Abundant somatic L1 retrotransposition occurs early during colorectal and pancreatic tumorigenesis. S. Solyom1, A. D. Ewing2, A. Gacita1, L. D. Wood3, F. Ma1, A. Makohon-Moore3, D. Xing3, R. Hruban3, C. A. Iacobuzio-Donahue3, S. J. Meltzer4, B. Vogelstein5, K. W. Kinzler5, H. H. Kazazian1 1) Johns Hopkins University School of Medicine, Baltimore, MD; 2) Mater Research Institute, University of Queensland, Australia; 3) Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD; 4) The Johns Hopkins Univ. School of Medicine & Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; 5) The Ludwig Center and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD.

   The somatic mobilization of retroelements in the cancer genome has only recently been established as a new mutational phenomenon. In particular, Long INterspersed Element-1 (L1) retrotransposition has been observed in epithelial cancers. L1s are autonomous mobile elements that comprise 17% of the human genome and retrotranspose by a copy and paste mechanism via an RNA intermediate. Here, we investigate the spatio-temporal map of these integration events in gastrointestinal tumors. We studied DNA from 4 colon cancer patients who had been previously diagnosed with colonic polyps, from 5 patients with colorectal dysplasia and cancer arising in inflammatory bowel disease, and from 7 patients with pancreatic carcinoma. Metastases were available in multiple instances. After dissection of abnormal from normal tissue, next generation L1-targeted resequencing (L1-seq) was carried out on DNA from these cases. After PCR-validation and Sanger sequencing of putative insertions, we found for the first time that pancreatic cancer is permissive for L1 mobilization and that certain pre-cancerous lesions are mutagenized by L1 insertions. We have so far validated 80 somatic insertions in these colon tumors, of which half occurred in adenomas and IBD dysplasias, while 24 insertions were validated in pancreatic cancers. However, by extrapolation, insertions in adenomas and matched colon cancers numbered in the hundreds. Surprisingly, multiple insertions in IBD dysplasias were also present in their paired carcinomas, and many insertions in primary colon and pancreatic cancers were also present in their paired metastases. In addition, among insertions tested in multiple sections of the same tumor, the majority were present in all sections of the tumors. Numerous genes were targeted by L1 insertions, including within exons. Together, these data suggest that: 1) insertions occur clonally; 2) somatic retrotransposition occurs early during the development of some gastrointestinal cancers; and 3) L1 insertions show potential as novel biomarkers of neoplastic disease progression. However, it is not yet known whether some insertions are cancer drivers, or to what extent retrotransposition contributes to genetic instability.

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