Transposable elements in cancer

Much of the human genome is repetitive sequence derived from transposable elements. These include copy-and-paste retrotransposons and cut-and-paste DNA transposons. Only retrotransposons are active as undomesticated mobile DNAs in humans.Ongoing retrotransposition in humans is attributed to long interspersed element-1 (LINE-1; also known as L1). Its activity creates genomic structural variants in human populations and alterations in cancer genomes. Endogenous retroviruses persist as promoter and protein-coding sequences.LINE-1 encodes open reading frame 1p (ORF1p) and ORF2p proteins. ORF1p is an RNA binding protein widely expressed in human malignancies. ORF2p encodes endonuclease and reverse transcriptase activities essential for retrotransposition.LINE-1 activity generates new copies of itself, and also other sequences, including Alu and short interspersed element (SINE)–variable number tandem repeat (VNTR)–Alu (SVA) retrotransposons, pseudogene copies of messenger transcripts and U6 ribosomal RNAs (rRNAs).In cancer, source LINE-1 elements escape genomic DNA methylation and transcriptional repression to contribute new LINE-1 insertions. Different source elements may be active over different phases of the evolution of a cancer.Somatically acquired LINE-1 insertions can cause driver mutations, particularly in gastrointestinal tract tumours, which support high levels of retrotransposition. Distinguishing contributing mutations from inert passenger mutations is an important challenge for the field.