2025

Nummi, Päivi; Cajuso, Tatiana; Norri, Tuukka; Taira, Aurora; Kuisma, Heli; Välimäki, Niko; Lepistö, Anna; Renkonen-Sinisalo, Laura; Koskensalo, Selja; Seppälä, Toni T.; Ristimäki, Ari; Tahkola, Kyösti; Mattila, Anne; Böhm, Jan; Mecklin, Jukka-Pekka; Siili, Emma; Pasanen, Annukka; Heikinheimo, Oskari; Bützow, Ralf; Karhu, Auli; Burns, Kathleen H.; Palin, Kimmo; Aaltonen, Lauri A.

Background Transposons are DNA sequences able to move or copy themselves to other genomic locations leading to insertional mutagenesis. Although transposon-derived sequences account for half of the human genome, most elements are no longer transposition competent. Moreover, transposons are normally repressed through epigenetic silencing in healthy adult tissues but become derepressed in several human cancers, with high activity detected in colorectal cancer. Their impact on non-malignant and malignant tissue as well as the differences between somatic and germline retrotransposition remain poorly understood. With new sequencing technologies, including long read sequencing, we can access intricacies of retrotransposition, such as insertion sequence details and nested repeats, that have been previously challenging to characterize. Results In this study, we investigate somatic and germline retrotransposition by analyzing long read sequencing from 56 colorectal cancers and 112 uterine leiomyomas. We identified 1495 somatic insertions in colorectal samples, while striking lack of insertions was detected in uterine leiomyomas. Our findings highlight differences between somatic and germline events, such as transposon type distribution, insertion length, and target site preference. Leveraging long-read sequencing, we provide an in-depth analysis of the twin-priming phenomenon, detecting it across transposable element types that remain active in humans, including Alus. Additionally, we detect an abundance of germline transposons in repetitive DNA, along with a relationship between replication timing and insertion target site. Conclusions Our study reveals a stark contrast in somatic transposon activity between colorectal cancers and uterine leiomyomas, and highlights differences between somatic and germline transposition. This suggests potentially different conditions in malignant and non-malignant tissues, as well as in germline and somatic tissues, which could be involved in the transposition process. Long-read sequencing provided important insights into transposon behavior, allowing detailed examination of structural features such as twin priming and nested elements.