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About the Authors:
Lauren G. Aoude
* E-mail: [email protected]
Affiliations Oncogenomics Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia, University of Queensland, Brisbane, Queensland, Australia
Karin Wadt
Affiliation: Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark
Anders Bojesen
Affiliation: Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark
Dorthe Crüger
Affiliation: Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark
Åke Borg
Affiliation: Department of Clinical Sciences Lund, Division of Oncology, Lund University, Lund, Sweden
Jeffrey M. Trent
Affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America
Kevin M. Brown
Affiliations Translational Genomics Research Institute, Phoenix, Arizona, United States of America, Laboratory of Translational Genomics, National Cancer Institute, Bethesda, Maryland, United States of America
Anne-Marie Gerdes
Affiliation: Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark
Göran Jönsson
Affiliation: Department of Clinical Sciences Lund, Division of Oncology, Lund University, Lund, Sweden
Nicholas K. Hayward
Affiliation: Oncogenomics Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
Introduction
BRCA-1 associated protein-1 (BAP1) is a tumor suppressor gene located on chromosome 3, a region that has been linked to uveal melanoma (UMM). In the first report to make an association between BAP1 and UMM Harbour and colleagues used a next-generation sequencing approach to exome-sequence two tumors from patients with metastatic UMM [1]. BAP1 was found to be the only gene that was mutated on chromosome 3 in each of these samples and both mutations led to truncation of the protein. They next interrogated 57 UMM tumors using Sanger sequencing and found that BAP1 mutations occurred predominantly in tumors that had metastasized. Overall, 26/31 of the metastasizing (high risk) tumors had inactivating BAP1 somatic mutations compared to only 1/26 of the low risk (non-metastatic) group. For the 20 samples with a matched normal DNA sample, almost all BAP1 mutations were found to be acquired somatically, the exception being a single case with a matching germline frameshift mutation. This mutation introduced the possibility that BAP1 defects could predispose to UMM. Leading on from the study by Harbour et. al., several groups have looked at the risk of disease conferred by germline BAP1 mutation. Testa and colleagues investigated BAP1 mutations in two American families presenting with mesothelioma and who had no contact with any of the known environmental risk factors for this disease...