sociodemographic characteristics as well as clinical outcomes. Results: Our cohort comprised 491 patients. The age average was 66.9 years, 61% female, 94.7% white, and 9% never smoked. Clinical Stage 1A and 1B corresponded to 86.5% of patients while in pathological stage it was 76%. The 5-year overall survival was 56.0%. Surgery occurred a median 40 days after the diagnosis and 43 days after the first visit and within 35 days if the first appointment was with a thoracic surgeon. The threshold time associated with statistically significant worse survival was 60 days after diagnosis. Surgery was performed more than 60 days of diagnosis in 115 (25.7%) patients, their OS was significantly worse than patients who had surgery earlier (HR=1.7 [95% CI: 1.1-2.6]). Conclusions: Greater intervals between diagnosis of early-stage NSCLC and surgery are associated with worse survival. Efforts to minimize delays, particularly factors that prolong the period from diagnosis to first contact with a lung cancer provider may improve survival

Disruption of medical care among individuals in the southeastern United States during the COVID-19 pandemic

Background: Widespread disruptions of medical care to mitigate COVID-19 spread and reduce burden on healthcare systems may have deleterious public health consequences. Design and Methods: To examine factors contributing to healthcare interruptions during the pandemic, we conducted a COVID-19 impact survey between 10/7-12/14/2020 among participants of the Southern Community Cohort Study, which primarily enrolled low-income individuals in 12 southeastern states from 2002-2009. COVID survey data were combined with baseline and follow-up data. Results: Among 4,463 respondents, 40% reported having missed/delayed a health appointment during the pandemic; the common reason was provider-initiated cancellation or delay (63%). In a multivariable model, female sex was the strongest independent predictor of interrupted care, with odds ratio (OR) 1.63 (95% confidence interval [CI] 1.40-1.89). Those with higher education (OR 1.27; 95% CI 1.05-1.54 for college graduate vs ≤high school) and household income (OR 1.47; 95% CI 1.16-1.86 for >$50,000 vs <$15,000) were at significantly increased odds of missing healthcare.  Having greater perceived risk for acquiring (OR 1.42; 95% CI 1.17-1.72) or dying from COVID-19 (OR 1.25; 95% CI 1.04-1.51) also significantly increased odds of missed/delayed healthcare. Age was inversely associated with missed healthcare among men (OR for 5-year increase in age 0.88; 95% CI 0.80-0.96) but not women (OR 0.97; 95% CI 0.91-1.04; p-interaction=0.04). Neither race/ethnicity nor comorbidities were associated with interrupted healthcare. Conclusions: Disruptions to healthcare disproportionately affected women and were primarily driven by health system-initiated deferrals and individual perceptions of COVID-19 risk, rather than medical co-morbidities or other traditional barriers to healthcare access

Household Exposure to Paint and Petroleum Solvents, Chromosomal Translocations, and the Risk of Childhood Leukemia

BackgroundFew studies have examined the association between home use of solvents and paint and the risk of childhood leukemia.ObjectivesIn this case-control 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.MethodsWe 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.ResultsALL 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).ConclusionsThe 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

Identification of Susceptibility Pathways for the Role of Chromosome 15q25.1 in Modifying Lung Cancer Risk

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer

Haplotypes of DNA repair and cell cycle control genes, X-ray exposure, and risk of childhood acute lymphoblastic leukemia

[[abstract]]Background: Acute leukemias of childhood are a heterogeneous group of malignancies characterized by cytogenetic abnormalities, such as translocations and changes in ploidy. These abnormalities may be influenced by altered DNA repair and cell cycle control processes. Methods: We examined the association between childhood acute lymphoblastic leukemia (ALL) and 32 genes in DNA repair and cell cycle pathways using a haplotype-based approach, among 377 childhood ALL cases and 448 controls enrolled during 1995-2002. Results: We found that haplotypes in APEX1, BRCA2, ERCC2, and RAD51 were significantly associated with total ALL, while haplotypes in NBN and XRCC4, and CDKN2A were associated with structural and numerical change subtypes, respectively. In addition, we observed statistically significant interaction between exposure to 3 or more diagnostic X-rays and haplotypes of XRCC4 on risk of structural abnormality-positive childhood ALL. Conclusions: These results support a role of altered DNA repair and cell cycle processes in the risk of childhood ALL, and show that this genetic susceptibility can differ by cytogenetic subtype and may be modified by exposure to ionizing radiation. To our knowledge, our study is the first to broadly examine the DNA repair and cell cycle pathways using a haplotype approach in conjunction with X-ray exposures in childhood ALL risk. If confirmed, future studies are needed to identify specific functional SNPs in the regions of interest identified in this analysis

I am hiQ—a novel pair of accuracy indices for imputed genotypes

Background: Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy with which genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately diversely across platforms. In the present paper, we introduce Iam hiQ, an independent pair of accuracy measures that can be applied to dosage files, the output of all imputation software. Iam (imputation accuracy measure) quantifies the average amount of individual-specific versus population-specific genotype information in a linear manner. hiQ (heterogeneity in quantities of dosages) addresses the inter-individual heterogeneity between dosages of a marker across the sample at hand. Results: Applying both measures to a large case–control sample of the International Lung Cancer Consortium (ILCCO), comprising 27,065 individuals, we found meaningful thresholds for Iam and hiQ suitable to classify markers of poor accuracy. We demonstrate how Manhattan-like plots and moving averages of Iam and hiQ can be useful to identify regions enriched with less accurate imputed markers, whereas these regions would by missed when applying the accuracy measure info (implemented in IMPUTE2). Conclusion: We recommend using Iam hiQ additional to other accuracy scores for variant filtering before stepping into the analysis of imputed GWAS data

Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer

Background: Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. Aim: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. Methods: Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant × variant interaction. All analyses were performed for overall lung cancer and for subgroups. Results: No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR = 1.20; 95% CI 1.13–1.27; p = 5.6 × 10–10) and never smokers (e.g., maker rs1133683 Axin2; OR = 1.27; 95% CI 1.19–1.35; p = 1.0 × 10–12). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants. Conclusions: The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers