Two new studies report germline mutations in BAP1

Abstract

Two new studies describe germline mutations in BAP1 in putatively dissimilar cancer-related syndromes. Although the predominant neoplasms – melanocytic tumors with distinct clinical and histopathological features versus mesothelioma – differ, uveal melanoma occurs, albeit infrequently, in both disorders.

BAP1 is a tumor suppressor gene located on chromosome 3p21 in a region that shows loss or deletions in numerous cancers, including lung and breast cancer, as well as uveal melanoma and mesothelioma. Two recent studies reported high frequencies of somatic mutations in BAP1 in uveal melanoma¹ and mesothelioma². Harbour et al¹ found inactivating somatic mutations of BAP1 in 47% (28/60) (Table 1) of uveal melanoma with a much higher frequency of somatic mutations (27/34, 79%) in metastasizing uveal melanoma. In addition, one tumor had a germline frameshift mutation, suggesting that this variant was a susceptibility allele. Bott et al² identified somatic inactivating mutations in BAP1 in 23% (12/53) of a discovery set of malignant pleural mesotheliomas (MPM), half from patients who reported asbestos exposure, and in 18% (12/68) of an independent set of MPM [total: 20% (24/121)]. In this issue, Wiesner, Bastian, Speicher and colleagues³ and Testa, Carbone, and colleagues⁴ provide further links between BAP1, uveal melanoma and mesothelioma by reporting on germline mutations of BAP1 in two putatively distinct cancer-related syndromes characterized predominantly by melanocytic tumors or mesothelioma, respectively, plus uveal melanoma in both disorders.

Table 1.

Tumors with somatic mutations in BAP1

Tumor Type	No. Tumors	Somatic Mutations		Reference
		No.	%
Melanocytic
Common nevi	29	0	0.0	Wiesner et al3
Spitz nevi	17	0	0.0	Wiesner et al3
Atypical Spitz nevi	18	2*	11.1	Wiesner et al3
Cutaneous melanoma	60	3	5.0	Wiesner et al3
Uveal melanoma, total	93	41	44.1	Wiesner et al3; Harbour et al1
Wiesner et al3 study	33	13	39.4	Wiesner et al3
Harbour et al1 study	60	28	46.7	Harbour et al1
Low metastatic risk	26	1	3.8	Harbour et al1
High metastatic risk	31	25	80.6	Harbour et al1
Metastatic	3	2	66.7	Harbour et al1
Mesothelioma, total	139	28	20.1	Testa et al; Bott et al2
Testa et al study4	18	4	22.2	Testa et al4
Bott et al study2	121	24	19.8	Bott et al2
Breast	251	1	0.6	Forbes et al, 2008 & 20115,6
Lung	322	2	0.4	Forbes et al, 2008 & 20115,6
Ovary	59	2	3.4	Forbes et al, 2008 & 20115,6
Pancreas	30	0	0.0	Forbes et al, 2008 & 20115,6

^*These tumors had morphologic features similar to the melanocytic tumors observed in families 1 and 2 (Wiesner et al³)

Two new cancer-related syndromes?

Wiesner et al³ identified co-segregating germline mutations of BAP1 in two families (1 and 2) with multiple members with melanocytic tumors that ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that had features that overlapped with cutaneous melanoma. Both families had one member with uveal melanoma and family 2 had multiple members with cutaneous melanoma. Affected family members had many (5 to >50) of the clinically and histopathologically distinct melanocytic tumors, whereas few melanomas developed suggesting that the risk of malignant potential in individual tumors was low. Examination of a subset of the familial melanocytic tumors revealed that the majority of tumors showed biallelic inactivation of BAP1 by various somatic alterations.

Testa et al⁴ discovered co-segregating germline mutations in BAP1 in two families (L and W) with 5 or more members with mesothelioma. The families had modest levels of asbestos exposure from having lived in asbestos-containing houses but did not have occupational asbestos exposure. The families also had multiple members with various malignancies including two members with uveal melanoma in family L. Somatic alterations of the familial mesothelioma tumors indicated biallelic inactivation of BAP1. Testa et al⁴ also sequenced BAP1 in germline DNAs from 26 sporadic mesothelioma cases and uncovered two inactivating frameshift mutations in patients subsequently found to have had uveal melanoma. Given the rarity of both uveal melanoma and mesothelioma in the United States, the authors concluded that it was extremely unlikely for these two malignancies to have occurred in the same individuals by chance.

Cancers and BAP1 mutations

Besides uveal melanoma, mesothelioma, and the distinct melanocytic tumors, numerous additional tumors were observed in the families^3,4. Several cancers including cutaneous melanoma (n=3), non-melanoma skin (n=2), ovarian (n=1), breast (n=1), renal (n=1), and pancreatic (n=1) cancer occurred in family members who inherited their family’s inactivating BAP1 mutation. Whether these cancers are part of the spectrum of tumors related to germline BAP1 mutations requires additional study.

Data from COSMIC (Catalogue Of Somatic Mutations In Cancer)^5,6 showed low frequencies of somatic BAP1 mutations in several of the observed tumors including breast (0.4%), ovarian (3.4%), and pancreatic (0.0%) cancer (table 1). In addition, Wiesner et al³ showed that five percent (3/60) of primary melanomas originating from acral skin (n=15), mucosa (n=15), or skin with (n=15) or without chronic sun damage had somatic BAP1 mutations. Finally, lung cancer, which was one of the first cancers originally reported to have BAP1 somatic mutations⁷, also had very few somatic mutations (0.6%)^5,6 suggesting that another gene in the 3p21 region may be implicated in some of the cancers that show loss/deletion in this region^8–10. Alternatively, a different mechanism of inactivation of BAP1 may be involved. In contrast to the low frequency of somatic mutations for the tumor types described above, 44% (41/93) of uveal melanoma and 20% (28/139) of sporadic mesotheliomas had somatic mutations of BAP1^1–4 (table 1). For most of the tumors evaluated, BAP1 showed biallelic loss. Harbour et al¹ hypothesized that biallelic loss of BAP1 was a key event in uveal melanoma metastasis. The current studies suggest a potentially more complex scenario that may depend on various combinations of the tissue of origin, environmental exposures, functional consequences of the BAP1 mutations, and mechanisms of inactivation of the second BAP1 allele.

BAP1 (ubiquitin carboxy-terminal hydrolase/BRCA1-associated protein 1), a 729 amino acid nuclear-localized deubiquitinating enzyme, was originally identified as an ubiquitin hydrolase that binds to the RING finger domain of BRCA1^7,11. BAP1 contains numerous functional domains including the ubiquitin carboxy-terminal hydrolase (UCH) domain, a host cell factor-1 (HCF-1) binding domain, and binding domains for BRCA1 and BARD1. BAP1 has been functionally implicated in numerous biologic processes including chromatin, DNA damage response, and regulation of the cell cycle and cell growth^{1,2,7,11–15}. Given its complexity, different germline mutations in BAP1 may predispose to divergent tumor types.

Future Directions

These studies raise several provocative questions. Are these disorders two distinct syndromes or a single syndrome with a wide phenotypic range? For what tumor types do germline mutations of BAP1 increase susceptibility? What role do exposures (e.g. asbestos, ultraviolet radiation) have on the tumor types that develop? Are there genotype-phenotype correlations between specific germline (or somatic) mutations and the resultant tumors? Answers to these questions will require extensive additional clinical, molecular genetic, genetic epidemiologic and functional studies. Since its original discovery in 1998⁷, BAP1 has captivated and beguiled scientists. The studies by Wiesner, Bastian, Speicher and colleagues³ and Testa, Carbone, and colleagues⁴ continue this trend.