CDKN2B Loss Promotes Progression from Benign Melanocytic Nevus to Melanoma.
Publication/Presentation Date
10-1-2015
Abstract
UNLABELLED: Deletion of the entire CDKN2B-CDKN2A gene cluster is among the most common genetic events in cancer. The tumor-promoting effects are generally attributed to loss of CDKN2A-encoded p16 and p14ARF tumor suppressors. The degree to which the associated CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here, we show that CDKN2B 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 BRAF(V600E)-activating mutation, nevi progressing to melanoma, and normal melanocytes engineered to inducibly express BRAF(V600E), 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, in vivo melanoma model, and demonstrate that p15 loss promotes the transition from benign nevus to melanoma.
SIGNIFICANCE: Although BRAF(V600E) 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 CDKN2B induction that is critical for restraining BRAF oncogenic effects, and when lost, contributes to melanoma.
Volume
5
Issue
10
First Page
1072
Last Page
1085
ISSN
2159-8290
Published In/Presented At
McNeal, A. S., Liu, K., Nakhate, V., Natale, C. A., Duperret, E. K., Capell, B. C., Dentchev, T., Berger, S. L., Herlyn, M., Seykora, J. T., & Ridky, T. W. (2015). CDKN2B Loss Promotes Progression from Benign Melanocytic Nevus to Melanoma. Cancer discovery, 5(10), 1072–1085. https://doi.org/10.1158/2159-8290.CD-15-0196
Disciplines
Medicine and Health Sciences
PubMedID
26183406
Department(s)
Department of Medicine
Document Type
Article