Somatic repetitive element insertions Define New Biomarkers in Pan-cancer genome

Repetitive elements insertions (REIs), including tandem repeat insertions (TRIs) and transposable element insertions (TEIs), which account for over 90% of large-scale (>50 bp) somatic insertions, are known to cause diseases and serve as biomarkers for precision oncology in cancers. However, the genomic landscape of large-scale REIs has not been systematically characterized in pan-cancer, primarily due to the limitations of short-read sequencing (SRS). Here, we precisely detected somatic REIs in 325 cancer genomes spanning 12 cancer types using long-read whole-genome sequencing technology and customized algorithms. The diverse sequence patterns of somatic TRIs and the insertion mechanisms of somatic TEs were characterized across different cancer types. A total of 152 high-frequency somatic TRIs were identified. Among these, 10 TRIs demonstrated significant pan-cancer shared characteristics, including somatic TRI events located within the intron of SHROOM2 and PALMD , as well as in the distal enhancer region upstream of PTPRZ1 . The MHC class II gene cluster exhibited the highest somatic TEI abundance, affecting ∼40% tumors. Adenocarcinomas and squamous cell carcinomas exhibit differing TEI distributions and varying levels of abundance within this region. Overall, our study suggests that REIs are important but under-explored sources of markers for personalized cancer diagnosis and immunotherapy.