Journal
SCIENCE
Volume 330, Issue 6009, Pages 1410-1413Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1194472
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Funding
- National Cancer Institute [R01 CA125970]
- Barnes-Jewish Hospital Foundation
- Kling Family Foundation
- Tumori Foundation
- Horncrest Foundation
- Research to Prevent Blindness, Inc.
- NIH [P30 EY02687c]
- NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR007279-31A1]
- Washington University
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Metastasis is a defining feature of malignant tumors and is the most common cause of cancer-related death, yet the genetics of metastasis are poorly understood. We used exome capture coupled with massively parallel sequencing to search for metastasis-related mutations in highly metastatic uveal melanomas of the eye. Inactivating somatic mutations were identified in the gene encoding BRCA1-associated protein 1 (BAP1) on chromosome 3p21.1 in 26 of 31 (84%) metastasizing tumors, including 15 mutations causing premature protein termination and 5 affecting its ubiquitin carboxyl terminal hydrolase domain. One tumor harbored a frameshift mutation that was germline in origin, thus representing a susceptibility allele. These findings implicate loss of BAP1 in uveal melanoma metastasis and suggest that the BAP1 pathway may be a valuable therapeutic target.
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