Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution
- Adam D. Ewing1,
- Anthony Gacita2,
- Laura D. Wood3,
- Florence Ma2,
- Dongmei Xing3,
- Min-Sik Kim4,5,
- Srikanth S. Manda4,5,
- Gabriela Abril2,
- Gavin Pereira2,
- Alvin Makohon-Moore3,
- Leendert H.J. Looijenga6,
- Ad J.M. Gillis6,
- Ralph H. Hruban3,
- Robert A. Anders3,
- Katharine E. Romans7,
- Akhilesh Pandey4,5,
- Christine A. Iacobuzio-Donahue3,9,
- Bert Vogelstein8,
- Kenneth W. Kinzler8,
- Haig H. Kazazian Jr.2 and
- Szilvia Solyom2
- 1Mater Research Institute, University of Queensland, Woolloongabba, Queensland 4102, Australia;
- 2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
- 3Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA;
- 4McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
- 5Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
- 6Department of Pathology, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands;
- 7The Johns Hopkins University School of Medicine Cancer Biology, Baltimore, Maryland 21205, USA;
- 8The Ludwig Center and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland 21287, USA
- Corresponding authors: hkazazi1{at}jhmi.edu, ssolyom1{at}jhmi.edu
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.
Footnotes
-
[Supplemental material is available for this article.]
-
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.196238.115.
- Received June 23, 2015.
- Accepted August 10, 2015.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
