Abstract Overexpression of LINE-1 (L1) elements is recognized as a hallmark of many cancers, yet their activity and the number of somatic LINE-1 retrotranspositions (soL1Rs) vary markedly across tumor types. Despite their ubiquity in certain cancers, such as esophageal and colorectal carcinomas, the biological significance of transposable elements in cancer development remains underappreciated. To elucidate the contribution of L1 activity to oncogenesis, we analyzed whole-genome sequencing (WGS) data from 8,000 tumor-normal pairs in The Cancer Genome Atlas (TCGA). In total, we identified over 132,000 soL1R events, with their distribution differing widely across cancer types. The highest soL1R burdens were observed in esophageal carcinoma (ESCA, 134.2 events per case), bladder carcinoma (BLCA, 74.0), head and neck squamous cell carcinoma (HNSC, 56.3), lung squamous cell carcinoma (LUSC, 53.3), colon adenocarcinoma (COAD, 29.7), and rectal adenocarcinoma (READ, 16.8). The number of transductions correlated strongly with the overall soL1R burden in each cohort. Activity of germline LINE-1 source elements, inferred from transduction counts, identified 22q12.1-2 as the most active locus, followed by Xp22.2-2, 5q14.3-2, and 14q23.1. Using L1 transduction events, we further discovered 12 previously unreported germline LINE-1 source loci. Functional analysis revealed that soL1R events contribute to oncogenesis through both direct disruption of tumor suppressor genes and complex genomic rearrangements mediated by retrotransposition. In summary, this population-scale WGS analysis delineates the pan-cancer landscape of somatic LINE-1 retrotranspositions, uncovers novel germline source elements, and highlights the multifaceted role of soL1R activity in cancer genome evolution. Citation Format: Beomki Lee, Ryul Kim, Chunyang Bao, Hansol Park, Gang-Hee Lee, Jonghoon Lee, Yoonsuh Lee, Won-Chul Lee, David Lehotzky, Ron Solan, Antonia Kowalewski, Xavi Loinaz, Vasuki Narasimha Swamy, David I. Heiman, Samantha Van Seters, Saveliy Belkin, Sam Wiseman, Andrew D. Cherniack, Luis Antonio Corchete Sanchez, Brian P. Danysh, Zachary Everton, Chip Stewart, Haruna Tomono, Gengchao Wang, Esther Rheinbay, Gad Getz, Cheng-Zhong Zhang, Young Seok Ju. Pan-cancer LINE-1 retrotransposition landscapes in TCGA whole-genome sequences 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 1980.
Lee et al. (Fri,) studied this question.