Abstract LB226: Deciphering lung adenocarcinoma evolution and the role of LINE-1 retrotransposition

Abstract Lung cancer is the leading cause of cancer-related mortality worldwide. Understanding lung cancer evolutionary dynamics can help identify tools to intercept its growth and suggest strategies for treatment. Multiple factors can impact the tumors’ natural history and distinctly affect growth rate. However, research on the evolutionary trajectories of lung cancer across demographic or exposure scenarios remains inadequate. Additionally, the roles of mutational processes and complex genomic alterations on the evolution of lung cancer are still largely unexplored. In the largest genomic study of lung cancer to date, we analyzed deep whole-genome sequencing (~ 81x) and other omics data of 1217 lung cancers from the Sherlock-Lung study. To ensure adequate statistical power for identifying subclone architectures and constructing lung cancer evolutionary histories, we utilized a metric known as NRPCC (number of reads per tumor chromosomal copy) to select 542 lung adenocarcinoma (LUAD) samples for clonal evolution analyses, including 186 and 181 samples from never-smoker subjects of European and Asian ancestry, respectively, and 121 samples from smokers of European ancestry. We found that major driver genes and exogenous mutations contribute to tumor initiation, while copy number gains and endogenous processes appear later in tumor evolution. Tumors harboring EGFR mutations in never-smoker females of European descent show long latency, while tumors with KRAS mutations have shorter latency regardless of ancestry and sex. Notably, tumors harboring the mutational signature ID2 have short latency and aggressive phenotype, accompanied by increased genomic instability, elevated hypoxia scores, high CpG methylator phenotype, low neoantigen burden, and propensity to develop metastasis. We show that LINE-1 retrotransposition-induced mutagenesis contributes to the origin of ID2 mutations. The transcriptional factor ZNF695, a member of the KZFP family, up-regulated in LUAD, appears to contribute to LINE-1 retrotransposition through a dominant-negative effect and LINE-1 promoter demethylation. In a multivariate analysis of genomics, exposures and demographic factors, LUAD latency was most significantly associated with ID2, followed by EGFR mutations, KRAS mutations, and sex, suggesting an independent impact of these factors on LUAD evolution. Our findings underscore the complex interplay of ancestry, sex, exogenous mutagenesis, epigenetic regulation, and LINE-1 retrotransposition in shaping LUAD evolutionary trajectories, paving the way for potential targeted therapeutic interventions. Citation Format: Tongwu Zhang, Wei Zhao, Christopher Wirth, Marcos Díaz-Gay, Jinhu Yin, Phuc H. Hoang, Jian Sang, John McElderry, Alyssa Klein, Azhar Khandekar, Caleb Hartman, Jennifer Rosenbaum, Frank Colon-Matos, Kristine M. Jones, Neil E. Caporaso, Robert Homer, Angela C. Pesatori, Dario Consonni, Lixing Yang, Bin Zhu, Jianxin Shi, Kevin Brown, Nathaniel Rothman, Stephen J. Chanock, Ludmil B. Alexandrov, Jiyeon Choi, Maurizio Cardelli, Qing Lan, Martin A. Nowak, David C. Wedge, Maria Teresa Landi. Deciphering lung adenocarcinoma evolution and the role of LINE-1 retrotransposition abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB226.