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Main unadjusted effects of smoking, childhood and adult exposure to tobacco smoke and lung cancer risk.

Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6, and DRD1 (dopamine receptor D1) were mined for SNPs that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3′UTR (untranslated region) SNP in DRD1 was associated with a lower risk of lung cancer among individuals exposed to secondhand smoke during childhood [OR, 0.69; 95% confidence interval (CI), 0.60–0.79; P < 0.0001]. This relationship was evident in both ever (OR, 0.74; 95% CI, 0.62–0.88; P = 0.001) and never smokers (OR, 0.61; 95% CI, 0.47–0.79; P < 0.0001), European American (OR, 0.65; 95% CI, 0.53–0.80; P < 0.0001), and African American (OR, 0.73; 95% CI, 0.62–0.88; P = 0.001) populations. Although much remains undefined about the long-term risks associated with exposure to secondhand smoke and heterogeneity between individuals in regard to their susceptibility to the effects of secondhand smoke, our data show an interaction between an SNP in the 3′UTR of DRD1 and exposure to secondhand smoke during childhood. Further work is needed to explore the mechanistic underpinnings of this SNP and the nature of the interaction between DRD1 and exposure to secondhand smoke during childhood. Cancer Prev Res; 7(12); 1210–8. ©2014 AACR.

Characteristics of cases and controls from three studies combined.

Association between rs4809294 and rs2292975 and lung cancer risk stratified by exposure to secondhand smoke during adulthood in the NCI-MD Cohort (European Americans).

Association between 3'UTR SNPs and lung cancer in the NCI-MD Cohort (European Americans).

NCI-MD Case-Control Study Genomic DNA was isolated from buffy coat samples containing white blood cells using Flexigene DNA Kit (Qiagen) according to the manufacturer's instructions.

Flowchart detailing the selection process of SNPs. Rs686 in DRD1 was selected from the literature as being a miRNA-binding modulating SNP (Huang and Li, 2009 Biol Pschiatry, 65 9 702-705).

Test for departure from additivity for rs686 and exposure to secondhand smoke during childhood.

Association between rs686 and lung cancer risk stratified by exposure to secondhand smoke during adulthood.

Relationship between rs686 and pack-years of smoking (A) in the NCI-MD (B) and Wayne State (C) studies. Relationship between rs686 and age at smoking initiation (D) in the NCI-MD study.

SNP Selection.

Supplementary Table S1. Concordance between blinded, randomized duplicates and average serum cytokine limits of detection

PDF file - 67K, Imputed SNP associations from the case-control analysis of lung cancer (by histology) in African-Americans (P

Tables S1-S6 and Figures S1-S3.

PDF file - 561K, Association of SNPs on chromosome 15q25.1 with lung cancer, with and without adjustment for missense variant rs16969968. Black circles depict association of SNPs with lung cancer, adjusted for sex, age, study site, % African ancestry, % European ancestry, and number of pack-years smoked. Open squares depict association of SNPs with lung cancer, adjusted for sex, age, study site, and % African ancestry, % European ancestry, number of pack-years smoked, AND conditioned on rs16969968 (marked with an X).

Supplementary Table S3. Association between serum cytokine levels and lung cancer among European Americans in PLCO study

Background: Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans.Methods: 1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate.Results: The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25–1.97; P, 1.1 × 10−4) and variants in the 5′-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48–0.85; P, 1.82 × 10−3). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73–0.93; P, 1.1 × 10−3). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65–0.86; P, 8.1 × 10−5).Conclusions: Polymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma.Impact: Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies. Cancer Epidemiol Biomarkers Prev; 22(2); 251–60. ©2012 AACR.

Background: Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. This study evaluates alternative measures of COPD based on spirometry and quantitative image analysis to better define a phenotype that predicts lung cancer risk.Methods: A total of 341 lung cancer cases and 752 volunteer controls, ages 21 to 89 years, participated in a structured interview, standardized CT scan, and spirometry. Logistic regression, adjusted for age, race, gender, pack-years, and inspiratory and expiratory total lung volume, was used to estimate the odds of lung cancer associated with FEV1/FVC, percent voxels less than −950 Hounsfield units on the inspiratory scan (HUI) and percent voxels less than −856 HU on expiratory scan (HUE).Results: The odds of lung cancer were increased 1.4- to 3.1-fold among those with COPD compared with those without, regardless of assessment method; however, in multivariable modeling, only percent voxels E as a continuous measure of air trapping [OR = 1.04; 95% confidence interval (CI), 1.03–1.06] and FEV1/FVC < 0.70 (OR = 1.71; 95% CI, 1.21–2.41) were independent predictors of lung cancer risk. Nearly 10% of lung cancer cases were negative on all objective measures of COPD.Conclusion: Measures of air trapping using quantitative imaging, in addition to FEV1/FVC, can identify individuals at high risk of lung cancer and should be considered as supplementary measures at the time of screening for lung cancer.Impact: Quantitative measures of air trapping based on imaging provide additional information for the identification of high-risk groups who might benefit the most from lung cancer screening. Cancer Epidemiol Biomarkers Prev; 25(9); 1341–7. ©2016 AACR.

SUPPLEMENTAL TABLE 1. Summary of the five previously reported lung cancer survival GWAS variants examined in the present study. SUPPLEMENTAL TABLE 2. Descriptive characteristics of African Americans with NSCLC participating in the KCI/WSU and UCSF studies. SUPPLEMENTAL TABLE 3. Allele frequency for the five variants previously associated with lung cancer survival in the NHGRIEBI GWAS Catalog in the SCCS (N=275), KCI/WSU (N=312), and UCSF (N=284) populations. Allele frequencies are also presented for the ASW 1000 Genomes African American reference population and for the 1000 Genomes reference population that matches the racial/ethnic group of the original discovery population (CEU or CHB). SUPPLEMENTAL TABLE 4. Adjusted multivariable Cox proportional hazards model results for African Americans with incident non-small cell lung cancer participating in the Southern Community Cohort Study (N=264) for the five candidate SNPs previously associated with lung cancer survival from the NHGRI GWAS catalog. SUPPLEMENTAL TABLE 5. Stage-stratified multivariable Cox proportional hazards results for the association of rs1878022 and overall survival in the SCCS and pooled KCI/WSU and UCSF populations. SUPPLEMENTAL TABLE 6. Allele frequency for common variants associated survival in the SCCS (N=275), KCI/WSU (N=312), and UCSF (N=284) populations. Allele frequencies are also presented for the ASW 1000 Genomes African American reference population. SUPPLEMENTAL TABLE 7. Adjusted multivariable Cox proportional hazards results for African Americans with incident non-small cell lung cancer participating in the Southern Community Cohort Study (N=264) for common variants assayed by the Illumina HumanExome BeadChip v1.1. SUPPLEMENTAL FIGURE 1. Flow chart of quality control (QC) for the SCCS genotyping data. SUPPLEMENTAL FIGURE 2. Distribution of stage at diagnosis across the SCCS (N=286), KCI/WSU (N=316), and UCSF (N=298.) SUPPLEMENTAL FIGURE 3. Global genetic ancestry estimates for African Americans with NSCLC participating in the (A) SCCS, (B) KCI/WSU, and (C) UCSF study populations.SUPPLEMENTAL FIGURE 4. Linkage disequilibrium (LD) patterns +/-10kb surrounding the CMKLR1 gene region in the YRI and CEU populations (A and B, respectively) from 1000 Genomes (phase 3). LD patterns surrounding rs1878022 (denoted by black arrow) are presented as inserts. 1000 Genomes data and Haploview software were utilized to display r2 values (filters:Hardy-Weinberg p-value > 0.001, genotyping efficiency > 90%, and minor allele frequency >0.05).SUPPLEMENTAL FIGURE 5. H3K4me1 and H3K27Ac histone modification marks surrounding rs1878022 in the CMKLR1 gene, visualized using the UCSC Genome Browser. Marks in (A) are specific to normal human lung fibroblast (NHLF) cell lines from the ENCODE project. Marks in (B) are for all cell lines (GM12878, H1-hESC, HSMM, HUVEC, K562, NHEK, and NHLF) in the ENCODE project.

PDF file - 559K, Association of SNPs on chromosome 15q25.1 with lung cancer, with and without adjustment for pack-years smoked. Black circles depict association of SNPs with lung cancer, adjusted for sex, age, study site, % African ancestry, % European ancestry, and number of pack-years smoked. Open squares depict association of SNPs with lung cancer, adjusted for sex, age, study site, and % African ancestry, % European ancestry, but NOT number of pack-years smoked.

Purpose:Identifying novel driver genes and mutations in African American non–small cell lung cancer (NSCLC) cases can inform targeted therapy and improve outcomes for this traditionally underrepresented population.Experimental Design:Tumor DNA, RNA, and germline DNA were collected from African American NSCLC patients who participated in research conducted at the Karmanos Cancer Institute (KCI) in Detroit, Michigan. Known mutations were ascertained through the Sequenom LungCarta panel of 214 mutations in 26 genes, RET/ROS1 fusions, amplification of FGFR1, and expression of ALK. Paired tumor and normal DNA was whole-exome sequenced for a subset of cases without known driver mutations.Results:Of the 193 tumors tested, 77 known driver mutations were identified in 66 patients (34.2%). Sixty-seven of the 127 patients without a known driver mutation were sequenced. In 54 of these patients, 50 nonsynonymous mutations were predicted to have damaging effects among the 26 panel genes, 47 of which are not found in The Cancer Genome Atlas NSCLC white or African American samples. Analyzing the whole-exome sequence data using MutSig2CV identified a total of 88 genes significantly mutated at FDR q < 0.1. Only 5 of these genes were previously reported as oncogenic.Conclusions:These findings suggest that broader mutation profiling including both known and novel driver genes in African Americans with NSCLC will identify additional mutations that may be useful in treatment decision-making.

Supplementary Table S6. Association between serum cytokine levels and lung cancer among European Americans from NCI-MD and PLCO studies, by smoking status

Agreement (Cohen's kappa) between measures of COPD among lung cancer cases (upper diagonal) and controls (lower diagonal).

PDF file - 926K, Triangle plot showing estimated admixture in the African-American case-control population. Estimates were performed using 102 AIMs and data from the International HapMap Project on 167 Yoruban African (Green dots), 165 European (Red dots), 84 Chinese (Yellow dots) and 86 Japanese (Dark Blue dots) founders. The figure depicts ancestry in 1308 African-American lung cancer cases (Pink dots) and 1241 controls (Light Blue dots).

Background: African Americans have the highest lung cancer mortality in the United States. Genome-wide association studies (GWASs) of germline variants influencing lung cancer survival have not yet been conducted with African Americans. We examined five previously reported GWAS catalog variants and explored additional genome-wide associations among African American lung cancer cases.Methods: Incident non–small cell lung cancer cases (N = 286) in the Southern Community Cohort Study were genotyped on the Illumina HumanExome BeadChip. We used Cox proportional hazards models to estimate HRs and 95% confidence intervals (CIs) for overall mortality. Two independent African American studies (N = 316 and 298) were used for replication.Results: One previously reported variant, rs1878022 on 12q23.3, was significantly associated with mortality (HR = 0.70; 95% CI: 0.54–0.92). Replication findings were in the same direction, although attenuated (HR = 0.87 and 0.94). Meta-analysis had a HR of 0.83 (95% CI, 0.71–0.97). Analysis of common variants identified an association between chromosome 6q21.33 and mortality (HR = 0.46; 95% CI, 0.33–0.66).Conclusions: We identified an association between rs1878022 in CMKLR1 and lung cancer survival. However, our results in African Americans have a different direction of effect compared with a prior study in European Americans, suggesting a different genetic architecture or presence of gene–environment interactions. We also identified variants on chromosome 6 within the gene-rich HLA region, which has been previously implicated in lung cancer risk and survival.Impact: We found evidence that inherited genetic risk factors influence lung cancer survival in African Americans. Replication in additional populations is necessary to confirm potential genetic differences in lung cancer survival across populations. Cancer Epidemiol Biomarkers Prev; 26(8); 1288–95. ©2017 AACR.

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Supplementary Table S2. Serum levels of cytokines (pg/mL) by population- and hospital-based controls and by race, NCI-MD study

Supplementary Table S5. Association between serum cytokine levels and lung cancer in WSU and PLCO studies, after adjusting for potential confounding

Supplementary Table S4. Association between serum cytokine levels and lung cancer in the NCI-MD study, after adjusting for potential confounding

Genome-wide association studies (GWAS) have identified several loci contributing to lung cancer and COPD risk independently; however, inflammation-related pathways likely harbor additional lung cancer risk-associated variants in biologically relevant immune genes that differ dependent on COPD. We selected single nucleotide polymorphisms (SNPs) proximal to 2,069 genes within 48 immune pathways. We modeled the contribution of these variants to lung cancer risk in a discovery sample of 1,932 lung cancer cases and controls stratified by COPD status and validation sample of 953 cases and controls also stratified by COPD. There were 43 validated SNPs in those with COPD and 60 SNPs in those without COPD associated with lung cancer risk. Furthermore, 29 of 43 and 28 of 60 SNPs demonstrated a statistically significant interaction with COPD in the pooled sample. These variants demonstrated tissue-dependent effects on proximal gene expression, enhanced network connectivity and resided together in specific immune pathways. These results reveal that key inflammatory related genes and pathways, not found in prior GWAS, impact lung cancer risk in a COPD-dependent manner. Genetic variation identified in our study supplements prior lung cancer GWAS and serves as a foundation to further interrogate risk relationships in smoking and COPD populations.

Background: Somatic EGFR mutations define a subset of non–small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. Results: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74–0.77) in the training and 0.77 (95% CI, 0.74–0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. Conclusions: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. Impact: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

PURPOSE: Computed tomography (CT) is an effective method for detecting and characterizing lung nodules in vivo. With the growing use of chest CT, the detection frequency of lung nodules is increasing. Noninvasive methods to distinguish malignant from benign nodules have the potential to decrease the clinical burden, risk, and cost involved in follow-up procedures on the large number of false-positive lesions detected. This study examined the benefit of including perinodular parenchymal features in machine learning (ML) tools for pulmonary nodule assessment. METHODS: Lung nodule cases with pathology confirmed diagnosis (74 malignant, 289 benign) were used to extract quantitative imaging characteristics from computed tomography scans of the nodule and perinodular parenchyma tissue. A ML tool development pipeline was employed using k-medoids clustering and information theory to determine efficient predictor sets for different amounts of parenchyma inclusion and build an artificial neural network classifier. The resulting ML tool was validated using an independent cohort (50 malignant, 50 benign). RESULTS: The inclusion of parenchymal imaging features improved the performance of the ML tool over exclusively nodular features (P < 0.01). The best performing ML tool included features derived from nodule diameter-based surrounding parenchyma tissue quartile bands. We demonstrate similar high-performance values on the independent validation cohort (AUC-ROC = 0.965). A comparison using the independent validation cohort with the Fleischner pulmonary nodule follow-up guidelines demonstrated a theoretical reduction in recommended follow-up imaging and procedures. CONCLUSIONS: Radiomic features extracted from the parenchyma surrounding lung nodules contain valid signals with spatial relevance for the task of lung cancer risk classification. Through standardization of feature extraction regions from the parenchyma, ML tool validation performance of 100% sensitivity and 96% specificity was achieved.

Background Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. Methods Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N = 12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium. Results Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR = 0.48, 95%CI = 0.30–0.75, p = 0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR = 0.68, 95%CI = 0.61–0.77, p = 4.9 ∗ 10–10). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype. Conclusion We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7 years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke., Highlights • CHRNA5 rs16969968 confers risk for earlier lung cancer diagnosis, but quitting produces benefit regardless of genotype. • Smokers can cut their risk of lung cancer in half and delay its onset by 7 years among those diagnosed. • Precision prevention allows clinicians to provide personalized health benefits of smoking cessation. This is a report on whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. We determined that quitting smoking is highly beneficial in reducing lung cancer risk levels for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Although CHRNA5 rs16969968 increases risk for earlier lung cancer by 4 years, quitting produces essentially the same benefit for smokers with either high or low genetic risks. Smokers can cut their risk of lung cancer in half and delay its onset by 7 years among those diagnosed. These results are important for smokers to prevent cancer. On average, smokers at all genetic risk levels can largely eliminate their elevated risk for lung cancer by quitting smoking.

Background: Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. This study evaluates alternative measures of COPD based on spirometry and quantitative image analysis to better define a phenotype that predicts lung cancer risk. Methods: A total of 341 lung cancer cases and 752 volunteer controls, ages 21 to 89 years, participated in a structured interview, standardized CT scan, and spirometry. Logistic regression, adjusted for age, race, gender, pack-years, and inspiratory and expiratory total lung volume, was used to estimate the odds of lung cancer associated with FEV1/FVC, percent voxels less than −950 Hounsfield units on the inspiratory scan (HUI) and percent voxels less than −856 HU on expiratory scan (HUE). Results: The odds of lung cancer were increased 1.4- to 3.1-fold among those with COPD compared with those without, regardless of assessment method; however, in multivariable modeling, only percent voxels Conclusion: Measures of air trapping using quantitative imaging, in addition to FEV1/FVC, can identify individuals at high risk of lung cancer and should be considered as supplementary measures at the time of screening for lung cancer. Impact: Quantitative measures of air trapping based on imaging provide additional information for the identification of high-risk groups who might benefit the most from lung cancer screening. Cancer Epidemiol Biomarkers Prev; 25(9); 1341–7. ©2016 AACR.

Background: African Americans have a higher risk of developing lung cancer than European Americans. Previous studies suggested that certain circulating cytokines were associated with lung cancer. We hypothesized that variations in serum cytokine levels exist between African Americans and European Americans, and increased circulating cytokine levels contribute to lung cancer differently in the two races. Methods: Differences in 10 serum cytokine levels, IL1β, IL4, IL5, IL6, IL8, IL10, IL12, granulocyte macrophage colony-stimulating factor, IFNγ, and TNFα, between 170 African-American and 296 European-American controls from the National Cancer Institute-Maryland (NCI-MD) case–control study were assessed. Associations of the serum cytokine levels with lung cancer were analyzed. Statistically significant results were replicated in the prospective Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the Wayne State University Karmanos Cancer Institute case–control study. Results: Six cytokines, IL4, IL5, IL8, IL10, IFNγ, and TNFα, were significantly higher among European-American as compared with African-American controls. Elevated IL6 and IL8 levels were associated with lung cancer among both races in all three studies. Elevated IL1β, IL10, and TNFα levels were associated with lung cancer only among African Americans. The association between elevated TNFα levels and lung cancer among European Americans was significant after adjustment for additional factors. Conclusions: Serum cytokine levels vary by race and might contribute to lung cancer differently between African Americans and European Americans. Impact: Future work examining risk prediction models of lung cancer can measure circulating cytokines to accurately characterize risk within racial groups. Cancer Epidemiol Biomarkers Prev; 25(3); 488–97. ©2015 AACR.

Background: Lung cancer continues to cause more deaths than other cancers, with mortality among African Americans higher than among whites. Despite this, research on the psychosocial aspects of lung cancer patients' quality of life lags behind that of other cancer types, such as breast or prostate. The Detroit Research on Cancer Survivors (ROCS) studies follow the experience of cancer survivors, including lung cancer patients, in Detroit, MI. The Detroit ROCS studies include the pilot study of whites and African Americans, and the ongoing study of African Americans only. Methods: Participants in the Detroit ROCS studies complete the Functional Assessment in Cancer Therapy (FACT) instrument to evaluate their health-related quality of life (QOL). FACT scores are derived from subscores evaluating physical, emotional, social, and functional well-being. Higher scores indicate better QOL. In addition, participants are asked to provide basic demographic information, health history, family history of cancer, and exposure history. Data related to their cancer diagnosis and census tract are gathered via the Metropolitan Detroit Cancer Surveillance System. We examined preliminary data collected from 227 (131 African American and 96 white) lung cancer survivors to assess racial differences in self-reported aspects of well-being. We compared descriptive characteristics using Pearson's Chi-square and Wilcoxon rank sum tests. We modeled adjusted mean well-being subscores using a general linear model. Results: The mean age of African American participants was 61.9 (SD=7.6) and the mean age of whites was 62.9 (SD=8.9). Among African American participants, 40.5% were male; of white participants, 45.8% were male. The distributions of age and sex did not differ significantly between groups. African American participants were less likely to have any college education (p=0.0480), and more likely to live in a census tract with at least 20% poverty (p Conclusions: While functional and physical well-being outcomes are similar for African American and white patients after a lung cancer diagnosis, emotional and social well-being outcomes diverge by race. These measures reflect disparities in QOL among lung cancer patients, whose QOL is minimally studied compared to survivors of cancers with lower mortality rates. Future analyses will identify factors influencing this disparity in emotional and social well-being, and describe additional determinants contributing to the QOL of lung cancer survivors. Citation Format: Julia Mantey, Angela Wenzlaff, Jennifer Beebe-Dimmer, Terrance Albrecht, Ann G. Schwartz. Health-related quality of life among Detroit lung cancer survivors: Findings from the Detroit ROCS studies [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B035.

Purpose: Identifying novel driver genes and mutations in African American non–small cell lung cancer (NSCLC) cases can inform targeted therapy and improve outcomes for this traditionally underrepresented population. Experimental Design: Tumor DNA, RNA, and germline DNA were collected from African American NSCLC patients who participated in research conducted at the Karmanos Cancer Institute (KCI) in Detroit, Michigan. Known mutations were ascertained through the Sequenom LungCarta panel of 214 mutations in 26 genes, RET/ROS1 fusions, amplification of FGFR1, and expression of ALK. Paired tumor and normal DNA was whole-exome sequenced for a subset of cases without known driver mutations. Results: Of the 193 tumors tested, 77 known driver mutations were identified in 66 patients (34.2%). Sixty-seven of the 127 patients without a known driver mutation were sequenced. In 54 of these patients, 50 nonsynonymous mutations were predicted to have damaging effects among the 26 panel genes, 47 of which are not found in The Cancer Genome Atlas NSCLC white or African American samples. Analyzing the whole-exome sequence data using MutSig2CV identified a total of 88 genes significantly mutated at FDR q < 0.1. Only 5 of these genes were previously reported as oncogenic. Conclusions: These findings suggest that broader mutation profiling including both known and novel driver genes in African Americans with NSCLC will identify additional mutations that may be useful in treatment decision-making.

Introduction: Lung cancer is the leading cause of cancer-related deaths in the US. The reasons for higher incidence and poorer sur- vival rates among black compared with white lung cancer patients have not been defined. We hypothesized that differential incidence of somatic cancer gene mutations may be a contributing factor. Previous genomic studies of non-small cell lung cancer (NSCLC) have not adequately represented black patients. Methods: A matrix-assisted laser desorption/ionization and time-of- flight mass spectrometry approach was used to analyze tumor DNA for 214 coding mutations in 26 cancer genes previously identified in NSCLC. The samples included NSCLC from 335 white patients and 137 black patients. For 299 of these, normal matched DNA was available and analyzed. Results: Epidermal growth factor receptor (EGFR) exon 19 deletions were only detected in women cases, with increased odds for black women compared with white women (odds ratio = 3.914, 95% confidence inter - val: 1.014-15.099, p = 0.048). Beyond race, variations in mutation fre- quencies were seen by histology. DDR2 alterations, previously described as somatic mutations, were identified as constitutional variants. Conclusions: This study is among the largest comparing somatic mutations in black and white patients. The results point to the molec- ular diversity of NSCLC and raise new questions as to the impor- tance of inherited alleles. Genomic tumor testing will benefit both populations, although the mutation spectrum appears to vary by sex, race, and histology.

Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6, and DRD1 (dopamine receptor D1) were mined for SNPs that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3′UTR (untranslated region) SNP in DRD1 was associated with a lower risk of lung cancer among individuals exposed to secondhand smoke during childhood [OR, 0.69; 95% confidence interval (CI), 0.60–0.79; P < 0.0001]. This relationship was evident in both ever (OR, 0.74; 95% CI, 0.62–0.88; P = 0.001) and never smokers (OR, 0.61; 95% CI, 0.47–0.79; P < 0.0001), European American (OR, 0.65; 95% CI, 0.53–0.80; P < 0.0001), and African American (OR, 0.73; 95% CI, 0.62–0.88; P = 0.001) populations. Although much remains undefined about the long-term risks associated with exposure to secondhand smoke and heterogeneity between individuals in regard to their susceptibility to the effects of secondhand smoke, our data show an interaction between an SNP in the 3′UTR of DRD1 and exposure to secondhand smoke during childhood. Further work is needed to explore the mechanistic underpinnings of this SNP and the nature of the interaction between DRD1 and exposure to secondhand smoke during childhood. Cancer Prev Res; 7(12); 1210–8. ©2014 AACR.

Introduction: Although lung cancer is the leading cause of cancer death in women, few studies have investigated the hormonal influence on survival after a lung cancer diagnosis and results have been inconsistent. We evaluated the role of reproductive and hormonal factors in predicting overall survival in women with non–small-cell lung cancer (NSCLC). Methods: Population-based lung cancer cases diagnosed between November 1, 2001 and October 31, 2005 were identified through the Metropolitan Detroit Surveillance, Epidemiology, and End Results Registry. Interview and follow-up data were collected for 485 women. Cox proportional hazard regression models were used to determine hazard ratios (HRs) for death after an NSCLC diagnosis associated with reproductive and hormonal variables. Results: Use of hormone therapy (HT) was associated with improved survival (HR, 0.69; 95% confidence interval, 0.54–0.89), adjusting for stage, surgery, radiation, education level, pack-years of smoking, age at diagnosis, race, and a multiplicative interaction between stage and radiation. No other reproductive or hormonal factor was associated with survival after an NSCLC diagnosis. Increased duration of HT use before the lung cancer diagnosis (132 months or longer) was associated with improved survival (HR, 0.54; 95% confidence interval, 0.37–0.78), and this finding remained significant in women taking either estrogen alone or progesterone plus estrogen, never smokers, and smokers. Conclusion: These findings suggest that HT use, in particular use of estrogen plus progesterone, and long-term HT use are associated with improved survival of NSCLC.

IntroductionBlack/white disparities in lung cancer incidence and mortality mandate an evaluation of underlying biological differences. We have previously shown higher risks of lung cancer associated with prior emphysema in African American compared with white patients with lung cancer.MethodsWe therefore evaluated a panel of 1440 inflammatory gene variants in a two-phase analysis (discovery and replication), added top genome-wide association studies (GWAS) lung cancer hits from white populations, and 28 single-nucleotide polymorphisms (SNPs) from a published gene panel. The discovery set (477 self-designated African Americans cases, 366 controls matched on age, ethnicity, and gender) were from Houston, Texas. The external replication set (330 cases and 342 controls) was from the EXHALE study at Wayne State University.ResultsIn discovery, 154 inflammation SNPs were significant (p < 0.05) on univariate analysis, as was one of the gene panel SNPs (rs308738 in REV1, p = 0.0013), and three GWAS hits, rs16969968 p = 0.0014 and rs10519203 p = 0.0003 in the 15q locus and rs2736100, in the HTERT locus, p = 0.0002. One inflammation SNP, rs950286, was successfully replicated with a concordant odds ratio of 1.46 (1.14–1.87) in discovery, 1.37 (1.05–1.77) in replication, and a combined odds ratio of 1.40 (1.17–1.68). This SNP is intergenic between IRF4 and EXOC2 genes. We also constructed and validated epidemiologic and extended risk prediction models. The area under the curve (AUC) for the epidemiologic discovery model was 0.77 and 0.80 for the extended model. For the combined datasets, the AUC values were 0.75 and 0.76, respectively.ConclusionsAs has been reported for other cancer sites and populations, incorporating top genetic hits into risk prediction models, provides little improvement in model performance and no clinical relevance.

Background: Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans. Methods: 1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate. Results: The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25–1.97; P, 1.1 × 10−4) and variants in the 5′-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48–0.85; P, 1.82 × 10−3). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73–0.93; P, 1.1 × 10−3). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65–0.86; P, 8.1 × 10−5). Conclusions: Polymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma. Impact: Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies. Cancer Epidemiol Biomarkers Prev; 22(2); 251–60. ©2012 AACR.

// Kyle M. Walsh 1 †, Christopher I. Amos 2 † * , Angela S. Wenzlaff 3 , Ivan P. Gorlov 4 , Jennette D. Sison 5 , Xifeng Wu 6 , Margaret R. Spitz 7 , Helen M. Hansen 5 , Emily Y. Lu 2 , Chongjuan Wei 6 , Huifeng Zhang 2 , Wei Chen 2 , Stacy M. Lloyd 8 , Marsha L. Frazier 6 , Paige M. Bracci 1 , Michael F. Seldin 9 , Margaret R. Wrensch 1,5 , Ann G. Schwartz 3* , John K. Wiencke 1,5* 1 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 2 Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 3 Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 4 Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 5 Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 6 Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, TX 7 Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 8 Department of Health Disparities Research, University of Texas M.D. Anderson Cancer Center, Houston, TX 9 Department of Biochemistry and Molecular Medicine, University of California, Davis † denotes equal contribution * CIA, AGS and JKW co-directed this research Correspondence: John K. Wiencke, email: // Keywords : Lung cancer, nicotine dependence, African-Americans, genetic association, smoking Received : November 13, 2012, Accepted : November 14, 2012, Published : November 16, 2012 Abstract Studies in European and East Asian populations have identified lung cancer susceptibility loci in nicotinic acetylcholine receptor (nAChR) genes on chromosome 15q25.1 which also appear to influence smoking behaviors. We sought to determine if genetic variation in nAChR genes influences lung cancer susceptibly in African-Americans, and evaluated the association of these cancer susceptibility loci with smoking behavior. A total of 1308 African-Americans with lung cancer and 1241 African-American controls from three centers were genotyped for 378 single nucleotide polymorphisms (SNPs) spanning the sixteen human nAChR genes. Associations between SNPs and the risk of lung cancer were estimated using logistic regression, adjusted for relevant covariates. Seven SNPs in three nAChR genes were significantly associated with lung cancer at a strict Bonferroni-corrected level, including a novel association on chromosome 2 near the promoter of CHRNA1 (rs3755486: OR = 1.40, 95% CI = 1.18-1.67, P = 1.0 x 10 -4 ). Association analysis of an additional 305 imputed SNPs on 2q31.1 supported this association. Publicly available expression data demonstrated that the rs3755486 risk allele correlates with increased CHRNA1 gene expression. Additional SNP associations were observed on 15q25.1 in genes previously associated with lung cancer, including a missense variant in CHRNA5 (rs16969968: OR = 1.60, 95% CI = 1.27-2.01, P = 5.9 x 10 -5 ). Risk alleles on 15q25.1 also correlated with an increased number of cigarettes smoked per day among the controls. These findings identify a novel lung cancer risk locus on 2q31.1 which correlates with CHRNA1 expression and replicate previous associations on 15q25.1 in African-Americans.

Objectives Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping. Materials and methods We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs ( p −5 ) in an independent set of 866 cases and 796 controls in stage 2. Results and conclusion In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 ( p =1.3×10 −9 ; OR=1.32; 95% CI=1.20–1.44) near CHRNA5 , and 5p15.33 marked by rs2853677 ( p =2.8×10 −9 ; OR=1.28; 95% CI=1.18–1.39) near TERT . The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer ( p =1.3×10 −8 ; OR=1.37; 95% CI=1.23–1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking − cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT , on 15q25.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans.

In a population-based case-control study, we explored the associations between 42 polymorphisms in seven genes in this region and non-small cell lung cancer (NSCLC) risk among Caucasian (364 cases; 380 controls) and African American (95 cases; 103 controls) women. TwoTERTregion SNPs, rs2075786 and rs2853677, conferred an increased risk of developing NSCLC, especially among African American women, andTERT-rs2735940 was associated with a decreased risk of lung cancer among African Americans. Five of the 20GHRpolymorphisms andSEPP1-rs6413428 were associated with a marginally increased risk of NSCLC among Caucasians. Random forest analysis reinforced the importance ofGHRamong Caucasians and identifiedAMACR, TERT, andGHRamong African Americans, which were also significant using gene-based risk scores. Smoking-SNP interactions were explored, and haplotypes inTERTandGHRassociated with NSCLC risk were identified. The roles ofTERT, GHR, AMACRandSEPP1genes in lung carcinogenesis warrant further exploration.

Because existing risk prediction models for lung cancer were developed in white populations, they may not be appropriate for predicting risk among African-Americans. Therefore, a need exists to construct and validate a risk prediction model for lung cancer that is specific to African-Americans. We analyzed data from 491 African-Americans with lung cancer and 497 matched African-American controls to identify specific risks and incorporate them into a multivariable risk model for lung cancer and estimate the 5-year absolute risk of lung cancer. We performed internal and external validations of the risk model using data on additional cases and controls from the same ongoing multiracial/ethnic lung cancer case-control study from which the model-building data were obtained as well as data from two different lung cancer studies in metropolitan Detroit, respectively. We also compared our African-American model with our previously developed risk prediction model for whites. The final risk model included smoking-related variables [smoking status, pack-years smoked, age at smoking cessation (former smokers), and number of years since smoking cessation (former smokers)], self-reported physician diagnoses of chronic obstructive pulmonary disease or hay fever, and exposures to asbestos or wood dusts. Our risk prediction model for African-Americans exhibited good discrimination [75% (95% confidence interval, 0.67–0.82)] for our internal data and moderate discrimination [63% (95% confidence interval, 0.57–0.69)] for the external data group, which is an improvement over the Spitz model for white subjects. Existing lung cancer prediction models may not be appropriate for predicting risk for African-Americans because (a) they were developed using white populations, (b) level of risk is different for risk factors that African-American share with whites, and (c) unique group-specific risk factors exist for African-Americans. This study developed and validated a risk prediction model for lung cancer that is specific to African-Americans and thus more precise in predicting their risks. These findings highlight the importance of conducting further ethnic-specific analyses of disease risk.

Purpose Estrogen receptor (ER) expression in lung tumors suggests that estrogens may play a role in the development of lung cancer. We evaluated the role of hormone-related factors in determining risk of non–small-cell lung cancer (NSCLC) in women. We also evaluated whether risk factors were differentially associated with cytoplasmic ER-α and/or nuclear ER-β expression–defined NSCLC in postmenopausal women. Patients and Methods Population-based participants included women aged 18 to 74 years diagnosed with NSCLC in metropolitan Detroit between November 1, 2001 and October 31, 2005. Population-based controls were identified through random digit dialing, matched to patient cases on race and 5-year age group. Interview data were analyzed for 488 patient cases (241 with tumor ER results) and 498 controls. Results Increased duration of hormone replacement therapy (HRT) use in quartiles was associated with decreased risk of NSCLC in postmenopausal women (odds ratio = 0.88; 95% CI, 0.78 to 1.00; P = .04), adjusting for age, race, pack-years, education, family history of lung cancer, current body mass index, years exposed to second-hand smoke in the workplace, and obstructive lung disease history. Among postmenopausal women, ever using HRT, increasing HRT duration of use in quartiles, and increasing quartiles of estrogen use were significant predictors of reduced risk of NSCLC characterized as ER-α and/or ER-β positive. None of the hormone-related variables were associated with nuclear ER-α–or ER-β–negative NSCLC. Conclusion These findings suggest that postmenopausal hormone exposures are associated with reduced risk of ER-α–and ER-β–expressing NSCLC. Understanding tumor characteristics may direct development of targeted treatment for this disease.

Lung cancer continues to be a major public health challenge in the United States despite efforts to decrease the prevalence of smoking; outcomes are especially poor for African-American patients compared to other races/ethnicities. Chronic obstructive pulmonary disease (COPD) co-occurs with lung cancer frequently, but not always, suggesting both shared and distinct risk factors for these two diseases. To identify germline genetic variation that distinguishes between lung cancer in the presence and absence of emphysema, we performed whole-exome sequencing on 46 African-American lung cancer cases (23 with and 23 without emphysema frequency matched on age, sex, histology and pack years). Using conditional logistic regression, we found 6305 variants (of 168 150 varying sites) significantly associated with lung cancer subphenotype (P ≤ 0.05). Next, we validated 10 of these variants in an independent set of 612 lung cancer cases (267 with emphysema and 345 without emphysema) from the same population of inference as the sequenced cases. We found one variant that was significantly associated with lung cancer subphenotype in the validation sample. These findings contribute to teasing apart shared genetic factors from independent genetic factors for lung cancer and COPD.

Item does not contain fulltext BACKGROUND: Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis. METHODS: Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided. RESULTS: The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10(-5)). CONCLUSION: These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk.

OBJECTIVE To investigate associations between prostate cancer and sexually transmitted diseases (STDs), prostatitis, benign prostatic hyperplasia (BPH), and vasectomy in a population-based case-control study in Wayne County, Michigan, among African American and white men aged 50--74 years.Incident prostate cancer cases (n=700) from 1996--1998 were identified from the Metropolitan Detroit Cancer Surveillance System. Controls (n=604) were identified through random digit dialing and Medicare recipient lists, and frequency matched to cases on age and race. History of potential prostate cancer risk factors was ascertained through in-person interview.Prostate cancer was not associated with STD or vasectomy history. History of prostatitis was associated with prostate cancer among all subjects (odds ratio [OR]=1.8, 95% confidence interval [CI]: 1.1, 2.9) and in African American men (OR=2.2, 95% CI: 1.1, 4.6). History of BPH was associated with prostate cancer among all subjects (OR=2.4, 95% CI: 1.8, 3.3); significant associations were observed in both African American (OR=2.7, 95% CI: 1.6, 4.4) and white (OR=2.3, 95% CI: 1.5, 3.4) men.Among all subjects, prostate cancer was associated with prostatitis and BPH history, but not with STD or vasectomy history. Prevention efforts could be enhanced if inflammatory or infectious etiologies are found to be of importance in the subsequent development of prostate cancer.