Data from <i>CDKN2B</i> Loss Promotes Progression from Benign Melanocytic Nevus to Melanoma

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<div>Abstract<p>Deletion of the entire <i>CDKN2B–CDKN2A</i> gene cluster is among the most common genetic events in cancer. The tumor-promoting effects are generally attributed to loss of <i>CDKN2A</i>-encoded p16 and p14ARF tumor suppressors. The degree to which the associated <i>CDKN2B</i>-encoded p15 loss contributes to human tumorigenesis is unclear. Here, we show that <i>CDKN2B</i> is highly upregulated in benign melanocytic nevi, contributes to maintaining nevus melanocytes in a growth-arrested premalignant state, and is commonly lost in melanoma. Using primary melanocytes isolated directly from freshly excised human nevi naturally expressing the common <i>BRAF</i><sup>V600E</sup>-activating mutation, nevi progressing to melanoma, and normal melanocytes engineered to inducibly express <i>BRAF</i><sup>V600E</sup>, we show that BRAF activation results in reversible, TGFβ-dependent, p15 induction that halts proliferation. Furthermore, we engineer human skin grafts containing nevus-derived melanocytes to establish a new, architecturally faithful, <i>in vivo</i> melanoma model, and demonstrate that p15 loss promotes the transition from benign nevus to melanoma.</p><p><b>Significance:</b> Although <i>BRAF</i><sup>V600E</sup> mutations cause melanocytes to initially proliferate into benign moles, mechanisms responsible for their eventual growth arrest are unknown. Using melanocytes from human moles, we show that BRAF activation leads to a <i>CDKN2B</i> induction that is critical for restraining BRAF oncogenic effects, and when lost, contributes to melanoma. <i>Cancer Discov; 5(10); 1072–85. ©2015 AACR</i>.</p><p>This article is highlighted in the In This Issue feature, p. 1005</p></div>