Nonoverlapping Clinical and Mutational Patterns in Melanomas from the Female Genital Tract and Atypical Genital Nevi  Oriol Yélamos, Emily A. Merkel, Lauren Meldi Sholl, Bin Zhang, Sapna M. Amin, Christina Y. Lee, Gerta E. Guitart, Jingyi Yang, Alexander T. Wenzel, Christopher G. Bunick, Pedram Yazdan, Jaehyuk Choi, Pedram Gerami  Journal of Investigative Dermatology  Volume 136, Issue 9, Pages 1858-1865 (September 2016) DOI: 10.1016/j.jid.2016.05.094 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Histological and fluorescence in situ hybridization findings in a genital melanoma and in an atypical genital nevus. (a) Low-power magnification shows extensive epithelial ulceration, extensive pagetoid spread, and prominent lentiginous growth in a genital melanoma. (b) At high-power magnification, the cells have severe nuclear atypia with pleomorphism, coarse chromatin, and high mitotic activity. (c) Fluorescence in situ hybridization showed numerous copy number gains involving chromosome bands 6p25 (red), 8q24 (aqua), and 11q13 (green). (d) Atypical genital nevus showing extensive junctional involvement with effacement of the rete ridges, back-to-back nesting, and focal pagetoid spread. (e) The BRAF VE1 immunostain showed that the cells in the atypical genital nevus harbored the BRAF V600E mutation. Scale bar = 100 μm. Journal of Investigative Dermatology 2016 136, 1858-1865DOI: (10.1016/j.jid.2016.05.094) Copyright © 2016 The Authors Terms and Conditions

Figure 2 Clustering of missense mutations in the juxtamembrane domain and activation loop of human KIT. Pictured is a ribbon diagram of the 1.6-Å resolution x-ray imaging crystal structure of the intracellular domains of human KIT (Protein Data Bank Code 3G0E). Each structural domain is colored and labeled. W557R and L576P mutations (red spheres) occur in the juxtamembrane domain (orange), clustering adjacent to other commonly mutated KIT residues (V559D, V560D; blue spheres). K642E mutation (red sphere) also occurs next to the juxtamembrane domain mutations but is positioned within a helix of the proximal kinase domain (pink). N822K mutation (red sphere) occurs in the activation loop (green), adjacent to the catalytic loop (gray) and D816 (blue sphere in activation loop). C, C-terminus; N, N-terminus. Journal of Investigative Dermatology 2016 136, 1858-1865DOI: (10.1016/j.jid.2016.05.094) Copyright © 2016 The Authors Terms and Conditions

Figure 3 Confirmed somatic mutations found in genital melanomas and atypical genital nevi. We tested 50 oncogenes and tumor suppressor genes. Genital melanomas showed mutually exclusive mutations in KIT and TP53, whereas the nevi showed a nonoverlapping pattern of pathogenic mutations, with most patients having mutations in BRAF. AGN, atypical genital nevi; GM, genital melanoma. Journal of Investigative Dermatology 2016 136, 1858-1865DOI: (10.1016/j.jid.2016.05.094) Copyright © 2016 The Authors Terms and Conditions

Figure 4 Melanoma signaling pathway showing differences in mutational patterns in genital melanomas, atypical genial nevi, and melanomas of sun-exposed skin. Mutations affecting the upstream oncogene, KIT, were found only in patients with genital melanoma and were not found in any of the genital nevi. Conversely, mutations found in atypical genital nevi such as BRAF, which is also common in sun-exposed melanomas, were not found in any of the genital melanomas. The proteins affected by these mutations are highlighted in blue. AGN, atypical genital nevi; ERK, extracellular signal-regulated kinase; GM, genital melanoma; MEK, mitogen-activated protein kinase kinase; MITF, microphthalmia-associated transcription factor. Journal of Investigative Dermatology 2016 136, 1858-1865DOI: (10.1016/j.jid.2016.05.094) Copyright © 2016 The Authors Terms and Conditions