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Case Report/Case Series |

Multiple Cutaneous Melanomas and Clinically Atypical Moles in a Patient With a Novel Germline BAP1 Mutation

Pedram Gerami, MD1,2; Oriol Yélamos, MD1; Christina Y. Lee, BA1; Roxana Obregon, BA1; Pedram Yazdan, MD1; Lauren M. Sholl, MS1; Gerta E. Guitart1; Ching-Ni Njauw, MS3,4; Hensin Tsao, MD, PhD3,4
[+] Author Affiliations
1Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
2Robert H. Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
3Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard University, Boston
4Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston
JAMA Dermatol. 2015;151(11):1235-1239. doi:10.1001/jamadermatol.2015.1701.
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ABSTRACT

Importance  Several kindreds having germline BAP1 mutations with a propensity for uveal and cutaneous melanomas and other internal malignancies have been described in an autosomal dominant tumor predisposition syndrome. However, clinically atypical moles have not been previously recognized as a component of this syndrome, to our knowledge. We describe the first kindred to date with a germline mutation in BAP1 associated with multiple cutaneous melanomas and classic dysplastic nevus syndrome.

Observations  We describe a 53-year-old man who was initially seen in 2003 with dysplastic nevus syndrome, multiple atypical melanocytic proliferations showing loss of immunostaining for BAP1, and 7 cutaneous melanomas. Germline testing was performed in the proband, his 16-year-old son, and his 13-year-old daughter, revealing a germline mutation in the BAP1 gene (c.592G>T, p.Glu198X) in the proband and in his 16-year-old son. CDKN2A and CDK4 genes were wild type. No members of this kindred reported a history of uveal melanoma.

Conclusions and Relevance  To our knowledge, this is the first report of a patient with multiple melanomas, dysplastic nevus syndrome, and an inactivating germline BAP1 mutation. The coexistence of dysplastic nevus syndrome and a BAP1 germline mutation extends the spectrum of the BAP1 tumor predisposition syndrome and may confer a greater risk for cutaneous melanomas.

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Figure 1.
Clinical and Histologic Findings of Dysplastic Nevi in the Proband

A, Shown is a patient with dysplastic nevus syndrome. B, The dysplastic compound nevus shows size variation of the junctional nests, elongation of the rete ridges, and shoulder phenomenon (hematoxylin-eosin, original magnification ×20). C, Bridging of nests and perireteal fibroplasia are shown (hematoxylin-eosin, original magnification ×100).

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Figure 2.
Histologic Findings in a Superficial Spreading Melanoma

A, Shown is a junctional proliferation of atypical melanocytes (hematoxylin-eosin, original magnification ×40). B, An irregular junctional proliferation of atypical melanocytes with suprabasal movement is shown (hematoxylin-eosin, original magnification ×100). C and D, Shown at intermediate-power magnification (red chromogen, ×100), the tumor cells do not immunostain with anti–BRAF V600E (C) or anti-BAP1 (D).

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Figure 3.
Histologic Findings in a BAP1-Deficient Tumor

A, Shown is a dermal proliferation of epithelioid melanocytes (hematoxylin-eosin, original magnification ×20). B, This proliferation comprises one component of normal-appearing nevoid cells and a second component of atypical epithelioid spitzoid cells (hematoxylin-eosin, original magnification ×100). C and D, The tumor is positive for BRAF V600E immunostaining (shown at intermediate-power magnification, red chromogen, ×100) (C), and the larger epithelioid cells show dotlike perinuclear BAP1 immunostaining but loss of nuclear expression (shown at high-power magnification, red chromogen, ×200) (D).

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Figure 4.
Electropherogram Showing a Nonsense Mutation in Exon 8 in the BAP1 Gene

A-C, In the proband, the mutation was found in the DNA from a BAP1-deficient tumor (A), a melanoma (B), and the saliva (C), thereby demonstrating germline origination. D, The same mutation was identified in the saliva of the patient’s 16-year-old son.

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