Frequent inactivation of the BAP1 gene in epithelioid‐type malignant mesothelioma
- 21 February 2012
- journal article
- Published by Wiley in Cancer Science
- Vol. 103 (5), 868-874
- https://doi.org/10.1111/j.1349-7006.2012.02223.x
Abstract
In the present study, we analyzed genomic alterations of BRCA1‐associated protein 1 (BAP1) in 23 malignant mesotheliomas (MMs), 16 epithelioid and seven non‐epithelioid, consisting of 18 clinical specimens and five established cell lines. In examining these samples for homozygous deletions and sequence‐level mutations, we found biallelic BAP1 gene alterations in 14 of 23 MMs (61%). Seven of these 14 MMs had homozygous deletions of the partial or entire BAP1 gene, another five had sequence‐level mutations, including small deletions, a nonsense mutation, and missense mutations with additional monoallelic deletions, and the remaining two had homozygous mutations without allelic loss. All but one of the 14 BAP1 gene mutations were found in the epithelioid‐type MMs; BAP1 mutations were found in 13 of 16 epithelioid‐type MMs, but in only one of seven non‐epithelioid‐type MMs (13/16 vs 1/7; P = 0.005). There was no BAP1 mRNA expression in MMs with biallelic deletion and repressed expression was confirmed in MM specimens with deletion/mutation as compared with Met5a, SV40‐transformed normal mesothelial cells. Western blot showed that seven of eight epithelioid MMs analyzed were BAP1 negative. Immunostaining with anti‐BAP1 antibody in normal lung tissues revealed clear nuclear staining of normal mesothelial cells. No nuclear staining was observed among BAP1 mutation‐positive MM tumors, whereas nuclear staining was observed among BAP1 mutation‐negative MM tumors. These results suggest that the lack of the tumor suppressor BAP1 may be more specifically involved in the pathogenesis of epithelioid MM rather than non‐epithelioid MM, and would be useful for diagnosis of epithelioid‐type MM. (Cancer Sci 2012; 103: 868–874)Keywords
This publication has 18 references indexed in Scilit:
- Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancersJournal of Medical Genetics, 2011
- Germline BAP1 mutations predispose to malignant mesotheliomaNature Genetics, 2011
- Germline mutations in BAP1 predispose to melanocytic tumorsNature Genetics, 2011
- The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesotheliomaNature Genetics, 2011
- Frequent Mutation of BAP1 in Metastasizing Uveal MelanomasScience, 2010
- Survival and Prognostic Factors in Malignant Pleural Mesothelioma: A Retrospective Study of 314 patients in the West Part of JapanJapanese Journal of Clinical Oncology, 2010
- The Deubiquitinating Enzyme BAP1 Regulates Cell Growth via Interaction with HCF-1Online Journal of Public Health Informatics, 2009
- Association of C-Terminal Ubiquitin Hydrolase BRCA1-Associated Protein 1 with Cell Cycle Regulator Host Cell Factor 1Molecular and Cellular Biology, 2009
- BRCA1-Associated Protein-1 Is a Tumor Suppressor that Requires Deubiquitinating Activity and Nuclear LocalizationCancer Research, 2008
- Latency of asbestos disease among insulation workers in the United States and CanadaCancer, 1980