Background: Lung cancer remains the leading cause of cancer-related death in the United States. Across all racial demographics, African Americans (AAs) have the highest lung cancer mortality. Studies have shown distinct DNA methylation patterns in AAs with cancer, highlighting a potential biological factor that influences disproportionate lung cancer mortality rates. AA-specific hypermethylation has been identified in many cancer types including prostate, bladder, and head and neck cancers. Active DNA demethylation pathways, like those involving the TET or APOBEC family of proteins, may play a role in the dysregulation of DNA methylation. Additionally, West African Ancestry (WAA) is a biological determinant that has been associated with survival and aggressive tumor biology.

Hypothesis: Active DNA demethylation varies between lung cancer patients with high and low WAA.

Methods: Using cBioPortal, clinical, demographic, and Illumina mRNA-sequencing data for active DNA demethylation enzymes were downloaded. STRUCTURE data for global genetic ancestry were downloaded from The Cancer Genetic Ancestry Atlas (TCGAA) and merged with other data. Differential gene expression analyses were performed in patients with high (>70%, n = 58)  and low (<70%, n = 636) WAA across two common lung cancer subtypes. 

Results: Patients with >70% WAA had lower mRNA expression of APOBEC3C in the LUAD subtype and APOBEC3H and APOBEC1 in the LUSC subtype. 

Conclusion: Lung cancer patients with high WAA had significantly less expression of three genes implicated in the active DNA demethylation pathway. These differences may be responsible for some variation in tumor biology between African Americans and European Americans. Additionally, APOBEC expression may be used to categorize patients and serve as new therapeutic targets.

Future Direction: Explore the functional relationship between WAA and active DNA demethylation pathway inhibition in lung cancer cell lines with high and low WAA.