Abstract B30: Lung cancer in African Americans is characterized by histone modifying enzyme gene signatures
Authors: Mitchell Khadijah A. , Zingone Adriana , Ryan Brid 
Published: May 2016

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.