Somatic retrotransposition in human cancer revealed by whole-genome and exome sequencing

Abstract

Retrotransposons constitute a major source of genetic variation, and somatic retrotransposon insertions have been reported in cancer. Here, we applied TranspoSeq, a computational framework that identifies retrotransposon insertions from sequencing data, to whole genomes from 200 tumor/normal pairs across 11 tumor types as part of The Cancer Genome Atlas (TCGA) Pan-Cancer Project. In addition to novel germline polymorphisms, we find 810 somatic retrotransposon insertions primarily in lung squamous, head and neck, colorectal, and endometrial carcinomas. Many somatic retrotransposon insertions occur in known cancer genes. We find that high somatic retrotransposition rates in tumors are associated with high rates of genomic rearrangement and somatic mutation. Finally, we developed TranspoSeq-Exome to interrogate an additional 767 tumor samples with hybrid-capture exome data and discovered 35 novel somatic retrotransposon insertions into exonic regions, including an insertion into an exon of the PTEN tumor suppressor gene. The results of this large-scale, comprehensive analysis of retrotransposon movement across tumor types suggest that somatic retrotransposon insertions may represent an important class of structural variation in cancer.

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

“…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.…”

A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer

“…The precise role of ST18 in the development of hepatocellular carcinoma is unknown, and thus it is unclear whether this L1 insertion might have influenced tumor initiation, or instead, later stages of tumorigenesis. Another strong example of a potential L1 driver mutation was identified in the sixth exon of the PTEN tumor suppressor gene in a case of uterine corpus endometrial carcinoma (Helman et al 2014). Because this insertion disrupted a coding exon, the tumor likely had lower levels of PTEN activity.…”

“…Next-generation sequencing has revolutionized somatic L1 discovery over the past 6 yr, leading to the identification of thousands of somatic L1 insertions in several types of human epithelial cancers (Iskow et al 2010;Lee et al 2012;Solyom et al 2012;Shukla et al 2013;Helman et al 2014;Tubio et al 2014;Doucet-O'Hare et al 2015;Ewing et al 2015;Rodic et al 2015). The fact that L1 mobilization occurs frequently in human tumors raises the possibility that somatic L1 insertions could act as driver mutations during tumor initiation, progression, and metastasis.…”

“…However, several broad surveys of somatic L1 insertions in human cancers have detected only a few strong L1 driver candidates Shukla et al 2013;Helman et al 2014;Tubio et al 2014), and it is unclear whether any of these insertions could have initiated tumorigenesis in the cancers in which they were discovered (see Discussion). Thus, somatic L1 drivers that affect the earliest stages of tumorigenesis have been elusive in these studies, and it is presently unclear whether L1 has the capacity to initiate tumorigenesis in somatic cells.…”

“…Until recently, L1 elements were thought to be mobilized primarily in the germline and then silenced in somatic cells throughout adulthood. However, several recent reports have shown that L1 elements are active in at least some adult somatic tissues, including the brain (Muotri et al 2005;Coufal et al 2009;Baillie et al 2011;Evrony et al 2012;Upton et al 2015) and epithelial somatic tumors Iskow et al 2010;Lee et al 2012;Solyom et al 2012;Shukla et al 2013;Helman et al 2014;Tubio et al 2014;Doucet-O'Hare et al 2015;Ewing et al 2015;Rodic et al 2015). These observations have led to the suggestion that L1 might play a role in initiating human cancers by mutating specific oncogenes or tumor suppressor genes in somatic cells.…”