Research

Extensive somatic L1 retrotransposition in colorectal tumors

    • 1McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
    • 2Center for Biomolecular Science and Engineering, University of California at Santa Cruz, Santa Cruz, California 95064, USA;
    • 3Department of Genetics, Cell Biology and Development and Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA;
    • 4Pre-doctoral training program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
    • 5Division of Epidemiology and Community Health, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA;
    • 6Department of Statistics and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
    • 7Cancer Biology Program, Mater Medical Research Institute, South Brisbane, Queensland 4101, Australia;
    • 8Division of Genetics and Genomics, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, EH25 9RG, United Kingdom;
    • 9School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia
    • 10 These authors contributed equally to this work.
    • 11 Corresponding author E-mail [email protected]
Published September 11, 2012. Vol 22 Issue 12, pp. 2328-2338. https://doi.org/10.1101/gr.145235.112
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Abstract

L1 retrotransposons comprise 17% of the human genome and are its only autonomous mobile elements. Although L1-induced insertional mutagenesis causes Mendelian disease, their mutagenic load in cancer has been elusive. Using L1-targeted resequencing of 16 colorectal tumor and matched normal DNAs, we found that certain cancers were excessively mutagenized by human-specific L1s, while no verifiable insertions were present in normal tissues. We confirmed de novo L1 insertions in malignancy by both validating and sequencing 69/107 tumor-specific insertions and retrieving both 5′ and 3′ junctions for 35. In contrast to germline polymorphic L1s, all insertions were severely 5′ truncated. Validated insertion numbers varied from up to 17 in some tumors to none in three others, and correlated with the age of the patients. Numerous genes with a role in tumorigenesis were targeted, including ODZ3, ROBO2, PTPRM, PCM1, and CDH11. Thus, somatic retrotransposition may play an etiologic role in colorectal cancer.

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