NIH-led study reveals role of mobile DNA elements in lung cancer progression
Research news (Dec 10, 2025): An NIH-led whole-genome sequencing analysis of >1,000 lung cancers, including 542 lung adenocarcinomas, linked an aggressive tumor subgroup enriched for the ID2 mutational signature (single base-pair deletion) to reactivation of LINE-1 (L1) mobile DNA elements. The authors suggest L1 reactivation could contribute to rapid tumor evolution. The study also associated KRAS-mutant tumors with rapid clonal evolution and EGFR-mutant tumors with greater subclonal architecture and a more prolonged evolutionary course.
NIH-led genomics study implicates LINE-1 reactivation in aggressive lung adenocarcinoma (research news)
An international team led by NIH/NCI researchers reported a potential mechanism underlying a subset of aggressive lung adenocarcinomas, based on whole-genome sequencing (WGS) data from the Sherlock-Lung study.
In a WGS analysis of >1,000 lung cancer cases, investigators focused on 542 lung adenocarcinomas with diverse clonal architectures. They identified a group of aggressive tumors enriched for the ID2 mutational signature, described as a single base-pair deletion. The authors report this signature was unexpectedly associated with reactivation of LINE-1 (L1), an ancient mobile DNA element normally silenced in healthy cells. They propose that L1 reactivation could help explain the rapid evolution and aggressiveness observed in this subgroup.
The study also linked major driver alterations to differing evolutionary patterns: KRAS-mutant tumors (reported as more frequent in smokers) showed signs of rapid clonal evolution, whereas tumors enriched for EGFR mutations (more common in never-smokers) exhibited more subclonal architecture, consistent with a more prolonged evolutionary course.
Source: Zhang T, et al. Nature. 2025. DOI: 10.1038/s41586-025-09825-y.