title: Extensive somatic L1 retrotransposition in colorectal tumors.
abstract: L1 retrotransposons comprise 17% of the human genome and are its only autonomous mobile elements. Although L1-induced insertional mutagenesis causes Mendelian disease, their mutagenic load in cancer has been elusive. Using L1-targeted resequencing of 16 colorectal tumor and matched normal DNAs, we found that certain cancers were excessively mutagenized by human-specific L1s, while no verifiable insertions were present in normal tissues. We confirmed de novo L1 insertions in malignancy by both validating and sequencing 69/107 tumor-specific insertions and retrieving both 5' and 3' junctions for 35. In contrast to germline polymorphic L1s, all insertions were severely 5' truncated. Validated insertion numbers varied from up to 17 in some tumors to none in three others, and correlated with the age of the patients. Numerous genes with a role in tumorigenesis were targeted, including ODZ3, ROBO2, PTPRM, PCM1, and CDH11. Thus, somatic retrotransposition may play an etiologic role in colorectal cancer.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Szilvia
authors.initials: S
authors.lastname: Solyom
authors.forename: Adam D
authors.initials: AD
authors.lastname: Ewing
authors.forename: Eric P
authors.initials: EP
authors.lastname: Rahrmann
authors.forename: Tara
authors.initials: T
authors.lastname: Doucet
authors.forename: Heather H
authors.initials: HH
authors.lastname: Nelson
authors.forename: Michael B
authors.initials: MB
authors.lastname: Burns
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
authors.forename: David F
authors.initials: DF
authors.lastname: Sigmon
authors.forename: Alex
authors.initials: A
authors.lastname: Casella
authors.forename: Bracha
authors.initials: B
authors.lastname: Erlanger
authors.forename: Sarah
authors.initials: S
authors.lastname: Wheelan
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Upton
authors.forename: Ruchi
authors.initials: R
authors.lastname: Shukla
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Faulkner
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
authors.forename: Haig H
authors.initials: HH
authors.lastname: Kazazian
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics*; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D008745:Methylation; D053842:Microsatellite Instability; D016254:Mutagenesis, Insertional; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015203:Reproducibility of Results; D018626:Retroelements / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D018626:Retroelements