PMC4488956_01
Imaging of patient with germline BAP1 mutation. a. Retinal examination revealed a melanocytic tumor with irregular margins involving the majority of the retina. b. CT of the abdomen prior to surgery identified a 32 mm lobulated lesion in segment 4B of the liver as indicated by the arrow
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Fig1
A 72-year-old, previously well, woman was found to have left ocular uveal melanoma on ophthalmology review (Fig. 1). An abdominal CT scan demonstrated a lesion within segments 4 and 7 of her liver (Fig. 1).
Pedigree of the patient's family with a BAP1 germline mutation. Black Squares indicate a diagnosis of malignant mesothelioma. Arrow indicates the presence of BAP1 mutation as determined by sequencing studies. Two of the patient's children passed away with renal cell carcinoma (RCC) and acute lymphocytic leukaemia (ALL)
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Fig2
The patient's father and brother had both died of malignant mesothelioma (Fig. 2) having had occupational exposure to asbestos. The patient had four children, and two of these had passed away with renal cell carcinoma and acute lymphocytic leukaemia at ages 41 and 17 respectively (Fig. 2).
Histological findings of patient with BAP1 germline mutation a. Liver biopsy demonstrating focally necrotic poorly differentiated intrahepatic adenocarcinoma (Hemosiderin and Eosin, original magnification 250x). b. Immunohistochemical labeling for BAP1 protein in the cholangiocarcinoma, showing loss of nuclear staining. (Santa Cruz BAP1 monoclonal antibody (sc-28383) 1: 200. Dako dual system detection, original magnification 400x) c. Peritoneal biopsy demonstrating malignant mesothelioma of epithelial type with invasion into the submesothelial adipose tissue. (Hemosiderin and Eosin, original magnification 250x). d. Immunohistochemical labeling for BAP1 for peritoneal biopsy showing retained BAP1 nuclear staining in malignant peritoneal mesothelioma (Tissue preparation s above, original magnification 400x)
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Fig3
Testing for BAP1 mutations by immunohistochemistry showed loss of nuclear BAP1 labeling in the primary biliary tract adenocarcinoma, but nuclear labeling for BAP1 was retained in the malignant mesothelioma (Fig. 3).
Germline BAP1 missense mutation found in this patient. Germline DNA was extracted from the patient's blood and analysed by Sanger sequencing. DNA amplification and sequencing were performed as previously described (Forward primer: GGAGTTGGCCAAGGCCCATAATAGC; reverse primer: CCTGGATACTCTCTGTCCCTCCCAAAG). Electropherogram shows BAP1 missense mutation (g.52441252A > G) within exon 7. This mutation produces an amino-acid sequence switch from tyrosine to cysteine in the ubiquitin hydrolase domain (UCH), and indicated by the diagram
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Fig4
Germline DNA sequencing was performed and revealed the patient to carry a germline missense mutation in the catalytic domain (g.52441252A > G, p.Tyr173Cys) located in exon 7 of the BAP1 gene (Fig. 4).