Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution
- Adam D. Ewing1,
- Anthony Gacita2,
- Laura D. Wood3,
- Florence Ma2,
- Dongmei Xing3,
- Min-Sik Kim2,
- Srikanth S. Manda2,
- Gabriela Abril2,
- Gavin Pereira2,
- Alvin Makohon-Moore3,
- Leendert H. J. Looijenga4,
- Ad J. M. Gillis4,
- Ralph H. Hruban3,
- Robert A. Anders3,
- Katharine E. Romans2,
- Akhilesh Pandey2,
- Christine A. Iacobuzio-Donahue3,
- Bert Vogelstein5,
- Kenneth W. Kinzler5,
- Haig H. Kazazian2 and
- Szilvia Solyom2,6
- 1 Mater Research Institute;
- 2 Johns Hopkins University School of Medicine;
- 3 Johns Hopkins Medical Institutions;
- 4 Erasmus MC;
- 5 The Ludwig Center and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center
- ↵* Corresponding author; email: 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.
- Received June 23, 2015.
- Accepted August 10, 2015.
- Published by Cold Spring Harbor Laboratory Press
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