Title: CDKN2B Loss Promotes Progression from Benign Melanocytic Nevus to Melanoma.
Authors: McNeal, Andrew S; Liu, Kevin; Nakhate, Vihang; Natale, Christopher A; Duperret, Elizabeth K; Capell, Brian C; Dentchev, Tzvete; Berger, Shelley L; Herlyn, Meenhard; Seykora, John T; Ridky, Todd W
Published In Cancer Discov, (2015 Oct)
Abstract: 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.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.
PubMed ID: 26183406
MeSH Terms: Animals; Cell Cycle Checkpoints/genetics; Cell Transformation, Neoplastic/genetics; Chromatin/genetics; Chromatin/metabolism; Cyclin-Dependent Kinase Inhibitor p15/deficiency*; Cyclin-Dependent Kinase Inhibitor p15/genetics*; Cyclin-Dependent Kinase Inhibitor p15/metabolism; DNA Mutational Analysis; Disease Models, Animal; Disease Progression; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Immunohistochemistry; Melanocytes/metabolism; Melanocytes/pathology; Melanoma/genetics*; Melanoma/metabolism; Melanoma/pathology*; Mice; Mutation; Nevus/genetics*; Nevus/metabolism; Nevus/pathology*; Proto-Oncogene Proteins B-raf/genetics; Signal Transduction; Transcriptional Activation; Transforming Growth Factor beta/metabolism