Pan-cancer multi-omic model of LINE-1 activity reveals locus heterogeneity of retrotransposition efficiency

• DOI: 10.1038/s41467-025-57271-1
• Publication Date: 2025-02-28T10:26:30Z
• Authors: Alexander Solovyov; Julie M. Behr; David Hoyos; Eric Banks; Alexander W. Drong; Bryan Thornlow; Jimmy Z. Zhong; Enrique Garcia-Ri...; Wilson McKerrow; Chong Chu; Cedric Arisdakessian; Dennis M. Zaller; Junne Kamihara; Liyang Diao; Menachem Fromer; Benjamin D. Green...
• Keywords: Retrotransposon

Abstract Somatic mobilization of LINE-1 (L1) has been implicated in cancer etiology. We analyzed a recent TCGA data release comprised nearly 5000 pan-cancer paired tumor-normal whole-genome sequencing (WGS) samples and ~9000 tumor RNA samples. developed TotalReCall an improved algorithm pipeline for detection L1 retrotransposition (RT), finding high correlation between expression “RT burden” per sample. Furthermore, we mathematically model the dual regulatory roles p53, where mutations TP53 disrupt regulation both retrotransposition. found those with Li-Fraumeni Syndrome (LFS) heritable pathogenic likely variants bear similarly activity compared to matched cancers from patients without LFS, suggesting this population be considered attempts target therapeutically. Due sensitivity, detect over 10 genes beyond whose correlate L1, including ATRX , other, potentially targetable, mechanisms underlying remain discovered.