Abstract Lung cancer is the leading cause of cancer death worldwide in both men and women. It is a highly heterogeneous disease primarily driven by tobacco smoking. About 20% of lung cancers occur among never smokers. There are major differences between lung cancers in patients who have never smoked (LCINS) and who have smoked in patient ancestry, sex, tumor histology and clinical features. LCINS occur more frequently in Asians and females and are predominantly adenocarcinomas. EGFR mutations are enriched in LCINS, whereas KRAS and TP53 mutations are more common in tumors from patients who have smoked. Our understanding of the etiology of LCINS is still limited. Here, we perform a comprehensive study in 1,209 whole-genome sequenced lung cancers collected from 30 different locations across four continents through Sherlock-Lung Project as well as published studies. Among these tumors, 1024 of them are adenocarcinomas and 864 are LCINS. This cohort represents the largest genomics cohort in lung cancer to date. Our study focuses on somatic structural variations (SVs) which are large-scale chromosomal rearrangements. In total, we detect 182,429 somatic SVs in 1209 tumor samples with an average of 151 SVs per sample. Complex SVs, such as chromothripsis, are studied separately from simple SVs because they arise through one-time catastrophic chromosome shattering and rejoining. About two-thirds of the SVs in our cohort are part of complex events. We deconvolute a total of 8 complex SV signatures based on event topology and 8 simple SV signatures using non-negative matrix factorization. They likely represent divergent molecular mechanisms. Among these, chromatin bridge signature, driven by dicentric chromosomes, is the most abundant complex SVs; and median size deletion is the most common simple SVs. SVs are more abundant in tumors from patients who have smoked; however, they are more complex and play more important roles in tumorigenesis in LCINS. The SV breakpoints have distinct distributions across the genome depending on the signatures due to combined effects of mutagenesis and positive selection. Many established cancer-driving genes are recurrently rearranged by multiple SV signatures suggesting functional convergence of these genome instability mechanisms. EGFR mutations and KRAS mutations profoundly and independently shape the SV landscape. EGFR mutant tumors have higher SV burden and more cancer-driving SVs. In contrast, KRAS mutations are associated with lower SV burden and fewer driver SVs. Our study has deepened our understanding of genomic landscape and etiology of lung cancer. Citation Format: YANG YANG, Tongwu Zhang, Lixing Yang, Maria Teresa Landi. Panorama of chromosomal instability in 1209 lung cancer genomes abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5937.
Yang et al. (Fri,) studied this question.