Lung Cancer In African Americans Research Articles

Dysregulation of lncRNA MALAT1 Contributes to Lung Cancer in African Americans by Modulating the Tumor Immune Microenvironment

African American (AA) populations present with notably higher incidence and mortality rates from lung cancer in comparison to other racial groups. Here, we elucidated the contribution of long non-coding RNAs (lncRNAs) in the racial disparities and their potential clinical applications in both diagnosis and therapeutic strategies. AA patients had elevated plasma levels of MALAT1 and PVT1 compared with cancer-free smokers. Incorporating these lncRNAs as plasma biomarkers, along with smoking history, achieved 81% accuracy in diagnosis of lung cancer in AA patients. We observed a rise in MALAT1 expression, correlating with increased levels of monocyte chemoattractant protein-1 (MCP-1) and CD68, CD163, CD206, indicative of tumor-associated macrophages in lung tumors of AA patients. Forced MALAT1 expression led to enhanced growth and invasiveness of lung cancer cells, both in vitro and in vivo, accompanied by elevated levels of MCP-1, CD68, CD163, CD206, and KI67. Mechanistically, MALAT1 acted as a competing endogenous RNA to directly interact with miR-206, subsequently affecting MCP-1 expression and macrophage activity, and enhanced the tumorigenesis. Targeting MALAT1 significantly reduced tumor sizes in animal models. Therefore, dysregulated MALAT1 contributes to lung cancer disparities in AAs by modulating the tumor immune microenvironment through its interaction with miR-206, thereby presenting novel diagnostic and therapeutic targets.

Cytokine Signatures for Lung Cancer Diagnosis in African American Populations.

Lung cancer is the leading cause of cancer-related deaths among both men and women. African Americans (AAs) experience disproportionately higher incidence and mortality compared to other ethnic groups. Cytokines play multifaceted and crucial roles in the initiation, progression, and spread of cancer. Our aim was to identify cytokine biomarkers for the early detection of lung cancer in AAs. We examined eight key cytokines (Interleukin-1, IL-6, IL-8, IL-10, IL-12p70, monocyte chemotactic protein-1 (MCP-1), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α)) in the plasma of 104 lung cancer patients and 48 cancer-free individuals using the FirePlex Immunoassay. These findings were subsequently validated in a separate cohort of 58 cases and 58 controls. IL-8, IFN-γ, and TNF-α exhibited elevated levels in both AA and White American (WA) lung cancer cases. Notably, IL-10 and MCP-1 displayed significant increases specifically in AA lung cancer patients, with MCP-1 levels associated with lung adenocarcinoma cases. Conversely, WA lung cancer patients showed heightened IL-6 levels, particularly linked to lung adenocarcinoma. The combined use of specific cytokines showed promise in lung cancer diagnosis, with IL-8, IL-10, and MCP-1 achieving 76% sensitivity and 79% specificity in AAs and IL-6 and IL-8 combined offering 76% sensitivity and 74% specificity in WAs. These diagnostic biomarkers were validated in the independent cohort. The ethnicity-related cytokine biomarkers hold promise for diagnosing lung cancer in AAs and WAs, potentially addressing the observed racial disparity.

Abstract 5218: Genome-wide association study of African Americans reveals new susceptibility loci contributing to lung cancer and mechanisms of population-specific etiology

Abstract Lung cancer incidence and mortality in the U.S. have substantial ethnic disparities. African Americans of both sexes have the high incidence rate at 56.8 and the highest death rate at 38.1 per 100,000 people from 2015 to 2019. Non-Hispanic black men have the highest incidence at 73.9 and the highest death rate at 56.3 per 100,000 people. While many genome-wide association studies (GWAS) of lung cancer have discovered ~45 putative risk loci, a large proportion of the heritability of lung cancer remains unexplained. To date, most single population-based GWAS have been performed in Europeans while there are a few Asian ancestry-specific genetic studies and two cross-ancestry studies. Non-European GWAS of lung cancer has been underrepresented. Although African Americans have higher lung cancer incidence and poorer lung cancer survival rate, and smoke fewer cigarettes per day compared to Europeans, few comprehensive GWAS of lung cancer in African Americans has been conducted. This study aims to decipher the genetic component of predisposition to lung cancer among African Americans. This study aims to decipher the genetic component of predisposition to lung cancer among African Americans. We conducted an African-ancestry GWAS comprising 2,280 lung cancer cases and 4,301 controls to comprehensively characterize common and low-frequency lung cancer genetic susceptibility loci using HRC imputed lung cancer data. The novel variants in or near VWF on 12p13.31 (OR=1.29, P=6.93 × 10−9) for overall lung cancer and GACAT3 on 2p24.3 (0.65, 1.24 × 10−9), TRIP13 on 5p15.33 (3.49, 1.00 × 10−8), ERC1 on 12p13.33 (4.64, 6.08 × 10−9), LMAN1L (near CYP1A1) on 15q24.1 (4.25, 8.71 × 10−9) for lung squamous cell cancer were identified at a genome-wide significance level. Our GWAS of lung cancer identified five novel genetic susceptibility associations and confirmed several variants on 15q25 and 19q13. Further works are required to elucidate the possible biological mechanisms underlying these associations among lung cancer and histological subtypes in African Americans. Citation Format: Jinyoung Byun, Younghun Han, Xiangjun Xiao, Christine Lusk, Hoda J. Badr, Rayjean Hung, Ann G. Schwartz, Christopher I. Amos, INTEGRAL Consortium. Genome-wide association study of African Americans reveals new susceptibility loci contributing to lung cancer and mechanisms of population-specific etiology. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5218.

Announcement of the 2022 winners of the Spychala and Women in Science Awards

Announcement of the 2022 winners of the Spychala and Women in Science Awards

Abstract 1265: The effects of ancestry and histology on the lung tumor methylome

Abstract Methylation-based biomarkers can provide molecular insight on the contribution of ancestry and histology to lung tumor biology. Loss of global methylation is a benchmark of aging and a signal of declining biological maintenance. In addition to aging, global loss of methylation occurs in response to some cancer-promoting exposures, including tobacco use. Reduced levels of global DNA methylation are associated with increased risk of several cancers, including lung. In lung tumors, global DNA hypomethylation is often associated with a more aggressive diseases and shorter survival time. Several studies have identified population-level differences in global methylation present at birth. Additionally, gender and ancestry influence DNA methylation age (DNAm) and may predispose some individuals to accelerated aging. We hypothesized that differences in global hypomethylation and accelerated aging may contribute to differences in lung tumor biology by genetic ancestry. Therefore, we investigated methylome differences between European Americans (EA) and African Americans (AA) from the NCI-Maryland Case Control Study, which is overrepresented with AA patients (~40%) from the Baltimore area. We assessed lung tumor and paired non-involved adjacent tissue (NAT) methylation (n = 77 EA, n = 39 AA) using the Illumina EPIC methylation array. We used the Repetitive Element Methylation Prediction (REMP) package in R to identify roughly 20,000 predicted LINE-1 CpG's. We observed significantly decreased LINE-1 methylation in tumor tissue compared with NAT in both AA and EA. Additionally, among tumor samples we observed significantly decreased LINE-1 methylation in AA LUSC samples compared to EA LUSC, with only modest differences between AA LUAD and EA LUAD. In addition to decreased levels, LINE-1 methylation in AA LUSC tumors also had the greatest heterogeneity within CpG's of the same sample and between other AA LUSC samples. We observed accelerated aging (increased DNAm relative to chronological age) in 57/67 EA NAT samples and 28/38 AA NAT samples with no significant differences in age acceleration between ancestry or histology. Our results show global hypomethylation of LINE-1 is a distinctive feature of LUSC in AA compared to EA, which is consistent with the enhanced genomic instability observed in AA LUSC relative to EA LUSC. We also observed accelerated aging in the vast majority of the NAT samples, which may implicate accelerated age with lung cancer risk. Future analysis will work towards completing a comprehensive analysis of the epigenetic landscape of lung cancer in AA and EA patients. We plan to study the relationship between global hypomethylation and genetic variants, smoking behaviors, and patient survival. Citation Format: Emily L. Rossi, Isaac Zhao, Rony F. Arauz, Adriana Zingone, Bríd M. Ryan. The effects of ancestry and histology on the lung tumor methylome [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1265.

Lung cancer in African-Americans and analysis of estrogen plus progestin use.

e18258 Background: The 15-year Women’s Health Initiative (WHI) sponsored by the NIH has provided a robust dataset on health risks for post-menopausal black women (BW), including the impact of hormone therapy (HRT) on cancer risk. Women enrolled in the WHI randomized, placebo-controlled trial and taking HRT demonstrated no increase in lung cancer incidence, but a statistically significant increase in mortality. However, effects of estrogen plus progestin on non-small cell lung cancer (NSCLC) incidence and outcomes has not been extensively examined, especially in African Ancestry (AA) and smoking history. Methods: Study participants were identified who met WHI clinical trial entry criteria. Cox regression models and Kaplan-Meier method plots were utilized. Analyses adjusted for age, BMI, education, smoking status, alcohol use, health status, and physical activity. A secondary analysis was performed on BW based on AA via Affymetrix Human SNP Array. Results: 161, 808 pts were enrolled from October 1993 to December 1998 (after exclusions total analytic cohort = 142,503). 128,682 (90%) were white (WW) and 13,821 (10%) were BW. BW had lower incidence of NSCLC compared to WW (HR 0.68; P < .0001). HRT participants had a 55% increase in incidence of NSCLC (p < .0001). Former alcohol users had highest risk of NSCLC incidence (HR 2.72; p < 0.0001). Age groups (55-59 years; 60-69 years; 70-79 years) were significantly less associated with BW compared to the youngest(50-54 years; P < .0001). HRT participants were more likely BW (OR 1.17; p < .0001). More current smokers were BW compared to WW (OR 1.75; p < .0001). HRT participants had increased risk of death to NSCLC (HR 1.29; p < .001). There was a trend for survival (p = 0.3667) in WW participants compared to BW (32 vs 28.0 months, respectively). BW who had > 80% AA had a decreased incidence NSCLC trend compared to BW with < 80% AA (HR 0.81; p = 0.2806). Conclusions: BW, especially those with high levels of AA had decreased incidence of NSCLC. Those patients who received HRT had higher incidence and death from NSCLC. Further investigations are required to understand the mechanisms that AA and HRT alter risks associated with NSCLC.

Circulating Inflammation Proteins Associated With Lung Cancer in African Americans

IntroductionLung cancer incidence is higher among African Americans (AAs) compared with European Americans (EAs) in the United States. We and others have previously shown a relationship between immune and inflammation proteins with lung cancer in EAs. Our aim was to investigate the etiologic relationship between inflammation and lung cancer in AAs. MethodsWe adopted a two-stage, independent study design (discovery cases, n = 316; control cases, n = 509) (validation cases, n = 399; control cases, n = 400 controls) and measured 30 inflammation proteins in blood using Meso Scale Discovery V- PLEX multiplex assays. ResultsWe identified and validated 10 proteins associated with lung cancer in AAS, some that were common between EAs and AAs (C-reactive proteins [OR: 2.90; 95% confidence interval (CI): 1.99–4.22], interferon γ [OR: 1.55; 95% CI: 1.10–2.19], interleukin 6 [OR: 6.28; 95% CI: 4.10–9.63], interleukin 8 [OR: 2.76; 95% CI: 1.92–3.98]) and some that are only observed among AAs (interleukin 10 [OR: 1.69; 95% CI: 1.20–2.38], interleukin 15 [OR: 2.83; 95% CI: 1.96–4.07], interferon gamma-induced protein 10 [OR: 1.54; 95% CI: 1.09–2.18], monocyte chemotactic protein-4 [OR: 0.54; 95% CI: 0.38–0.76], macrophage inflammatory protein-1 alpha [OR: 1.57; 95% CI: 1.12–2.21], and tumor necrosis factor β [OR: 0.52; 95% CI: 0.37–0.74]). We did not find evidence that either menthol cigarette smoking or global genetic ancestry drove these population differences. ConclusionsOur results highlight a distinct inflammation profile associated with lung cancer in AAs compared with EAs. These data provide new insight into the etiology of lung cancer in AAs. Further work is needed to understand what drives this relationship with lung cancer and whether these proteins have utility in the setting of early diagnosis.

Cross-Cancer Pleiotropic Associations with Lung Cancer Risk in African Americans.

Identifying genetic variants with pleiotropic associations across multiple cancers can reveal shared biologic pathways. Prior pleiotropic studies have primarily focused on European-descent individuals. Yet population-specific genetic variation can occur, and potential pleiotropic associations among diverse racial/ethnic populations could be missed. We examined cross-cancer pleiotropic associations with lung cancer risk in African Americans. We conducted a pleiotropic analysis among 1,410 African American lung cancer cases and 2,843 controls. We examined 36,958 variants previously associated (or in linkage disequilibrium) with cancer in prior genome-wide association studies. Logistic regression analyses were conducted, adjusting for age, sex, global ancestry, study site, and smoking status. We identified three novel genomic regions significantly associated (FDR-corrected P <0.10) with lung cancer risk (rs336958 on 5q14.3, rs7186207 on 16q22.2, and rs11658063 on 17q12). On chromosome16q22.2, rs7186207 was significantly associated with reduced risk [OR = 0.43; 95% confidence interval (CI), 0.73-0.89], and functional annotation using GTEx showed rs7186207 modifies DHODH gene expression. The minor allele at rs336958 on 5q14.3 was associated with increased lung cancer risk (OR = 1.47; 95% CI, 1.22-1.78), whereas the minor allele at rs11658063 on 17q12 was associated with reduced risk (OR = 0.80; 95% CI, 0.72-0.90). We identified novel associations on chromosomes 5q14.3, 16q22.2, and 17q12, which contain HNF1B, DHODH, and HAPLN1 genes, respectively. SNPs within these regions have been previously associated with multiple cancers. This is the first study to examine cross-cancer pleiotropic associations for lung cancer in African Americans. Our findings demonstrate novel cross-cancer pleiotropic associations with lung cancer risk in African Americans.

Abstract 4658: Inflammatory based diagnostic markers of lung cancer in African Americans

Abstract African Americans have a higher risk of developing lung cancer compared with all other ethnic groups in the USA. Previous studies based on a small panel of markers suggested that certain circulating cytokines were associated with lung cancer. Given the complexity of the immune response in lung cancer and the multitude of cell types involved, we reasoned that examining a broad panel of inflammatory markers—including cytokines, chemokines, angiogenic and other pro-inflammatory factors—might identify a diagnostic signature of lung cancer for African American patients. Differences in 30 inflammatory marker serum levels were measured in 316 African-American cases and 508 African American controls from the National Cancer Institute-Maryland (NCI-MD) case-control study using a Mesoscale (MSD) multiplex platform. The panel of 30 serum inflammatory markers included chemokines, cytokines and other inflammatory related proteins. Logistic regression analyses were conducted to investigate the association between levels of inflammatory marker expression and lung cancer risk. Expression levels above the median threshold defined within the control samples were considered high. Statistical models were also adjusted for potential confounding factors such as age, gender, pack-years and smoking status. Nineteen inflammatory markers (CRP, IFN-ϒ, IL-10, IL-15, IL-17A, IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-7, IL-8, IP-10, MCP-4, MIP-1α, TARC, TNF-α, TNF-β and VEGF) were significantly different among African American cases compared with African American controls (P&amp;lt;0.05). In agreement with our previous observations, levels of IL-10, IL-1β, IL-6, IL-8, and TNF-α were associated with lung cancer risk. In addition, we found that CRP, IFN-ϒ, IL-15, IL-7, IP-10, MCP-4, MIP-1 α, TARC, TNF-β and VEGF were associated with lung cancer in African Americans. The associations between CRP, IFN-ϒ, IL-10, IL-15, IL-1β, IL-5, IL-6, IL-7, IL-8, IP-10, MCP-4, MDC, MIP-1α, TNF-α and TNF-β levels and lung cancer among African Americans was significant after adjustment for additional potential confounding factors. Serum cytokine levels vary by race and might contribute to lung cancer differently in African Americans and European Americans. The findings presented here build upon recent work that identified associations between elevated levels of IL-10, IL-1β, IL-6, IL-8, TNF-α and lung cancer specifically among African Americans. By analyzing a broader spectrum of inflammatory measures, we have identified additional markers of lung cancer for African American patients. Further to this, we have integrated GWAS and MSD data for 137 cases and 203 controls that allows us to examine the genetic basis to the relationship between risk of lung cancer and modulated inflammatory marker expression. Markers identified here as significant for lung cancer risk will be further analyzed using case-control samples from an independent African American validation cohort. Citation Format: Claire L. Meaney, Khadijah A. Mitchell, Adriana Zingone, Derek Brown, Wei Tang, Yunkai Yu, Liang Cao, Angela S. Wenzlaff, Ann G. Schwartz, Brid M. Ryan. Inflammatory based diagnostic markers of lung cancer in African Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4658. doi:10.1158/1538-7445.AM2017-4658

Abstract B60: Inflammatory-based diagnostic markers of lung cancer in African Americans

Abstract Background: African Americans have a higher risk of developing lung cancer compared with all other ethnic groups in the USA. Previous studies based on a small panel of markers suggested that certain circulating cytokines were associated with lung cancer. Given the complexity of the immune response in lung cancer and the multitude of cell types involved, we reasoned that examining a broad panel of inflammatory markers — including cytokines, chemokines, angiogenic and other pro-inflammatory factors — might identify a diagnostic signature of lung cancer for African American patients. Methods: Differences in 30 inflammatory marker serum levels, were measured in 308 African-American cases and 501 African American controls from the National Cancer Institute-Maryland (NCI-MD) case-control study using a Mesoscale multiplex platform (MSD). The panel of 30 serum inflammatory markers, included chemokines, cytokines and other inflammatory related proteins (Mesoscale VPLEX assay). Associations of the serum cytokine levels with lung cancer were analyzed using Stata statistical software (StataCorp, TX) Results: Fifteen inflammatory markers (CRP, IFN-gamma, IL-10, IL-15, IL-17A, IL-1beta, IL-6, IL-7, IL-8, IP-10, MCP-4, MIP-1alpha, TARC, TNF-alpha and VEGF) were significantly different among African American cases compared with African American controls. In agreement with our previous observations, levels of IL-10, IL-1beta, IL-6, IL-8, and TNF-alpha were associated with lung cancer risk. In addition, we found that CRP, IFN-gamma, IL-15, IL-7, IP-10, MCP-4, MIP-1alpha, TARC, and VEGF were associated with lung cancer in African Americans. The associations between CRP, IFN-gamma, IL-10, IL-15, IL-1beta, IL-6, IL-7, IL-8, IP-10 and MCP-4 levels and lung cancer among African Americans were significant after adjustment for additional potential confounding factors. Conclusions: Serum cytokine levels vary by race and might contribute to lung cancer differently between African Americans and European Americans. The findings presented here build upon recent work that identified associations between elevated levels of IL-10, IL-1beta, IL-6, IL-8, TNF-alpha and lung cancer among African Americans. Furthermore, by analyzing a broader spectrum of inflammation, we have identified additional markers of lung cancer for African American patients. Citation Format: Claire L. Meaney, Khadijah A. Mitchell, Adriana Zingone, Derek Brown, Wei Tang, Yunkai Yu, Liang Cao, Brid M. Ryan. Inflammatory-based diagnostic markers of lung cancer in African Americans. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B60.

Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population

ObjectivesGenome-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 methodsWe genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p<1.51×10−5) in an independent set of 866 cases and 796 controls in stage 2. Results and conclusionIn 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.

Abstract IA02: Genetic, environmental, and biological contributions to racial disparities in lung cancer incidence

Abstract Lung cancer is the leading cause of cancer-related deaths in the United States (1). In addition, there are significant disparities in lung cancer across populations. Compared with European Americans, African Americans are disproportionally affected by lung cancer, both in terms of incidence and survival (2,3). Lung adenocarcinoma among African Americans is 1.30 (1.10 - 1.90) times higher compared with European Americans; squamous cell carcinoma 1.80 (95% C.I. 1.1 - 2.3) times higher (4). There are also differences in lung cancer outcomes between European Americans and African Americans (2,5), some of which may be due to differences in cell biology between these two populations. However, studies have generally shown that differences in access to care may explain most of the variance in survival times (5-7). In addition, the gains in survival over the past 20 years among lung cancer patients have been similar in both European Americans and African Americans. Thus, the causal factors – genetic, environmental or otherwise – that lead to a greater incidence of lung cancer in African Americans are largely unknown. Smoking is the strongest risk factor for lung cancer development. However, several studies suggest that smoking prevalence and behaviors do not fully explain the disparity in lung cancer incidence. For example, African Americans have a lower smoking prevalence than European Americans and only 5.8% of African Americans are heavy smokers, compared with 19.2% of European Americans (8). In fact, when one compares smoking rates across ethnic groups matched for equal levels of smoking, African Americans still experience a higher burden of lung cancer incidence (8) - although this is attenuated with higher numbers of cigarettes smoked per day. This has led some to suggest that African Americans are more susceptible to the carcinogenic effects of tobacco at lower doses. However, this has not been empirically tested. It is possible that there are differences in nicotine and tobacco carcinogen metabolism between European Americans and European Americans that could account for the differences in cancer incidence between. On average, 72% of nicotine is converted to cotinine, the primary proximate metabolite of nicotine (9). Racial and ethnic differences in urinary (10,11) and blood cotinine (11-13) concentration per cigarette smoked have been well established. In addition, studies have found that levels of NNK metabolites (11,14) and thiocyanate (11) are higher in African Americans compared with European Americans. However, no clear genes or pathways have yet been identified that explain the disparity. And, given the strong relationship between smoking and lung cancer, it is hard to completely discount smoking as a cause of incidence disparities (8). Other risk factors to explain higher lung cancer incidence among African Americans include genetics, SES, smoking, BMI, and/or alcohol consumption. Recent studies show that the same loci associated with risk of lung cancer in European American smokers, i.e., chr15q25, are also associated with lung cancer in African Americans (15-18). Disparities in lung cancer incidence could be driven by the environment. For example, a recent study found that African Americans were more likely to reside in areas with the highest levels of air toxin exposure (19). Studies of breast and prostate cancer (20,21) have shown that whatever the cause of cancer health disparities, the consequences of these disparities manifest themselves as differences in the molecular and cell biology of the cancer. In lung cancer, we have explored the biological differences between lung cancer in European Americans and African Americans. These studies show that while some of the perturbed pathways in lung cancer remain the same for European Americans and African Americans, there are specific differences distinct to African Americans. Continued research efforts in the field are needed to determine the contribution of smoking, and indeed other factors, to lung cancer disparities. This work needs to be complemented with research that dissects the consequences of these disparities and the translation of these discoveries into improved patient care.

Abstract B30: Lung cancer in African Americans is characterized by histone modifying enzyme gene signatures

Abstract Lung cancer is the second most common cancer in the US and the leading cause of cancer-related death. African Americans (AA) have the highest lung cancer incidence rates compared with any other population in the country. Smoking is the strongest risk factor for lung cancer development; however research to date does not fully explain the disparities in incidence. For example, the prevalence of both smoking and heavy smoking is lower among AA. In addition, although most AA choose menthol cigarettes, a recent study has shown there is no increased risk of lung cancer among menthol cigarette smokers compared with non-menthol cigarette smokers. Furthermore, a large study of never smokers demonstrated that AA still had a higher incidence of lung cancer and when matched for number of cigarettes smoked per day, AA still have a higher lung cancer incidence. Combined, these data suggest that smoking behavior alone does not account for the lung cancer disparities observed among AA. While the different causes of lung cancer across ethnic groups have not been resolved, few studies have examined whether there are differences in the tumor biology between AA and European American (EA) patients. Indeed, numerous cancer disparities studies in other organ types report clear differences in tumor biology between AA and EA patients. For example, immune response gene signatures can accurately differentiate between AA and EA prostate cancers, and AA breast tumors are more likely to lack hormone receptors linked with high survival than EA women. To date, few studies have investigated molecular differences between lung cancer in AA and EA patients. We hypothesized AA and EA lung cancers have different tumor biology, and that these differences can both inform disease etiology and be leveraged for translational means. Using the NCI-MD case control study, we profiled the coding transcriptome of 66 matched lung tumor and normal tissues (n = 33 AA, n = 33 EA) and performed subsequent Gene Set Enrichment Analysis (GSEA) and Connectivity Mapping (CM). Here we demonstrated that AA lung tumors have distinct molecular phenotypes when compared with EA. Approximately 1,000 genes were differentially expressed between cancer and normal tissue in AA tumors only. Genes specifically upregulated in prostate and breast tumors from AA compared with EA were also upregulated in lung tumors from AA, suggesting some common differences in tumor biology by race. However, GSEA revealed novel differences also: histone modifying enzyme signatures were positively enriched in lung tumors from AA and inversely enriched in EA. Furthermore, CM strongly suggested that lung tumors from AA and EA would have varying sensitivities to histone deacetylase inhibitors (HDACi). Treatment of population-specific cell lines confirmed these CM predictions. HDACs were also found to be differentially regulated in AA tumors, suggesting a mechanistic basis for differential responses to HDACi treatment. We also conducted non-coding transcriptome profiling of 199 individuals (n = 86 AA, n = 113 EA). We found that there were 23 differentially expressed microRNAs in lung cancer tissues from AA. Moreover, using a hypergeometric test we observed that differential expression of miRNAs within lung cancer from AA and EA does not drive differences in the observed gene expression signatures. Understanding the biological factors that contribute to cancer health disparities and exploring the causes and consequences of such can help to reduce or limit the outcomes of these disparities. To our knowledge, this study is the first to profile the coding and non-coding landscape of lung cancer in AA and provides the first evidence that HDAC tumor biology differs in lung cancers from AA and EA. This may allow for more precise molecular targeting for responsive patients and improve cancer outcomes. Citation Format: Khadijah A. Mitchell, Adriana Zingone, Brid Ryan. Lung cancer in African Americans is characterized by histone modifying enzyme gene signatures. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B30.

Abstract IA03: Lung cancer risk in African Americans: Familial aggregation and genetic susceptibility

Abstract IA03: Lung cancer risk in African Americans: Familial aggregation and genetic susceptibility

Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans

BackgroundGenome-wide association studies have identified polymorphisms linked to both smoking exposure and risk of lung cancer. The degree to which lung cancer risk is driven by increased smoking, genetics, or gene–environment interactions is not well understood. MethodsWe analyzed associations between 28 single nucleotide polymorphisms (SNPs) previously associated with smoking quantity and lung cancer in 7156 African-American females in the Women's Health Initiative (WHI), then analyzed main effects of top nominally significant SNPs and interactions between SNPs, cigarettes per day (CPD) and pack-years for lung cancer in an independent, multi-center case–control study of African-American females and males (1078 lung cancer cases and 822 controls). FindingsNine nominally significant SNPs for CPD in WHI were associated with incident lung cancer (corrected p-values from 0.027 to 6.09×10−5). CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527[A](betaSNP*CPD=−0.017, p=0.0061, corrected p=0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans. InterpretationThese results suggest that chromosome 15q25.1 variants are robustly associated with CPD and lung cancer in African-Americans and that the allelic dose effect of these polymorphisms on lung cancer risk is most pronounced in lighter smokers.

Somatic Mutation Spectrum of Non–Small-Cell Lung Cancer in African Americans: A Pooled Analysis

The mutational profile of non-small-cell lung cancer (NSCLC) has become an important tool in tailoring therapy to patients, with clear differences according to the population of origin. African Americans (AAs) have higher lung cancer incidence and mortality than Caucasians, yet discrepant results have been reported regarding the frequency of somatic driver mutations. We hypothesized that NSCLC has a distinct mutational profile in this group. We collected NSCLC samples resected from self-reported AAs in five sites from Tennessee, Michigan, and Ohio. Gene mutations were assessed by either SNaPshot or next generation sequencing, and ALK translocations were evaluated by fluorescence in situ hybridization. Two hundred sixty patients were included, mostly males (62.3%) and smokers (86.6%). Eighty-one samples (31.2%) were squamous cell carcinomas. The most frequently mutated genes were KRAS (15.4%), epidermal growth factor receptor (EGFR, 5.0%), PIK3CA (0.8%), BRAF, NRAS, ERBB2, and AKT1 (0.4% each). ALK translocations were detected in two nonsquamous tumors (1.7%), totaling 61 cases (23.5%) with driver oncogenic alterations. Among 179 nonsquamous samples, 54 (30.2%) presented a driver alteration. The frequency of driver alterations altogether was lower than that reported in Caucasians, whereas no difference was detected in either EGFR or KRAS mutations. Overall survival was longer among patients with EGFR mutations. We demonstrated that NSCLC from AAs has a different pattern of somatic driver mutations than from Caucasians. The majority of driver alterations in this group are yet to be described, which will require more comprehensive panels and assessment of noncanonical alterations.

Genomic Characterization of Non-Small-Cell Lung Cancer in African Americans by Targeted Massively Parallel Sequencing.

Technologic advances have enabled the comprehensive analysis of genetic perturbations in non-small-cell lung cancer (NSCLC); however, African Americans have often been underrepresented in these studies. This ethnic group has higher lung cancer incidence and mortality rates, and some studies have suggested a lower incidence of epidermal growth factor receptor mutations. Herein, we report the most in-depth molecular profile of NSCLC in African Americans to date. A custom panel was designed to cover the coding regions of 81 NSCLC-related genes and 40 ancestry-informative markers. Clinical samples were sequenced on a massively parallel sequencing instrument, and anaplastic lymphoma kinase translocation was evaluated by fluorescent in situ hybridization. The study cohort included 99 patients (61% males, 94% smokers) comprising 31 squamous and 68 nonsquamous cell carcinomas. We detected 227 nonsilent variants in the coding sequence, including 24 samples with nonoverlapping, classic driver alterations. The frequency of driver mutations was not significantly different from that of whites, and no association was found between genetic ancestry and the presence of somatic mutations. Copy number alteration analysis disclosed distinguishable amplifications in the 3q chromosome arm in squamous cell carcinomas and pointed toward a handful of targetable alterations. We also found frequent SMARCA4 mutations and protein loss, mostly in driver-negative tumors. Our data suggest that African American ancestry may not be significantly different from European/white background for the presence of somatic driver mutations in NSCLC. Furthermore, we demonstrated that using a comprehensive genotyping approach could identify numerous targetable alterations, with potential impact on therapeutic decisions.

Perspectives of African Americans on lung cancer: a qualitative analysis.

Disparities in incidence and mortality for lung cancer in African Americans are well documented; however, the extent to which disparities reflect differences in patient perceptions of tobacco and lung cancer treatment is unclear. The objective of this study was to explore African Americans' knowledge of lung cancer, perceived risk, interest in smoking cessation, attitudes toward lung cancer treatment, and lung cancer diagnosis and treatment experiences. The cohort comprised 32 African-American current and former smokers without a cancer diagnosis who participated in focus groups and 10 African Americans with lung cancer who participated in in-depth interviews. Transcripts were analyzed using a modified grounded theory approach. Participants without a cancer diagnosis were aware of the link between smoking and lung cancer, the common symptoms of the disease, and its poor prognosis. They desired specific, personalized smoking-cessation information. If diagnosed, the majority reported, they would seek medical care. Most believed that insurance and socioeconomic factors were more likely to affect treatment access than racial discrimination. Participants with a cancer diagnosis were also aware of the relationship between smoking and lung cancer. They felt their treatment plans were appropriate and trusted their physicians. Most did not believe that race affected their care. This qualitative study suggests that African-American smokers are aware of the relationship between smoking and lung cancer and are interested in smoking-cessation treatment. These data also indicate that lung cancer disparities are unlikely to be associated with differential willingness to receive care but that African Americans may perceive financial and insurance barriers to lung cancer treatment.

Genomic Characterization of Non-Small Cell Lung Cancer in African Americans by Targeted Massively Parallel Sequencing: Translational Research

Genomic Characterization of Non-Small Cell Lung Cancer in African Americans by Targeted Massively Parallel Sequencing: Translational Research

Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 Regions Identifies Functional and Histology-Specific Lung Cancer Susceptibility Loci in African-Americans

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. 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. 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)). 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. Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies.