Frequent inactivation of the BAP1 gene in epithelioid-type malignant mesothelioma

Our plain-English summary of Frequent inactivation of the BAP1 gene in epithelioid-type malignant mesothelioma, by Y. Yoshikawa, A. Sato, T. Tsujimura, et al (Cancer Science, 2012).

The study

• Authors: Y. Yoshikawa, A. Sato, T. Tsujimura, M. Emi, T. Morinaga, K. Fukuoka, S. Yamada, A. Murakami, N. Kondo, S. Matsumoto, Y. Okumura, F. Tanaka, S. Hasegawa, T. Nakano, T. Hashimoto-Tamaoki
• Journal: Cancer Science
• Published: 2012;103(5):868-74
• Cited by: 146 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2012 Japanese Cancer Association.

In plain English

In this genetic study from Hyogo College of Medicine, Japan, the authors looked for damage to the BAP1 gene in 23 malignant mesotheliomas. These were 18 patient samples from their hospital and five established cell lines; 16 were epithelioid type and seven non-epithelioid. The article did not report asbestos exposure. Both copies of BAP1 were altered in 14 of the 23 mesotheliomas (61%). In seven of them, the gene was partly or entirely deleted from both copies. Alterations were found in 13 of 16 epithelioid mesotheliomas (81%) but only one of seven non-epithelioid ones (P = 0.005, statistically significant). BAP1 messenger RNA was absent in six patient samples with both copies deleted. A protein test found no BAP1 protein in seven of eight epithelioid samples analyzed. Tumors with BAP1 alterations generally lacked BAP1 staining in cell nuclei, though some tumor cells in one case stained; tumors with a normal gene stained. The authors concluded that loss of BAP1 expression could be useful in diagnosing epithelioid mesothelioma. They noted changes during cell culture could not be fully ruled out.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory genetic study of tumor samples and cell lines (gene sequencing, gene expression, protein and tissue staining)
• Who was studied: 23 malignant mesotheliomas (16 epithelioid, 7 non-epithelioid): samples from 18 patients diagnosed at the hospital of Hyogo College of Medicine, Japan (16 primary cell cultures and 2 tissue specimens), plus four cell lines from the American Type Culture Collection and one from the Riken Bioresource Center
• Exposure: Not studied. The article does not report asbestos exposure for the patients; the study examined alterations of the BAP1 gene.
• Main results:
  • Both copies of the BAP1 gene were altered in 14 of 23 mesotheliomas (61%)
  • Seven of the 14 had deletions of BAP1 on both copies
  • BAP1 alterations were found in 13 of 16 epithelioid mesotheliomas (81%). Only one non-epithelioid mesothelioma (MM62-P) had them. The frequency was significantly higher in the epithelioid type (P = 0.005).
  • Alterations were judged to have arisen in the tumor (somatic) in nine cases where matched blood was available
  • No BAP1 mRNA expression was found in six of 16 patient primary cell cultures, attributed to deletion of both gene copies
  • Western blotting showed that seven of eight epithelioid mesotheliomas analyzed were BAP1 protein negative
  • Tumor tissues from mesotheliomas with BAP1 alterations showed no nuclear BAP1 staining, with one exception: some, but not all, tumor cells of MM56 stained. Normal mesothelial cells and tumors with the normal (wild-type) gene did show nuclear staining.
• The authors' conclusion: The authors concluded that lack of BAP1 may be more specifically involved in the development of epithelioid than non-epithelioid mesothelioma, and that loss of BAP1 expression could be useful in diagnosing epithelioid-type mesothelioma
• Limitations the authors state:
  • Genomic or expression changes during cell culture could not be completely ruled out
  • The authors could not prove that two samples (H28 and MM62-P) had homozygous mutations without allelic loss
  • Whether alterations were somatic could not be determined in three cases because matched normal tissue was unavailable
  • The significance of granular cytoplasmic staining seen in some tumors with BAP1 inactivation was not determined

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Epithelioid, Malignant Mesothelioma, Non-epithelioid, Homozygous Deletion, SV40, Mesothelial Cells.

Related studies

• Frequent deletion of 3p21.1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells — Y. Yoshikawa, A. Sato, et al. (2011)
• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)
• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)
• BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma — H. Alakus, S.E. Yost, et al. (2015)
• Sarcomatoid Mesothelioma: A CDKN2A molecular analysis of 53 cases with immunohistochemical correlation with BAP1 — M. Zaleski, N. Kalhor, et al. (2020)
• Functional differences between wild-type and mutant-type BRCA1-associated protein 1 tumor suppressor against malignant mesothelioma cells — S. Hakiri, H. Osada, et al. (2015)

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