BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma

Our plain-English summary of BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma, by H. Alakus, S.E. Yost, B. Woo, et al (Journal of Translational Medicine, 2015).

The study

• Authors: H. Alakus, S.E. Yost, B. Woo, R. French, G.Y. Lin, K. Jepsen, K.A. Frazer, A.M. Lowy, O. Harismendy
• Journal: Journal of Translational Medicine
• Published: 2015;13:122
• Cited by: 56 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma (MM) arises from mesothelial cells that line the pleural, peritoneal and pericardial surfaces. The majority of MMs are pleural and have been associated with asbestos exposure. Previously, pleural MMs have been genetically characterized by the loss of BAP1 (40-60%) as well as loss of NF2 (75%) and CDKN2A (60%). The rare peritoneal form of MM occurs in ~10% cases. With only ~300 cases diagnosed in the US per year, its link to asbestos exposure is not clear and its mutational landscape unknown.

Methods: We analyzed the somatic mutational landscape of 12 peritoneal MM of epitheloid subtype using copy number analysis (N = 9), whole exome sequencing (N = 7) and targeted sequencing (N = 12).

Results: Peritoneal MM display few copy number alterations, with most samples having less than 10 Mbp total changes, mostly through deletions and no high copy number amplification. Chromosome band 3p21 encoding BAP1 is the most recurrently deleted region (5/9), while, in contrast to pleural MM, NF2 and CDKN2A are not affected. We further identified 87 non-silent mutations across 7 sequenced tumors, with a median of 8 mutated genes per tumor, resulting in a very low mutation rate (median 1.3 10(-6)). BAP1 was the only recurrently mutated gene (N = 3/7). In one additional case, loss of the entire chromosome 3 leaves a non-functional copy of BAP1 carrying a rare nonsense germline variant, thus suggesting a potential genetic predisposition in this patient. Finally, with targeted sequencing of BAP1 in 3 additional cases, we conclude that BAP1 is frequently altered through copy number losses (N = 3/12), mutations (N = 3/12) or both (N = 2/12) sometimes at a sub-clonal level.

Conclusion: Our findings suggest a major role for BAP1 in peritoneal MM susceptibility and oncogenesis and indicate important molecular differences to pleural MM as well as potential strategies for therapy and prevention.

In plain English

This laboratory study looked at genetic changes in tumors from 12 patients with peritoneal malignant mesothelioma of the epithelioid subtype. The tumor samples were collected during surgery. The researchers ran copy number arrays on 9 tumors, whole exome sequencing on 7, and targeted sequencing of the BAP1 gene on all 12. The study did not report the patients' asbestos exposure. The tumors showed few copy number changes. The chromosome region holding BAP1 (3p21) was lost in 5 of 9 tumors. Sequenced tumors carried 47 to 133 mutations each, and BAP1 was the only gene mutated in more than one tumor (3 of 7). Overall, BAP1 was altered in 8 of 12 cases. The authors found no NF2 or CDKN2A alterations, which are common in pleural mesothelioma, in the cases they evaluated. One patient carried a BAP1 variant in blood DNA, and the authors said family history was needed to establish its risk. The authors concluded that their findings suggested BAP1 loss is characteristic of peritoneal mesothelioma. They added that the lack of NF2 and CDKN2A changes supports the idea of genetic differences from pleural mesothelioma. They noted that more samples are needed.

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 analysis of tumor samples (copy number arrays, whole exome sequencing and targeted BAP1 sequencing)
• Who was studied: Tumors from 12 patients with epithelioid peritoneal malignant mesothelioma, collected during surgery. The Institutional Review Board of the University of California, San Diego approved use of the samples. The article does not give the collection site or dates. Copy number analysis was done on 9 tumors, exome sequencing on 7 with matched blood DNA, and targeted BAP1 sequencing on all 12.
• Exposure: Not studied. The study examined genetic changes in tumors and reported no information on the patients' asbestos or other exposures.
• Main results:
  • Of the 9 tumors analyzed by copy number array, 3 had no large copy number events, 3 had between 1 and 6, and 3 had between 14 and 95 segments.
  • The 3p21 chromosome region containing BAP1 was lost in 5 of 9 tumors.
  • The 7 exome-sequenced tumors carried between 47 and 133 mutations each, of which 2 to 33 were non-silent.
  • BAP1 was the only gene mutated in more than one of the 7 exome-sequenced tumors, affecting 3 tumors.
  • One patient (AA2463T) carried a loss of function BAP1 variant in germline DNA, and that patient's tumor had lost chromosome 3. The authors said family history evaluation would be needed to establish the genetic risk of this variant.
  • Across all 12 cases, BAP1 was altered in 66% (8/12): by somatic mutation in 3, by copy number loss in 3, or by both in 2.
  • The authors reported no NF2 or CDKN2A alterations, which they describe as common in pleural MM, in the peritoneal MM cases they evaluated. Three of the 12 cases had only targeted sequencing of BAP1.
• The authors' conclusion: The authors concluded that their report suggests loss of BAP1 is a molecular alteration characteristic of peritoneal MM, occurring without other strong recognized cancer drivers. They also said the lack of NF2 and CDKN2A alterations supports the idea of distinct genomic features between pleural and peritoneal MM.
• Limitations the authors state:
  • The study included only the epithelioid subtype.
  • More samples are needed to link the genetic findings to clinical and environmental features.
  • The unusual length of one BAP1 deletion may have caused the fraction of tumor DNA carrying it to be underestimated.
  • The genetic risk of the germline BAP1 variant could not be established without the patient's family history.

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: BAP1, Malignant Mesothelioma, Mesothelial Cells, Pericardial, Asbestos Exposure, CDKN2A, Germline Mutation, Oncogenesis.

Related studies

• BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas — N. Leblay, F. Leprêtre, et al. (2017)
• Tumours associated with BAP1 mutations — R. Murali, T. Wiesner, et al. (2013)
• Mesothelioma families without inheritance of a BAP1 predisposing mutation — V. Ascoli, I. Cozzi, et al. (2016)
• Malignant cells from pleural fluids in malignant mesothelioma patients reveal novel mutations — S. Sneddon, I. Dick, et al. (2018)
• An asbestos-exposed family with multiple cases of pleural malignant mesothelioma without inheritance of a predisposing BAP1 mutation — M. Cheung, Y. Kadariya, et al. (2015)
• High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma — M. Nasu, M. Emi, et al. (2015)

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