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 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.
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA. harbour@vision.wustl.edu
J William
JW
Harbour
Michael D
MD
Onken
Elisha D O
ED
Roberson
Shenghui
S
Duan
Li
L
Cao
Lori A
LA
Worley
M Laurin
ML
Council
Katie A
KA
Matatall
Cynthia
C
Helms
Anne M
AM
Bowcock
D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D016368:Frameshift Mutation; D018095:Germ-Line Mutation; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000556:secondary*; D009154:Mutation; D020125:Mutation, Missense; D009362:Neoplasm Metastasis; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014604:Uveal Neoplasms / Q000235:genetics*
C400134:BAP1 protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase