Extensive somatic L1 retrotransposition in colorectal tumors

Abstract

L1 retrotransposons comprise 17% of the human genome and are its only autonomous mobile elements. Although L1-induced insertional mutagenesis causes Mendelian disease, their mutagenic load in cancer has been elusive. Using L1-targeted resequencing of 16 colorectal tumor and matched normal DNAs, we found that certain cancers were excessively mutagenized by human-specific L1s, while no verifiable insertions were present in normal tissues. We confirmed de novo L1 insertions in malignancy by both validating and sequencing 69/107 tumor-specific insertions and retrieving both 5′ and 3′ junctions for 35. In contrast to germline polymorphic L1s, all insertions were severely 5′ truncated. Validated insertion numbers varied from up to 17 in some tumors to none in three others, and correlated with the age of the patients. Numerous genes with a role in tumorigenesis were targeted, including ODZ3, ROBO2, PTPRM, PCM1, and CDH11. Thus, somatic retrotransposition may play an etiologic role in colorectal cancer.

Activation of transcription and retrotransposition of a novel retroelement, Steamer , in neoplastic hemocytes of the mollusk Mya arenaria

“…Transposons create insertional mutations upon each transposition event and thus can be agents of profound genome instability in cancers (46,47). The scale of activation of Steamer in leukemic cells seen here is extraordinary, unprecedented in magnitude for an induction of transposition in a natural setting.…”

Human transposon insertion profiling: Analysis, visualization and identification of somatic LINE-1 insertions in ovarian cancer

“…This conclusion is even more true for Alu insertion variants (45,46). These studies have also demonstrated that several types of epithelial cancers acquire somatic insertions of LINE-1 as they develop (15,19,24,26). Recent projects mining whole-genome sequencing data have extended our understanding of the scope of heritable LINE-1 insertions (20,21,47) and somatic retrotransposition (22,23,48) greatly.…”

“…Recently, however, strategies for mapping these elements have been developed based on selective PCR amplification (15)(16)(17), hybridizationbased enrichment (18,19), and read selection from wholegenome sequencing data (20)(21)(22). These studies underscore the continued activity of LINE-1 in modern humans, and demonstrated somatic insertions in several types of human malignancy (15,19,(22)(23)(24)(25)(26)(27).…”

ROBO2 gene variants in children with primary nonsyndromic vesicoureteral reflux with or without renal hypoplasia/dysplasia

“…Retrotransposons can disrupt gene function in many ways, including insertional mutagenesis, alternative splicing, epigenetic effects, and the expression of small noncoding RNAs (28). Two recent studies report that ROBO2 gene is a target for L1 retrotransposons insertional mutagenesis in intronic regions (15% frequency) and was found in a pathogenic cancer phenotype (28,29).…”

“…Two recent studies report that ROBO2 gene is a target for L1 retrotransposons insertional mutagenesis in intronic regions (15% frequency) and was found in a pathogenic cancer phenotype (28,29). The mutational analysis in this study included only the exons and their intronic boundaries, leaving out the noncoding regions of the gene.…”