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

Abstract

Retrotransposons comprise over 40% of the human genome and constitute a major source of genetic variation. Somatic retrotransposon insertions have been reported in cancer. Here we present a comprehensive analysis of somatic retrotransposon insertions across multiple cancers. We applied TranspoSeq, a computational framework that identifies somatic retrotransposon insertions from massively parallel sequencing data, to whole-genome sequences from 200 tumor/normal pairs across 11 cancer types as part of the Pan-Cancer Project in The Cancer Genome Atlas (TCGA). In addition to novel germline polymorphisms, we find 810 somatic retrotransposon insertions primarily in lung squamous cell, head and neck, colorectal and endometrial carcinomas. Many somatic retrotransposon insertions fall into genic regions of known and putative cancer genes, as well as into exons. High somatic retrotransposition rates in tumors are associated with high rates of genomic rearrangement and somatic mutation. In addition, we developed TranspoSeq-Exome and interrogated TCGA hybrid-capture exome data in 767 tumor/normal pairs for retrotransposon movement, thereby discovering 35 additional somatic retrotransposon insertions into exonic regions, including a novel insertion into an exon of the PTEN tumor suppressor gene. These results suggest that somatic retrotransposon insertions may represent an important class of structural variation in cancer.