Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X

Our plain-English summary of Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X, by N.M. Joseph, Y.Y. Chen, A. Nasr, et al (Modern Pathology, 2017).

The study

• Authors: N.M. Joseph, Y.Y. Chen, A. Nasr, I. Yeh, E. Talevich, C. Onodera, B.C. Bastian, J.T. Rabban, K. Garg, C. Zaloudek, D.A. Solomon
• Journal: Modern Pathology
• Published: 2017;30(2):246-254
• Cited by: 83 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is a rare cancer that arises from the mesothelial cells that line the pleural cavity and less commonly from the peritoneal lining of the abdomen and pelvis. Most pleural mesotheliomas arise in patients with a history of asbestos exposure, whereas the association of peritoneal mesotheliomas with exposure to asbestos and other potential carcinogens is less clear, suggesting that the genetic alterations that drive malignant peritoneal mesothelioma may be unique from those in pleural mesothelioma. Treatment options for all malignant mesotheliomas are currently limited, with no known targeted therapies available. To better understand the molecular pathogenesis of malignant peritoneal mesothelioma, we sequenced 510 cancer-related genes in 13 patients with malignant mesothelioma arising in the peritoneal cavity. The most frequent genetic alteration was biallelic inactivation of the BAP1 gene, which occurred in 9/13 cases, with an additional two cases demonstrating monoallelic loss of BAP1. All 11 of these cases demonstrated loss of BAP1 nuclear staining by immunohistochemistry, whereas two tumors without BAP1 alteration and all 42 cases of histologic mimics in peritoneum (8 multilocular peritoneal inclusion cyst, 6 well-differentiated papillary mesothelioma of the peritoneum, 16 adenomatoid tumor, and 12 low-grade serous carcinoma of the ovary) demonstrated intact BAP1 nuclear staining. Additional recurrently mutated genes in this cohort of malignant peritoneal mesotheliomas included NF2 (3/13), SETD2 (2/13), and DDX3X (2/13). While these genes are known to be recurrently mutated in pleural mesotheliomas, the frequencies are distinct in peritoneal mesotheliomas, with nearly 85% of peritoneal tumors harboring BAP1 alterations versus only 20-30% of pleural tumors. Together, these findings demonstrate the importance of epigenetic modifiers including BAP1, SETD2, and DDX3X in mesothelial tumorigenesis and suggest opportunities for targeted therapies.

In plain English

This laboratory study from the University of California, San Francisco examined tumors from 13 patients with malignant peritoneal mesothelioma (mesothelioma of the abdominal lining), diagnosed between 1991 and 2015. The authors sequenced 510 cancer-related genes in each tumor and stained the tumors for the BAP1 protein. The article does not report the patients' asbestos or other exposures. Eleven of the 13 tumors (85%) had alterations in the BAP1 gene, with both copies affected in 9. One patient carried a BAP1 mutation that was also present in normal body cells (a germline mutation). These same 11 tumors had lost BAP1 staining. All 42 selected tumors that can look similar under the microscope, including ovarian low-grade serous carcinomas, kept BAP1 staining. Other genes altered in more than one tumor were NF2 (3 of 13), SETD2 (2 of 13) and DDX3X (2 of 13). CDKN2A deletion appeared in only one tumor. Earlier studies had reported BAP1 changes in 20–30% of pleural tumors. The authors concluded that pleural and peritoneal mesotheliomas share similar genetic changes, but at different frequencies. They noted that clinical outcome data were limited.

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 genomic (DNA sequencing) and immunohistochemistry study of archived tumor tissue
• Who was studied: 13 patients with primary malignant peritoneal mesothelioma (8 female aged 19–89, 5 male aged 53–71) from University of California, San Francisco pathology archives, 1991–2015. Also 42 comparison tumors that can resemble it under the microscope (8 multilocular peritoneal inclusion cyst, 6 well-differentiated papillary mesothelioma of the peritoneum, 16 adenomatoid tumor, 12 low-grade serous carcinoma of the ovary), 2000–2015.
• Exposure: Not studied: the article does not report asbestos or other exposure histories for these patients. The study examined genetic alterations in the tumors.
• Main results:
  • BAP1 gene alterations were found in 11 of 13 peritoneal mesotheliomas (85%).
  • Both copies of BAP1 were inactivated in 9 of the 13 tumors.
  • One patient had a germline (present in normal cells) frameshift mutation in BAP1.
  • Other recurrently mutated genes in the 13 peritoneal mesotheliomas were NF2 (3/13), SETD2 (2/13) and DDX3X (2/13).
  • CDKN2A deletion was seen in only 1 of the 13 peritoneal mesotheliomas, the only case with a sarcomatoid component.
  • Loss of BAP1 protein staining was seen in 11 of 13 peritoneal mesotheliomas (85%).
  • All 42 selected comparison tumors (histologic mimics: well-differentiated papillary mesothelioma of the peritoneum, multilocular peritoneal inclusion cyst, adenomatoid tumor, and low-grade serous carcinoma of the ovary) kept intact BAP1 staining.
• The authors' conclusion: The authors concluded that pleural and peritoneal mesotheliomas are defined by a similar spectrum of genetic alterations, but at different frequencies depending on where the tumor arises. They also concluded that BAP1 loss is much more common in peritoneal than pleural mesotheliomas, and suggested possible targeted-therapy opportunities.
• Limitations the authors state:
  • Only limited clinical outcome data were available for the 13 patients.
  • The sequencing test may have missed some BAP1 changes. In two tumors with only one BAP1 copy lost, the BAP1 protein was still absent, suggesting an alteration the test did not detect.

Topics

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

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, BAP1, Malignant Mesothelioma, Mesothelial Cells, Pleural Cavity, Pleural Mesothelioma, Asbestos Exposure, Peritoneal Cavity.

Related studies

• Genomic profiling of the genes on chromosome 3p in sporadic clear cell renal cell carcinoma — Y. Togo, Y. Yoshikawa, et al. (2016)
• Integrated profiling reveals a global correlation between epigenetic and genetic alterations in mesothelioma — B.C. Christensen, E.A. Houseman, et al. (2010)
• 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)
• Functional Genomic Screen in Mesothelioma Reveals that Loss of Function of BRCA1-Associated Protein 1 Induces Chemoresistance to Ribonucleotide Reductase Inhibition — A. Okonska, S. Bühler, 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)
• Morphological difference between pleural mesothelioma cells in effusion smears with either BAP1 loss or 9p21 homozygous deletion and reactive mesothelial cells without the gene alterations — S. Matsumoto, M. Hamasaki, et al. (2019)

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