High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma

Our plain-English summary of High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma, by M. Nasu, M. Emi, S. Pastorino, et al (Journal of Thoracic Oncology, 2015).

The study

• Authors: M. Nasu, M. Emi, S. Pastorino, M. Tanji, A. Powers, H. Luk, F. Baumann, Y.A. Zhang, A. Gazdar, S. Kanodia, M. Tiirikainen, E. Flores, G. Gaudino, M.J. Becich, H.I. Pass, H. Yang, M. Carbone
• Journal: Journal of Thoracic Oncology
• Published: 2015;10(4):565-76
• Cited by: 257 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Breast cancer 1-associated protein 1 (BAP1) is a nuclear deubiquitinase that regulates gene expression, transcription, DNA repair, and more. Several findings underscore the apparent driver role of BAP1 in malignant mesothelioma (MM). However, the reported frequency of somatic BAP1 mutations in MM varies considerably, a discrepancy that appeared related to either methodological or ethnical differences across various studies.

Methods: To address this discrepancy, we carried out comprehensive genomic and immunohistochemical (IHC) analyses to detect somatic BAP1 gene alterations in 22 frozen MM biopsies from U.S. MM patients.

Results: By combining Sanger sequencing, multiplex ligation-dependent probe amplification, copy number analysis, and cDNA sequencing, we found alteration of BAP1 in 14 of 22 biopsies (63.6%). No changes in methylation were observed. IHC revealed normal nuclear BAP1 staining in the eight MM containing wild-type BAP1, whereas no nuclear staining was detected in the 14 MM biopsies containing tumor cells with mutated BAP1. Thus, IHC results were in agreement with those obtained by genomic analyses. We then extended IHC analysis to an independent cohort of 70 MM biopsies, of which there was insufficient material to perform molecular studies. IHC revealed loss of BAP1 nuclear staining in 47 of these 70 MM biopsies (67.1%).

Conclusions: Our findings conclusively establish BAP1 as the most commonly mutated gene in MM, regardless of ethnic background or other clinical characteristics. Our data point to IHC as the most accessible and reliable technique to detect BAP1 status in MM biopsies.

In plain English

This laboratory study looked for somatic (tumor-only) changes in the BAP1 gene in malignant mesothelioma (MM) from U.S. patients. The authors tested 22 frozen MM biopsies from New York University Langone Medical Center with several genetic methods and with immunohistochemistry (IHC), a staining test for the BAP1 protein. Matching blood DNA carried normal BAP1 in all 22 patients. Sanger sequencing alone found BAP1 mutations in 6 of 22 biopsies (27.3%); adding the other genetic methods raised this to 14 of 22 (63.6%). All 14 altered tumors lacked BAP1 staining in the cell nucleus, while the 8 unaltered tumors stained normally. BAP1 promoter methylation was low (1–4%) in every one of the 22 biopsies. In a separate set of 70 biopsies tested by IHC only, 47 (67.1%) lacked nuclear BAP1 staining. The authors found no significant relationship between BAP1 alterations and sex, age, ethnicity or asbestos exposure history, while noting the small sample size. They concluded that BAP1 is the most commonly mutated gene in MM and that IHC is a reliable way to identify BAP1 mutations.

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 study of tumor biopsies using several genetic tests (Sanger sequencing, MLPA, TaqMan copy number analysis, RNA/cDNA sequencing, methylation analysis) together with immunohistochemistry
• Who was studied: 22 frozen MM biopsies with matching normal blood cells from U.S. patients at New York University Langone Medical Center. A separate cohort of 70 U.S. MM biopsy slides (63 Caucasian, 7 non-Caucasian) came from the National Mesothelioma Virtual Bank, University of Pittsburgh. Dates are not given.
• Exposure: Not an asbestos exposure study. The study examined somatic (tumor-only) BAP1 gene alterations. Patients' asbestos exposure history was collected and compared with BAP1 status. No fiber types, products, jobs or doses are given in the text.
• Main results:
  • Normal (blood) DNA of all 22 patients carried the normal (wild-type) BAP1 gene, so none had an inherited BAP1 mutation
  • Sanger sequencing alone detected BAP1 mutations in 6 of 22 biopsies (27.3%)
  • Combining all genetic methods, BAP1 was altered in 14 of 22 biopsies (63.6%)
  • All 14 biopsies with BAP1 alterations lacked BAP1 staining in the cell nucleus
  • The 8 biopsies without detected BAP1 alterations showed nuclear BAP1 staining in all tumor cells
  • BAP1 promoter methylation, measured at seven sites just upstream of the gene's start, was consistently low (1–4%) in all 22 biopsies
  • In database (TCGA) data from other tumor types, four sites in the BAP1 gene body and 3′ untranslated region were heavily methylated in all tissues examined, while the other 15 sites, including all those in the promoter/exon 1 region, were completely or nearly completely unmethylated
  • In the separate cohort tested by IHC only, nuclear BAP1 staining was lost in 47 of 70 biopsies (67.1%) and in 44 of the 63 Caucasian biopsies (69.8%)
  • In the separate cohort, six specimens contained a mix of tumor cells with and without nuclear BAP1 staining
  • No significant relationship was found between BAP1 alterations and sex, age at diagnosis, ethnicity or history of asbestos exposure
  • Patients with altered BAP1 had survival similar to patients with normal BAP1
  • BAP1 alterations appeared more frequent in epithelial-type MM than in other histological subtypes. No statistic is given for this.
• The authors' conclusion: The authors concluded that the more than 60% frequency of BAP1 mutations they found in sporadic MM identifies BAP1 as the most commonly mutated gene in MM. They also concluded that IHC is a reliable way to identify BAP1 mutations.
• Limitations the authors state:
  • Because of the small sample size, the authors did not draw conclusions about clinical correlations (demographics, histology, survival) with BAP1 status
  • Molecular studies could not definitely establish loss of the second gene copy (LOH) in eight altered samples, possibly because of contaminating normal-cell DNA
  • The 70-case cohort could be tested only by IHC, not by genetic analysis
  • The characteristics of the patients who supplied the control tissues are not known
  • The gene-body methylation analysis relied on other tumor types because methylation data on MM were not available in the TCGA database

Topics

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

Medical terms in this study, explained in our Lexicon: BAP1, Malignant Mesothelioma.

Related studies

• BAP1 gene mutations in Egyptian patients with advanced sporadic malignant pleural mesothelioma (MPM): relation with clinical outcomes and survival — A.A. Bahnasy, R.S. El-Din, et al. (2018)
• Germline BAP1 mutations induce a Warburg effect — A. Bononi, H. Yang, et al. (2017)
• BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma — H. Alakus, S.E. Yost, et al. (2015)
• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)
• Genetic Basis of Mesothelioma--More Than Asbestos Exposure — D. Lee (2016)
• BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos — F. Novelli, A. Bononi, et al. (2021)

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