Abstract 6630: Ancestry and lung adenocarcinoma: exploring ancestry-associated variations in tumor metabolism, mitochondrial dysfunction, and immune dynamics

Lung adenocarcinoma (LUAD) is a highly heterogeneous cancer, characterized by diverse genetic mutations, metabolic reprogramming, and complex immune microenvironments. Patients of African ancestry (AFR) often experience distinct clinical outcomes in LUAD (Manojlovic Z, et al. 2017), potentially driven by unique genetic and metabolic adaptations within tumors (Telonis, Aristeidis G et al. 2024, Kap EJ, Seibold P, et al.,. 2016). Global and local ancestry analyses have shown that genetic ancestry can influence tumor behavior, including immune interactions and cellular energy metabolism (Manojlovic Z, et al., Telonis, Aristeidis G et al. 2024). However, there is limited understanding of how AFR ancestry impacts LUAD, particularly regarding tumor metabolism, mitochondrial dynamics, programmed cell death (PCD) pathways, and immune response. The immune microenvironment of LUAD tumors varies widely, and understanding how ancestry affects immune compartment composition and immune cell infiltration could offer insight into observed disparate phenotypic severity and differential responses to therapy. This study aims to uncover the ancestry-linked mutational landscape across tumor metabolism, mitochondrial dynamics, and immune recruitment in LUAD, hypothesizing that these differences may contribute to demonstrative disparities in differential LUAD malignancy severity and patient outcomes. We hypothesize that LUAD tumors in patients of AFR genetic similarity will exhibit unique mutations and transcriptional profiles in metabolic, mitochondrial, and immune-related genes, resulting in distinct metabolic programs, immune infiltration patterns, and differential activation of PCD pathways. These variations could influence tumor progression, immune evasion, and response to treatment in an ancestry-dependent manner. By combining spatial, single-cell, and genetic profiling techniques, this study aims to uncover the ancestry-associated interplay between tumor metabolism, mitochondrial dynamics, PCD, and immune compartment composition in LUAD. Insights from this work could inform ancestry-tailored therapeutic strategies and ultimately improve clinical outcomes for LUAD patients across diverse populations. Admixture analysis highlighted genetic diversity within our diverse LUAD patient cohort as Black patients illustrated predominant AFR genetic similarity with varying proportions of EUR, AMR and SAS similarity. Local ancestry analysis revealed admixture across different regions of the genome demonstrating variations in ancestral contributions within and between individuals of the same cohort and compared to counterparts in other populations. Additionally, we observed associations between high AFR genetic similarity and mutations in metabolic, immune and mitochondrial genes. Citation Format: Yuxin Jin, Yonatan Amzaleg, Angel P. Hunt, Benecia Jackson, Dan Raz, Loretta Erhunmwunsee, John Carpten, Aaron M. Neely. Ancestry and lung adenocarcinoma: exploring ancestry-associated variations in tumor metabolism, mitochondrial dysfunction, and immune dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6630.