Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases

Abstract

The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma. However, the frequency of the syndrome in patients with UM and the association with other cancers are still not clear. In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1. We also studied four additional patients with a personal or family history suggestive of BAP1 hereditary cancer syndrome. We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1. Two of these three patients presented with UM and the third with a metastatic adenocarcinoma likely from a hepatic cholangiocarcinoma. Reported family histories included UM, mesothelioma, RCC, CM, and several other internal malignancies. The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC. However, other cancers, such as cholangiocarcinoma and breast carcinoma may be part of the phenotype of this hereditary cancer predisposition syndrome. In addition, the results support the existence of other candidate genes in addition to BAP1 contributing to hereditary predisposition to UM.

Figure 1

Summary of the patients included in the study. (A) Venn diagram summarizing the cancer history of the 46 UM patients included in the study. CM: cutaneous melanoma; UM: uveal melanoma; RCC: renal cell carcinoma. Black plus sign indicates individuals with mutation identified by sequencing. Grey plus sign indicates obligate carriers. (B) FUM 064: Individuals IV.1 and III.12 were heterozygous for a truncating mutation in BAP1 the c.2050C>T, p.Gln684*. Individuals II.1, III.1 and II.4 are obligate carriers. Mutations reported in the family were UM (III.1, IV.1, and IV.5), mesothelioma (II.3, III.3, III.11, and III.12), RCC (III.9), stomach (II.4), unknown primary (II.1, II.2), spindle cell malignancy (IV.1), pancreatic (III.5), papillary thyroid (III.4), colorectal (IV.3), and breast (III.2). (C) FUM 104: Individuals III.1, II.5, and IV.3 were heterozygous for a frame shift mutation (c.1882_1885delT-CAC, p. Ser628Profs*8) in BAP1. Cancers reported in the family were UM (III.1), RCC (III.3, III.4, III.5, and IV.3), mesothelioma (III.3, III.4), colon (III.1), lung (III.3, III.4), breast (II.5, III.6, IV.1, IV. 5), hematological (IV.6), bladder (IV.4), and pancreatic (not listed). No other individuals were tested. (D) FUM103: Individual III.1 was heterozygous for a truncating mutation, c.1182C>G, p.Tyr394*. Patient presented with metastatic adenocarcinoma likely from a hepatic cholangiocarcinoma. Cancers reported in the family were pancreatic (II.2), CM (II.1), ovarian (II.5), mesothelioma (II.3), unknown (II.4, II.3), and nonmelanoma skin cancer (III.2). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 2

Mutations detected and BAP1 expression in tumors. (A) The identified mutations in the three families. Heterozygous mutations were detected in the germline of the three families and in the tumors from FUM064/III-12 and FUM103/III-1. PB: peripheral blood and T: tumor. All chromatograms are utilizing forward primer. (B) BAP1 immunostaining in the tumor of FUM064/III-12 show loss of nuclear staining of tumor cells (thick arrow) with positive staining of the nuclei in the stromal cells (thin arrows). (C) BAP1 immunostaining in the tumor of FUM103/III-1 show strong cytoplasmic expression of BAP1 with loss of nuclear localization in the tumor cells (thick arrow) with positive staining of the nuclei in the stromal cells (thin arrows). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]