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. 2011 Aug 28;43(10):1018-21.
doi: 10.1038/ng.910.

Germline mutations in BAP1 predispose to melanocytic tumors

Thomas Wiesner  1 , Anna C Obenauf, Rajmohan Murali, Isabella Fried, Klaus G Griewank, Peter Ulz, Christian Windpassinger, Werner Wackernagel, Shea Loy, Ingrid Wolf, Agnes Viale, Alex E Lash, Mono Pirun, Nicholas D Socci, Arno Rütten, Gabriele Palmedo, David Abramson, Kenneth Offit, Arthur Ott, Jürgen C Becker, Lorenzo Cerroni, Heinz Kutzner, Boris C Bastian, Michael R Speicher
Affiliations

Germline mutations in BAP1 predispose to melanocytic tumors

Thomas Wiesner et al. Nat Genet. .

Abstract

Common acquired melanocytic nevi are benign neoplasms that are composed of small, uniform melanocytes and are typically present as flat or slightly elevated pigmented lesions on the skin. We describe two families with a new autosomal dominant syndrome characterized by multiple, skin-colored, elevated melanocytic tumors. In contrast to common acquired nevi, the melanocytic neoplasms in affected family members ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that showed overlapping features with melanoma. Some affected individuals developed uveal or cutaneous melanomas. Segregating with this phenotype, we found inactivating germline mutations of BAP1, which encodes a ubiquitin carboxy-terminal hydrolase. The majority of melanocytic neoplasms lost the remaining wild-type allele of BAP1 by various somatic alterations. In addition, we found BAP1 mutations in a subset of sporadic melanocytic neoplasms showing histological similarities to the familial tumors. These findings suggest that loss of BAP1 is associated with a clinically and morphologically distinct type of melanocytic neoplasm.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
BAP1 germline mutations in two families; left panel: family 1; right panel: family 2. (a) Pedigrees. Ages of onset of the first melanoma or ‘melanocytic tumor of uncertain malignant potential’ are written below the symbols. Only subjects older than 18 years were tested for mutations. An extended pedigree of family 1 is shown in Supplementary Fig. 15. (b) Representative melanocytic neoplasms from affected individuals (II-4 and II-7 from family 1; III-1 and III-3 from family 2). Note the characteristic inconspicuous, skin-colored to reddish-brown, dome-shaped appearance. Scale bars, 1 mm. (c) Histopathology of representative melanocytic tumors from both families showing relatively symmetrical intradermal proliferations of large epithelioid melanocytes with abundant cytoplasm and enlarged, irregularly-shaped, vesicular nuclei, some with prominent nucleoli. Scale bars, 50 μm. Scale bars inset, 1 mm.
Figure 2
Figure 2
Identification of the syndrome-causing gene. (a) Recurrent deletions affecting chromosome 3 in the melanocytic neoplasms of family 1. The two uppermost array-CGH profiles illustrate deletions of the entire chromosome 3, whereas the other profiles show focal deletions in 3p21. The minimally deleted region (black arrows) encompassed approximately 6 megabases. The next to last profile shows in addition a loss of chromosome 11 and the last profile a gain of chromosome 15. (b) Gene structure of BAP1 and germline mutations observed in affected individuals from family 1 and 2.
Figure 3
Figure 3
Bi-allelic BAP1 loss is associated with characteristic histological features in familial melanocytic neoplasms. (a) A melanocytic neoplasm from patient III-3, family 2, presents as a combined lesion with (b) an area of small cells (common acquired nevus) on the left, and (c) an area of large epithelioid cells on the right. Scale bars, 50 μm. Fluorescence in-situ hybridization (red signal: chr. 3p21 [BAP1]; orange: chr. 3p25 [control]; green: chr. 4p12 [control]) shows loss of BAP1 in the area with large epithelioid melanocytes (insert in c: one red BAP1 signal, but 2 orange and green control signals per nucleus. Scale bar, 10 μm), but no loss in the region of the common nevus (insert in b: two signals of each probe. Scale bar, 10 μm.). (d) BAP1 immunohistochemistry at the transition area between common nevus and epithelioid cell area shows a strong nuclear staining in the common nevus component (left) and loss of nuclear staining in the epithelioid component (right). Scale bar, 100 μm.
Figure 4
Figure 4
Progression of a nevus to melanoma is associated with loss of BAP1. (a) Scanning magnification of a sporadic melanoma (M) arising within a nevus (N) (hematoxylin-eosin stain). (b) Nevus component with bland melanocytes containing monomorphous round and oval-shaped nuclei. Scale bar, 50 μm. (c) Melanoma component showing melanocytes with large vesicular nuclei and prominent nucleoli. Scale bar, 50 μm. (d) MIB-1 immunohistochemistry shows a high proliferation rate in the melanoma compared to the nevus component. Scale bar, 100 μm. (e) BAP1 immunohistochemistry displays a conspicuous nuclear staining in the nevus contrasted with absent nuclear staining in the melanoma. Scale bar 100 μm. (f) The nevus component shows a BRAFV600E mutation, but no BAP1 mutation or chromosomal aberrations in aCGH. (g) The melanoma component shows the same BRAF mutation and in addition a focal loss of chromosome region 3p21 spanning the BAP1-locus in aCGH. The electropherogram of BAP1 demonstrates a frameshift mutation of the second BAP1 allele.
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