A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer
- Emma C. Scott1,2,8,
- Eugene J. Gardner1,2,8,
- Ashiq Masood2,3,4,9,
- Nelson T. Chuang1,2,5,
- Paula M. Vertino6,7 and
- Scott E. Devine1,2,3,4
- 1Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA;
- 2Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA;
- 3Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA;
- 4Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA;
- 5Division of Gastroenterology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA;
- 6Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia 30322, USA;
- 7Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA
- Corresponding author: sdevine{at}som.umaryland.edu
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↵8 Co-first authors
Abstract
Although human LINE-1 (L1) elements are actively mobilized in many cancers, a role for somatic L1 retrotransposition in tumor initiation has not been conclusively demonstrated. Here, we identify a novel somatic L1 insertion in the APC tumor suppressor gene that provided us with a unique opportunity to determine whether such insertions can actually initiate colorectal cancer (CRC), and if so, how this might occur. Our data support a model whereby a hot L1 source element on Chromosome 17 of the patient's genome evaded somatic repression in normal colon tissues and thereby initiated CRC by mutating the APC gene. This insertion worked together with a point mutation in the second APC allele to initiate tumorigenesis through the classic two-hit CRC pathway. We also show that L1 source profiles vary considerably depending on the ancestry of an individual, and that population-specific hot L1 elements represent a novel form of cancer risk.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.201814.115.
- Received November 12, 2015.
- Accepted April 19, 2016.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
