title: Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution.
abstract: Somatic L1 retrotransposition events have been shown to occur in epithelial cancers. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds, and many were present in multiple tumor sections, implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth.
authors.affiliation: Mater Research Institute, University of Queensland, Woolloongabba, Queensland 4102, Australia;
authors.forename: Adam D
authors.initials: AD
authors.lastname: Ewing
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Anthony
authors.initials: A
authors.lastname: Gacita
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA;
authors.forename: Laura D
authors.initials: LD
authors.lastname: Wood
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Florence
authors.initials: F
authors.lastname: Ma
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA;
authors.forename: Dongmei
authors.initials: D
authors.lastname: Xing
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Min-Sik
authors.initials: MS
authors.lastname: Kim
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Srikanth S
authors.initials: SS
authors.lastname: Manda
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Gabriela
authors.initials: G
authors.lastname: Abril
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Gavin
authors.initials: G
authors.lastname: Pereira
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA;
authors.forename: Alvin
authors.initials: A
authors.lastname: Makohon-Moore
authors.affiliation: Department of Pathology, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands;
authors.forename: Leendert H J
authors.initials: LH
authors.lastname: Looijenga
authors.affiliation: Department of Pathology, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands;
authors.forename: Ad J M
authors.initials: AJ
authors.lastname: Gillis
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA;
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA;
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.affiliation: The Johns Hopkins University School of Medicine Cancer Biology, Baltimore, Maryland 21205, USA;
authors.forename: Katharine E
authors.initials: KE
authors.lastname: Romans
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA;
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.affiliation: The Ludwig Center and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland 21287, USA.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: The Ludwig Center and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland 21287, USA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Haig H
authors.initials: HH
authors.lastname: Kazazian
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
mesh_terms: D018450:Disease Progression; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D013997:Time Factors
chemical_list: D009363:Neoplasm Proteins