Abstract 1502: Hypoxia-driven genomic instability and EcDNA formation in lung cancer: insights from TRACERx

Abstract Tumors exhibit dynamic oxygen gradients, leading to hypoxia, which is linked to poor prognosis and genomic instability. The molecular features of hypoxia and their role in lung cancer outcomes remain unclear. Hypoxia has been linked to the forma on of fragile sites, resulting in chromosomal instability. Recent research has highlighted the generation of extrachromosomal DNA (EcDNA) because breaks. Genes amplified as EcDNA exist acentric circular structures capable driving rapid and significant genomic copy number amplifications. Inherent instability oncogene amplification on EcDNA provides tumor cells with a selective advantage adapting to changing environments. Thus, hypothesize that formation hypoxic tumors provide survivein unfavorable conditions like hypoxia contributes their poor prognosis. This study aims investigate impact disease outcomes formation. Furthermore, can act pressure, we examined its effects mutational burden, positive selection mutations, mutational signatures associated with hypoxia lung TRACERx cohort. TRACERx is multicenter prospective study collects samples from various regions of primary for high-depth next-generation sequencing. Analyzed bulk RNA sequencing data establish levels examine and EcDNA detection. Our preliminary findings reveal variability within between primary tumors, indicating inter- intratumoral hypoxia heterogeneity. High status correlates poorer overall disease-free survival in LUAD, but not LUSC. Additionally, presence significantly associated necrosis. Hypoxia increased circulating tumor (ctDNA) shedding (p < 0.05) and elevated whole-genome index (wgii) scores. High-hypoxia exhibit alterations, tumor suppressor b2m, increased expression immunosuppressive chemokines (cxcl8, ccl8, cxcl10). Furthermore, extrachromosomal was detected both LUAD average" hypoxia scores were -0.006 EcDNA-positive compared -0.248 EcDNA-negative samples, highlighting prevalence tumors. In conclusion, shows existence heterogeneity of hypoxia within cohort association clinical outcomes. We highlight link hypoxia, detection, the increased expression contributing a tumor microenvironment. Citation Format: Natasha Sharma, Chris Bailey, Corentin Richard, Jeanette Kittle, Charles Swanton, Mariam Jamal-Hanjani, Nnennaya Kanu. Hypoxia-driven genomic instability and EcDNA formation in lung cancer: insights from TRACERx [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 1502.