Abstract C169: Investigating the effects of ancestry in KRAS mediated lung adenocarcinoma: Exploring intratumoral heterogeneity and mitochondrial dynamics

Abstract

Abstract Demonstrating a combination of high prevalence, late detection, and low survival, Lung cancer is the leading cause of cancer related deaths worldwide (Sainz de Aja J, 2021) and Lung Adenocarcinoma (LUAD) is its most prevalent pathologic subtype (Zhou, 2021). Emerging from within the distal alveolar epithelium, LUAD presents with vast heterogeneity in histology, mutational spectra, and epigenomic dysregulation (Sainz de Aja J, 2021) (Zhou, 2021). Additionally, LUAD’s considerable intratumoral heterogeneity manifests vast genomic and phenotypic diversity across tumor cells and cellular components of the tumor microenvironment (TME) within the same tumor tissue. LUAD also reveals significant racial disparities in incidence, survival and mortality rates between White and Black men in the United States. The occurrence of 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. Further, survival outcomes indicate that Black men generally exhibit lower 5-year relative survival rates compared to White men, highlighting greater mortality risk and conspicuously poorer prognosis (Siegel RL et al., 2023). While addressing the social determinants of health is vital for the mitigation of health disparities, understanding the genetic and molecular foundations that underly racial health inequities is essential for developing comprehensive interventions and advancing more precise therapeutic modalities for more 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. To elucidate the biological underpinnings of racial health disparities in LUAD, 10 Black and 10 White male LUAD patients’ tumor and normal corresponding adjacent tissues underwent molecular profiling for KRAS mutation status, Whole Exome Sequencing (WES) to determine ancestry, and analysis of associated LUAD induced Mitochondrial Somatic Nucleotide Variants (mtSNVs). We also employed the 10X Visium HD spatial transcriptomic platform to evaluate spatially resolved molecular and cellular differences in KRAS mediated LUAD between Black and White men. Hypothesis: Thus, we propose that global ancestry is associated with variations in intratumoral heterogeneity, TME composition, and mitochondrial dynamics, indicating a potential role in the observed disparities in susceptibility, malignancy and mortality in LUAD across diverse patient populations. Citation Format: Eun Kyu Sung, Yuxin Jin, Yonatan Amzaleg, John Carpten, William Dean Wallace, Dan Raz, Aaron M. Neely. Investigating the effects of ancestry in KRAS mediated lung adenocarcinoma: Exploring intratumoral heterogeneity and mitochondrial dynamics [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C169.