Abstract
BackgroundGermline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma. Alternatively, somatic mutations in BAP1 in UM have been associated with high risk for metastasis. In this study, we compare the risk of metastasis in UM that carry germline versus somatic BAP1 mutations and mutation-negative tumors.MethodsDNA extracted from 142 UM and matched blood samples was sequenced using Sanger or next generation sequencing to identify BAP1 gene mutations.ResultsEleven of 142 UM (8%) carried germline BAP1 mutations, 43 (30%) had somatic mutations, and 88 (62%) were mutation-negative. All BAP1 mutations identified in blood samples were also present in the matched UM. There were 52 unique mutations in 54 tumors. All were pathogenic or likely pathogenic.A comparison of tumors carrying somatic vs. germline mutations, or no mutations, showed a higher frequency of metastasis in tumors carrying somatic mutations: 74% vs. 36%, P=0.03 and 74% vs. 26% P<0.001, respectively. Tumors with a somatic mutation compared to mutation-negative had an older age of diagnosis of (61.8 vs. 52.2 years, P=0.002), and shorter time to metastasis (16 vs. 26 months, P=0.04). Kaplan-Meier analysis further showed that tumors with somatic (vs. germline) mutations demonstrated a greater metastatic risk (P=0.03). Cox multivariate analysis showed in addition to chromosome-3 monosomy and larger tumor diameter, the presence of BAP1 somatic, but not germline mutations, was significantly associated with risk of metastasis(P=0.02).Personal or family history of BAP1-TPDS was available for 79 of the cases. All eight cases with germline mutations reported a history of BAP1-TPDS, which was significantly greater than what was observed in cases with somatic mutations (10 of 23, P=0.009) or mutation-negative cases (11 of 48, P<0.001).ConclusionsDefining germline vs. somatic nature of BAP1 mutations in UM can inform the individual about both the risk of metastasis, and the time to metastasis, which are critically important outcomes for the individual. This information can also change the cascade screening and surveillance of family members.
Highlights
Germline mutations in BRCA1-associated protein 1 (BAP1) have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma
Germline BAP1 mutations have been associated with hereditary predisposition to multiple different cancers that include uveal and cutaneous melanoma, malignant mesothelioma on exposure to asbestos, renal cell carcinoma and other cancer types, such as lung adenocarcinoma and meningioma, that are collectively referred to as BAP1 Tumor Predisposition Syndrome (BAP1-TPDS, OMIM #614327) [4, 5]
Kaplan-Meier analysis further showed that tumors with somatic mutations were associated with the poorest metastatic outcome, while there was no significant difference between tumors carrying a germline mutation and mutation-negative tumors
Summary
Germline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma. Germline BAP1 mutations have been associated with hereditary predisposition to multiple different cancers that include uveal and cutaneous melanoma, malignant mesothelioma on exposure to asbestos, renal cell carcinoma and other cancer types, such as lung adenocarcinoma and meningioma, that are collectively referred to as BAP1 Tumor Predisposition Syndrome (BAP1-TPDS, OMIM #614327) [4, 5]. The prognosis for UM is poor in approximately 50% of cases primarily due to metastasis to the liver within a short time [10, 11] Factors such as large tumor size, location and chromosome 3 monosomy [12,13,14,15,16,17,18], as well as a specific 12-gene expression pattern [19,20,21] have all been associated with an increased risk of metastasis. The presence of inactivating somatic [22,23,24,25,26,27,28,29] or germline [30] BAP1 mutations often in conjunction with chromosome 3 monosomy, loss of BAP1 expression, or lack of immunohistochemical staining, have all been associated with metastasizing UM
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