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Nat Med. 2015 Sep;21(9):1060-4. doi: 10.1038/nm.3919. Epub 2015 Aug 10.

Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma.

Author information

1
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
3
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
4
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
5
Department of Molecular Biology &Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
6
High Throughput (HiT) Biology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
7
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland, USA.
8
The Sol Goldman Center for Pancreatic Cancer Research, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
9
Institute for Systems Genetics, New York University Langone School of Medicine, New York, New York, USA.

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.

Comment in

PMID:
26259033
PMCID:
PMC4775273
DOI:
10.1038/nm.3919
[Indexed for MEDLINE]
Free PMC Article

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