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Updated: Jun 13, 2026

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
06:09

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

Published on: June 7, 2019

Disruption of CTCF binding by germline non-coding variants in CDKN2B suppress CDKN2A expression and predispose to

Jessica L Scales, Jayne A Barbour, Alisa M Goldstein

    Medrxiv : the Preprint Server for Health Sciences
    |June 12, 2026
    PubMed

    Insights

    Rare variants in a non-coding region of CDKN2B impact CDKN2A expression, increasing melanoma risk. These findings identify novel high-penetrance susceptibility alleles for melanoma in affected families.

    Area of Science:

    • Genetics
    • Cancer Biology
    • Molecular Oncology

    Background:

    • Some melanoma-prone families lack pathogenic variants in known susceptibility genes like CDKN2A.
    • The 9p21 locus is strongly associated with melanoma susceptibility.

    Purpose of the Study:

    • To investigate non-coding variants in melanoma susceptibility.
    • To identify the functional impact of rare variants in a conserved regulatory region near CDKN2A.

    Main Methods:

    • Whole-exome and targeted sequencing were used to identify variants.
    • In vitro assays assessed CTCF binding and promoter interactions.
    • CRISPR-based editing and transcript expression analysis were performed.

    Main Results:

    • Three rare single-nucleotide variants were identified in melanoma cases and families.
    • These variants disrupt CTCF binding and reduce CDKN2A (p14 and p16) transcript expression.
    • UK Biobank data showed enrichment of these variants in melanoma cases.

    Conclusions:

    • Non-coding regulatory variants in the CDKN2B intron can act as high-penetrance melanoma susceptibility alleles.
    • Altered CDKN2A regulation by these variants contributes to melanoma predisposition.
    • This expands the understanding of genetic risk factors for familial melanoma.

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