Research

A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer

    • 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
    • 8 Co-first authors
    • 9 Present address: Siteman Cancer Center, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA
Published May 10, 2016. Vol 26 Issue 6, pp. 745-755. https://doi.org/10.1101/gr.201814.115
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cover of Genome Research Vol 36 Issue 4
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April 2026, Vol. 36, No. 4
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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.

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