Abstract A33: Race, DNA methylation, and regulation of cancer immunotherapy response genes: A comparison of non-small cell lung cancers from African Americans and European Americans

Abstract

Abstract African Americans (AA) have the highest non-small cell lung cancer incidence and lowest 5-year survival rates compared with any other population in the United States. Smoking is the strongest risk factor for lung cancer development. Paradoxically, AA smoke less than European Americans (EA). Even AA never-smokers have higher rates of lung cancer when compared with EA. This suggests other factors may contribute to lung cancer health disparities, both nonbiologic and biologic in scope. Biologic determinants are largely understudied. Recently, breakthroughs in cancer immunotherapy have revolutionized treatment paradigms. However, AA lung cancer patients may not benefit from these therapeutic advances as much as their EA counterparts if the underlying lung tumor biology differs in cancer immunotherapy response gene regulation. Previous work across cancers has shown clear immune system differences in AA compared with EA patients. Additionally, smoking is known to mediate DNA methylation. We hypothesize that population-specific differences in DNA methylation regulate cancer immunotherapy response genes. Comparative integrative genomics was performed using clinical demographic and lung tumor tissue data from TCGA (Illumina 450K methylation array, mRNA-seq). The DNA methylation status of 554 recently identified essential genes for cancer immunotherapy response was assessed in both LUAD (n=53 AA, 367 EA) and LUSC (n=48 AA, 274 EA) patients. Although many genes varied significantly by race (P value + FDR = ≤0.01) in both histologies (n=285), some gene signatures were LUAD-enriched (n=19), while others were LUSC-enriched (n=101). Significant DNA methylation decreases at a LUAD-enriched gene (SHISA4) in AA compared with EA corresponded with upregulation of this gene in 15% AA and 14% EA LUAD patients, respectively. Similarly, we observed significant decreases in DNA methylation at a LUSC-enriched gene (RAD1) in AA compared with EA, and this correlated with mRNA upregulation in 15% AA and 49% EA LUSC patients. Decreased immunotherapy response gene expression in AA suggests that targeted immunotherapy would be less effective in this population. This work is the first study to explore how DNA methylation differences between AA and EA with lung cancer may translate to differences in cancer immunotherapy drug response. Future studies include exploring other LUAD- and LUSC-enriched genes and their relationship with smoking, validating these findings in lung cancer cell lines from AA and EA, and elucidating novel biologic mechanisms for therapeutic purposes. Citation Format: Allison McHayle, Amy Boles, Lysa Diarra, Khadijah A. Mitchell. Race, DNA methylation, and regulation of cancer immunotherapy response genes: A comparison of non-small cell lung cancers from African Americans and European Americans [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A33.