Abstract 1056: Exploring the impact of ancestry on metabolic dysregulation in lung adenocarcinoma: Implications for racial health inequities and targeted therapeutics

Abstract Introduction. The occurrence of lung adenocarcinoma (LUAD) is approximately 68.3 per capita for Black men and 61.5 per capita for White men, reflecting an 11% higher rate in the former. Black patients experience a poorer prognosis and significantly higher mortality rates compared to their White counterparts. Purpose. Understanding the genetic and molecular foundations that underly racial health inequities is essential for developing comprehensive interventions and advancing more precise therapeutic modalities for diverse patient populations. Single Nucleotide Polymorphisms (SNPs) can influence oncogenic transformation and may be associated with distinct molecular landscapes in tumors and adjacent TME. Furthermore, ancestry may play a pivotal role in shaping individual susceptibility and risk for mitochondrial dysfunction and ensuing oncogenic transformation. Methods. We employed germline VCFs for ancestry analysis of 36 LUAD patients (18 Black and 18 White) from the ORIEN data set, while genotype data from the 1000 Genomes Project phase 3, grouped by super population served as reference. Oncoplots were generated using a combination of patients’ somatic VCF and metadata from ORIEN. Regression analysis adjusting for age, staging, and gender was performed to determine association between ancestry and gene mutations. Global admixture was estimated using STRUCTURE v2.3.4 with k=5, NUMREPS=2000, and BURNIN=50000. VCFs were subset and merged by 1126 ancestry-informative markers (AIMs) and converted to STRUCTURE format with PLINK. PCA was conducted using R. Local ancestry analysis was performed with LAMP-LD v1.3 using a window length of 50 SNPs and 20 states, based on 20, 803 SNPs. Results were visualized with ggplot2 in R. Results. In Black patients, admixture analysis showed predominant AFR genetic similarity with varying proportions of EUR, AMR and SAS similarity. Local ancestry analysis using LAMPLD reveals admixture across different regions of the genome illustrating the variation in ancestral contributions within and between individuals of the same cohort and compared to counterparts in other populations. Mutations in ACADVL, HK2, SREBF1, COX6L, BID, POLG2, SLC2A2, SLC22A5, and ACKR1 are associated with AFR status >/= 0.5. Mutations in ACADSB, HK3, PPARGC1A are associated with AFR status < 0.5. Conclusions. Mutations in metabolic and mitochondrial genes emerged as being highly enriched in LUAD patients with high relative to low African genetic ancestry, suggesting opportunities for improved risk-prediction and therapeutic targeting in this subpopulation. Citation Format: Benecia A. Jackson, Yuxin Jin, Yonatan Amzaleg, Angel Perez Hunt, Nikita Jinna, Dan Raz, Loretta Erhunmwunsee, John Carpten, Aaron Neely. Exploring the impact of ancestry on metabolic dysregulation in lung adenocarcinoma: Implications for racial health inequities and targeted therapeutics [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 1056.