Title | Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Rodić N, Steranka JP, Makohon-Moore A, Moyer A, Shen P, Sharma R, Kohutek ZA, Huang CRan, Ahn D, Mita P, Taylor MS, Barker NJ, Hruban RH, Iacobuzio-Donahue CA, Boeke JD, Burns KH |
Journal | Nat Med |
Volume | 21 |
Issue | 9 |
Pagination | 1060-4 |
Date Published | 2015 Sep |
ISSN | 1546-170X |
Keywords | Apoptotic Protease-Activating Factor 1, Carcinoma, Pancreatic Ductal, Clonal Evolution, Humans, Long Interspersed Nucleotide Elements, Pancreatic Neoplasms |
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. |
DOI | 10.1038/nm.3919 |
Alternate Journal | Nat. Med. |
PubMed ID | 26259033 |
PubMed Central ID | PMC4775273 |
Grant List | P50CA62924 / CA / NCI NIH HHS / United States F31 CA180682 / CA / NCI NIH HHS / United States T32 GM007814 / GM / NIGMS NIH HHS / United States R01 CA163705 / CA / NCI NIH HHS / United States R01 CA179991 / CA / NCI NIH HHS / United States P50 CA062924 / CA / NCI NIH HHS / United States R01 GM103999 / GM / NIGMS NIH HHS / United States P50GM107632 / GM / NIGMS NIH HHS / United States P50 GM107632 / GM / NIGMS NIH HHS / United States R01CA179991 / CA / NCI NIH HHS / United States R01 CA161210 / CA / NCI NIH HHS / United States F31CA180682 / CA / NCI NIH HHS / United States R01CA163705 / CA / NCI NIH HHS / United States R01GM103999 / GM / NIGMS NIH HHS / United States |
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