Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers

Abstract

Long interspersed nuclear element-1 (L1) retrotransposons are normally suppressed in somatic tissues mainly by DNA methylation and antiviral defense. However, L1s can be desuppressed in cancers to act as insertional mutagens and cause genomic instability by creating DNA double strand breaks and chromosomal rearrangements. Whereas the frequency of somatic L1 insertions varies greatly among individual tumors, much remains to be learned about underlying genetic, cellular, or environmental factors. Here, our pan-gastrointestinal cancer genome analyses for stomach, colorectal, and esophageal tumors identified multiple correlates of L1 activity. Clinical indicators of tumor progression, such as tumor grade and patient age, showed positive association. Potential L1 expression suppressors such as TP53 and DNMT1, a DNA methyltransferase, were inactivated in tumors with frequent L1 insertions. Importantly, tumors with high immune activity, for example, due to viral infection or high tumor-antigen load, tended to carry a low number of L1 insertions in their genomes with high expression levels of L1 suppressors such as APOBEC3s and SAMHD1. Our analysis of the transcriptional effects of intragenic retrotransposon insertions demonstrated an increased risk of gene disruption in retrotransposition-prone cancers. In particular, we found a splicing-disrupting L1 insertion in an exon of MOV10, a key L1 suppressor, which caused exon skipping with evidence of nonsense-mediated decay in a tumor with a high L1 insertion load. Our results indicate that cancer immunity may contribute to genome stability by suppressing L1 retrotransposition particularly in gastrointestinal cancers.