Abstract
Abstract Background: Colorectal cancer (CRC) is the third most frequent cancer worldwide, and approximately a third of patients die from the disease. There is therefore an urgent need to better understand CRC biology. A particular feature in (colorectal) cancer is the activation of LINE-1 (L1) retrotransposons: DNA fragments which propagate to other places in the genome through an RNA intermediate. Per genome, about 100-150 genomic L1 copies are still retrotransposition-competent, but repressed in most somatic tissues. Their role in tumor development is currently unknown. Recently, the PCAWG consortium characterized the landscape of somatic L1 retrotranspositions in a series of primary cancers of different origin, and identified 124 recurrently active L1 source regions. However, only a limited number of these concerned CRC. Aim: This study aims to perform a comprehensive analysis of L1 activity in a large cohort of metastatic colorectal cancer. Methods: To this end, we retrieved data from the Hartwig Medical Foundation, comprising deep (106x) whole genome sequencing (WGS) data from metastatic CRC (n=745), to compare to breast (n=888) and lung cancer samples (n=640). We determined L1 activity as the number of somatic L1 insertions reported by the HMF DNA analysis pipeline and used the activity of each of the 124 L1 sources as previously reported by the PCAWG consortium. Results: 99% of mCRC samples (n=741) displayed at least 1 somatic L1 retrotransposition, with at least 10 retrotranspositions in 89% of samples. L1 retrotransposition is more prevalent in mCRC than in metastatic lung and breast cancer, in which only 40% and 20% had at least 10 retrotranspositions per sample, respectively. Each cancer type showed a unique profile of active L1 sources. We did not observe a clear preference of L1 insertions for a single genomic region. However, in CRC, the gene most frequently affected in an exon was APC (n=13), an important tumor-suppressor gene. An analysis of somatic SNVs and SVs confirmed an association of mutations in some known L1 regulators such as TP53 with increased L1 activity, whereas mutations in others showed no change in the number of somatic retrotranspositions. Conclusions: We conclude that somatic L1 retrotranspositions are highly prevalent in metastatic colorectal cancer. Presence of L1 insertions in APC suggests retrotranspositions start very early in CRC development and prompts further investigation into earlier CRC stages. Citation Format: Renske de Wit, Soufyan Lakbir, Caterina Buranelli, Gerrit A. Meijer, Sanne Abeln, Remond J. Fijneman. Comprehensive analysis of LINE-1 transposable elements in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4344.
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