Frequent Mutation of BAP1 in Metastasizing Uveal Melanomas

By J. Harbour, M. Onken, E. Roberson, Shenghui Duan, Li Cao, Lori A. Worley, M. Council, K. Matatall, C. Helms, A. Bowcock. Science, 2010

1,349 citations recorded by the source corpus.

An Eye on Metastasis Despite the considerable progress being made in elucidating the cell biology of metastasis, little is known about the genetic alterations that promote metastasis of human tumors, the cause of most cancer deaths. A potentially important clue now emerges from the work of Harbour et al. (p. 1410, published online 4 November), who used an exome-sequencing approach to search for genetic mutations in uveal melanomas, an eye cancer associated with a high rate of fatal metastasis. Remarkably, over 80% of tumor samples with a high metastatic risk had inactivating somatic mutations in the gene encoding BAP1 (BRCA1-associated protein 1), a nuclear protein involved in controlling protein degradation. Thus, in this tumor type, mutational inactivation of BAP1 may be a key event in the acquisition of metastatic competence. A gene implicated in the control of protein degradation is mutated at high frequency in a metastatic eye cancer. 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.

Subfields: Genetics, Molecular Biology, Ophthalmology

View Paper: https://www.semanticscholar.org/paper/93c73db558935a737fd7b79c01902bf638bc2eb9

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Citations in the corpus

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. (2018, background): “Loss-of-function mutations in BAP1, which is located on 3p21, have been identified in M3-UM (Harbour et al., 2010), and decreased BAP1 mRNA and protein expression, indicating BAP1 aberrancy, are highly correlated with the development of UM metastases (Kalirai et al.”