Somatic retrotransposition in human cancer revealed by whole-genome and exome sequencing.
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.
Harvard-MIT Division of Health Sciences & Technology, Cambridge, Massachusetts 02139, USA; Broad Institute of MIT and Harvard, Cambridge, Masachusetts 02142, USA;
Elena
E
Helman
Broad Institute of MIT and Harvard, Cambridge, Masachusetts 02142, USA;
Michael S
MS
Lawrence
Broad Institute of MIT and Harvard, Cambridge, Masachusetts 02142, USA;
Chip
C
Stewart
Broad Institute of MIT and Harvard, Cambridge, Masachusetts 02142, USA;
Carrie
C
Sougnez
Broad Institute of MIT and Harvard, Cambridge, Masachusetts 02142, USA; Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
Gad
G
Getz
Harvard-MIT Division of Health Sciences & Technology, Cambridge, Massachusetts 02139, USA; Broad Institute of MIT and Harvard, Cambridge, Masachusetts 02142, USA; Center for Cancer Genome Discovery and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Matthew
M
Meyerson
D001483:Base Sequence; D019295:Computational Biology / Q000379:methods; D004251:DNA Transposable Elements; D030561:Databases, Nucleic Acid; D059472:Exome; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016254:Mutagenesis, Insertional; D009369:Neoplasms / Q000235:genetics*; D018626:Retroelements / Q000235:genetics*; D017422:Sequence Analysis, DNA
D004251:DNA Transposable Elements; D018626:Retroelements