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. 2012 Aug 30:10:179.
doi: 10.1186/1479-5876-10-179.

BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs

Michele Carbone  1 , Laura Korb Ferris, Francine Baumann, Andrea Napolitano, Christopher A Lum, Erin G Flores, Giovanni Gaudino, Amy Powers, Peter Bryant-Greenwood, Thomas Krausz, Elizabeth Hyjek, Rachael Tate, Joseph Friedberg, Tracey Weigel, Harvey I Pass, Haining Yang
Affiliations

BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs

Michele Carbone et al. J Transl Med. .

Abstract

Background: BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene located on chromosome 3p21. Germline BAP1 mutations have been recently associated with an increased risk of malignant mesothelioma, atypical melanocytic tumors and other neoplasms. To answer the question if different germline BAP1 mutations may predispose to a single syndrome with a wide phenotypic range or to distinct syndromes, we investigated the presence of melanocytic tumors in two unrelated families (L and W) with germline BAP1 mutations and increased risk of malignant mesothelioma.

Methods: Suspicious cutaneous lesions were clinically and pathologically characterized and compared to those present in other families carrying BAP1 mutations. We then conducted a meta-analysis of all the studies reporting BAP1-mutated families to survey cancer risk related to the germline BAP1 mutation (means were compared using t-test and proportions were compared with Pearson χ2 test or two-tailed Fisher's exact test).

Results: Melanocytic tumors: of the five members of the L family studied, four (80%) carried a germline BAP1 mutation (p.Gln684*) and also presented one or more atypical melanocytic tumors; of the seven members of W family studied, all carried a germline BAP1 mutation (p.Pro147fs*48) and four of them (57%) presented one or more atypical melanocytic tumors, that we propose to call "melanocytic BAP1-mutated atypical intradermal tumors" (MBAITs). Meta-analysis: 118 individuals from seven unrelated families were selected and divided into a BAP1-mutated cohort and a BAP1-non-mutated cohort. Malignant mesothelioma, uveal melanoma, cutaneous melanoma, and MBAITs prevalence was significantly higher in the BAP1-mutated cohort (p ≤ 0.001).

Conclusions: Germline BAP1 mutations are associated with a novel cancer syndrome characterized by malignant mesothelioma, uveal melanoma, cutaneous melanoma and MBAITs, and possibly by other cancers. MBAITs provide physicians with a marker to identify individuals who may carry germline BAP1 mutations and thus are at high risk of developing associated cancers.

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Figures

Figure 1
Figure 1
Clinical presentations of MBAITs. MBAITs have variable clinical presentations including pink polypoid papules (1, from shoulder of patient W-F1-IV-9), raised pink papules (2, from groin of L-F1-IV-15), and lightly pigmented papules (3, from cheek of L-F1-IV-4). These lesions were clinically difficult to distinguish from banal dermal nevi, as pictured in (4), which shows a clinically similar lesion also from the chest of the same patient pictured in (2).
Figure 2
Figure 2
Histology and immunohistochemistry of MBAITs. Representative biopsy from individual W-III-04. The histologic examination (hematoxylin and eosin, H/E, of the nevi at the low power (H&E, 4X Original Magnification) magnification shows an intradermal melanocytic nevus with superficial nests and deeper single melanocytic units. This background melanocytic nevus shows maturation with depth. A second distinct, central, circumscribed population of melanocytes is identified at the mid-reticular dermis (1). This second population of melanocytes on higher power (H&E, 20X Original Magnification) shows variably sized, large epithelioid and spindled melanocytes. There is marked cytologic atypia comprised of pleomorphic, hyperchromatic nuclei (2). The immunohistochemistry for BAP1 demonstrates distinct staining between the background melanocytic nevus and the embedded clusters of atypical epithelioid melanocytes. Identified is strong nuclear positivity in the background melanocytic nevus and negative nuclear staining in the large epithelioid cells (3: BAP-1, 20X Original Magnification). On higher power, the background melanocytes show strong nuclear staining in this superficial nest (4: BAP-1, 40X Original Magnification). Large epithelioid cells with their pleomorphic nuclei demonstrate negative nuclear staining with variable cytoplasmic staining (5: BAP-1, 40X Original Magnification).
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