Abstract
Genomic instability pathways in colorectal cancer (CRC) have been extensively studied, but the role of retrotransposition in colorectal carcinogenesis remains poorly understood. Although retrotransposons are usually repressed, they become active in several human cancers, in particular those of the gastrointestinal tract. Here we characterize retrotransposon insertions in 202 colorectal tumor whole genomes and investigate their associations with molecular and clinical characteristics. We find highly variable retrotransposon activity among tumors and identify recurrent insertions in 15 known cancer genes. In approximately 1% of the cases we identify insertions in APC, likely to be tumor-initiating events. Insertions are positively associated with the CpG island methylator phenotype and the genomic fraction of allelic imbalance. Clinically, high number of insertions is independently associated with poor disease-specific survival.
Highlights
Genomic instability pathways in colorectal cancer (CRC) have been extensively studied, but the role of retrotransposition in colorectal carcinogenesis remains poorly understood
14 out of 15 3′ transductions from two samples were validated by long-distance inversePCR (LDI-PCR) and Nanopore sequencing in a separate study[22]
Since common fragile sites are prone to copy number alterations (CNAs)[35], we evaluated whether retrotransposition and CNAs—in this study detected as AI36—were correlated (Supplementary Data 3)
Summary
Genomic instability pathways in colorectal cancer (CRC) have been extensively studied, but the role of retrotransposition in colorectal carcinogenesis remains poorly understood. We characterize retrotransposon insertions in 202 colorectal tumor whole genomes and investigate their associations with molecular and clinical characteristics. Two types of retrotransposons have been identified in the human genome; autonomous and non-autonomous Autonomous elements, such as Long Interspersed Nuclear Element-1s (LINE-1s) and Endogenous retroviruses (ERVs), provide the required machinery for retrotransposition. High retrotransposon activity has been reported in several human cancers, especially in tumors arising from the gastrointestinal tract, such as colorectal cancer (CRC)[10,11,17,18,19,20]. We characterize somatic retrotransposon insertions in 201 CRCs and one colorectal adenoma utilizing whole genome sequencing (WGS), and investigate the associations between somatic retrotransposon activity and clinical characteristics
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