Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma

Nemanja Rodić, Jared P. Steranka, Alvin Makohon-Moore, Allison Moyer, Peilin Shen, Reema Sharma, Zachary A. Kohutek, Cheng Ran Huang, Daniel Ahn, Paolo Mita, Martin S. Taylor, Norman J. Barker, Ralph H. Hruban, Christine A. Iacobuzio-Donahue, Jef D. Boeke, Kathleen H. Burns

Research output: Contribution to journalArticle

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed after the disease has metastasized; it is among the most lethal forms of cancer. We recently described aberrant expression of an open reading frame 1 protein, ORF1p, encoded by long interspersed element-1 (LINE-1; L1) retrotransposon, in PDAC. To test whether LINE-1 expression leads to somatic insertions of this mobile DNA, we used a targeted method to sequence LINE-1 insertion sites in matched PDAC and normal samples. We found evidence of 465 somatic LINE-1 insertions in 20 PDAC genomes, which were absent from corresponding normal samples. In cases in which matched normal tissue, primary PDAC and metastatic disease sites were available, insertions were found in primary and metastatic tissues in differing proportions. Two adenocarcinomas secondarily involving the pancreas, but originating in the stomach and duodenum, acquired insertions with a similar discordance between primary and metastatic sites. Together, our findings show that LINE-1 contributes to the genetic evolution of PDAC and suggest that somatic insertions are acquired discontinuously in gastrointestinal neoplasms.

Original languageEnglish (US)
Pages (from-to)1060-1064
Number of pages5
JournalNature medicine
Volume21
Issue number9
DOIs
StatePublished - Sep 8 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Rodić, N., Steranka, J. P., Makohon-Moore, A., Moyer, A., Shen, P., Sharma, R., Kohutek, Z. A., Huang, C. R., Ahn, D., Mita, P., Taylor, M. S., Barker, N. J., Hruban, R. H., Iacobuzio-Donahue, C. A., Boeke, J. D., & Burns, K. H. (2015). Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma. Nature medicine, 21(9), 1060-1064. https://doi.org/10.1038/nm.3919