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High Frequency Strand Slippage Mutations in CTCF in MSI-Positive Endometrial Cancers

Authors

  • Israel Zighelboim,

    1. Department of Obstetrics and Gynecology and Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
    Current affiliation:
    1. Gynecologic Oncology, St. Luke's Cancer Care Associates, Assistant Clinical Professor of Obstetrics, Gynecology and Reproductive Services Temple University School of Medicine
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  • David G. Mutch,

    1. Department of Obstetrics and Gynecology and Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
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  • Amy Knapp,

    1. Department of Obstetrics and Gynecology and James Comprehensive Cancer Center, Columbus, Ohio
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  • Li Ding,

    1. The Genome Institute, Washington University in St. Louis, St. Louis, Missouri
    2. Department of Genetics, Washington University in St. Louis, St. Louis, Missouri
    3. Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri
    4. Department of Medicine, Washington University in St. Louis, St. Louis, Missouri
    5. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri
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  • Mingchao Xie,

    1. The Genome Institute, Washington University in St. Louis, St. Louis, Missouri
    2. Department of Genetics, Washington University in St. Louis, St. Louis, Missouri
    3. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri
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  • David E. Cohn,

    1. Department of Obstetrics and Gynecology and James Comprehensive Cancer Center, Columbus, Ohio
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  • Paul J. Goodfellow

    Corresponding author
    1. Department of Obstetrics and Gynecology and James Comprehensive Cancer Center, Columbus, Ohio
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  • Communicated by Mark H. Paalman

  • Contract grant sponsor: National Institutes of Health (R21 CA155674, U01 HG006517).

ABSTRACT

Tumors with defective mismatch repair acquire large numbers of strand slippage mutations including frameshifts in coding sequence repeats. We identified a mutational hotspot, p.T204fs, in the insulator-binding protein (CTCF) in MSI-positive endometrial cancers. Although CTCF was described as a significantly mutated gene by the endometrial cancer TCGA, the A7 track variants leading to T204 frameshifts were not reported. Reanalysis of TCGA data using Pindel revealed frequent T204fs mutations, confirming CTCF is an MSI target gene and revealed the same frameshifts in tumors with intact mismatch repair. We show that T204fs transcripts are subject to nonsense-mediated decay and as such, T204fs mutations are unlikely to act as dominant negatives. The spectrum and pattern of mutations observed is consistent with CTCF acting as a haploinsufficient tumor suppressor.

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