Disruption of CTCF binding by germline non-coding variants in CDKN2B suppress CDKN2B expression in melanoma-prone families

Germline non-coding variants disrupting CTCF binding sites downstream of CDKN2B, transcriptional repression, alternative mechanism for melanoma predisposition

In melanoma-prone families linked to the 9p21 locus but lacking pathogenic CDKN2A coding variants, three rare non-coding variants are identified in two families and one sporadic case. These variants disrupt CTCF architectural factor binding sites downstream of CDKN2B, causing transcriptional repression of CDKN2B — a tumor suppressor contiguous to CDKN2A. This study establishes CDKN2B as a new melanoma predisposition gene via an epigenetic regulatory mechanism, detectable only by WGS or targeted non-coding genotyping.

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Identification of pathogenic non-coding variants in a CDKN2A-contiguous gene for familial melanoma is a major advance: it explains a fraction of 9p21-linked families unresolved by standard sequencing and establishes a novel CTCF mechanism in melanoma oncogenetics. This preprint will need peer-reviewed validation but the mechanism is robust.

Clinical impact: 3/3 · Evidence strength: 3/3 · Novelty: 2/2 · Sample size: 1/1 · Publication status: 0/1 → Total: 9/10