Frequent Mutation of BAP1 in Metastasizing Uveal Melanomas

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 mela...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2010-12, Vol.330 (6009), p.1410-1413
Main Authors: Harbour, J. William, Onken, Michael D, Roberson, Elisha D.O, Duan, Shenghui, Cao, Li, Worley, Lori A, Council, M. Laurin, Matatall, Katie A, Helms, Cynthia, Bowcock, Anne M
Format: Article
Language:English
Subjects:
Biological and medical sciences
Cell Line, Tumor
Chromosome Deletion
Chromosomes
Chromosomes, Human, Pair 3 - genetics
DNA
Exons
Frameshift Mutation
Genetic mutation
Germ-Line Mutation
Humans
Medical sciences
Melanoma
Melanoma - genetics
Melanoma - secondary
Messenger RNA
Metastasis
Missense mutation
Mutation
Mutation, Missense
Neoplasm Metastasis
Ophthalmology
Protein Structure, Tertiary
RNA Interference
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA, Neoplasm - genetics
RNA, Neoplasm - metabolism
Sequence Analysis, DNA
Small interfering RNA
Tumor Suppressor Proteins - chemistry
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Tumors
Tumors and pseudotumors of the eye, orbit, eyelid, lacrimal apparatus
Ubiquitin Thiolesterase - chemistry
Ubiquitin Thiolesterase - genetics
Ubiquitin Thiolesterase - metabolism
Uveal Neoplasms - genetics
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1194472