Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma

Our plain-English summary of Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma, by J. Xu, Y. Kadariya, M. Cheung, et al (Cancer Research, 2014).

The study

• Authors: J. Xu, Y. Kadariya, M. Cheung, J. Pei, J. Talarchek, E. Sementino, Y. Tan, C.W. Menges, K.Q. Cai, S. Litwin, H. Peng, J. Karar, F.J. Rauscher, J.R. Testa
• Journal: Cancer Research
• Published: 2014;74(16):4388-97
• Cited by: 116 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos. Germline-inactivating mutations of BAP1 predispose to mesothelioma and certain other cancers. However, why mesothelioma is the predominate malignancy in some BAP1 families and not others, and whether exposure to asbestos is required for development of mesothelioma in BAP1 mutation carriers are not known. To address these questions experimentally, we generated a Bap1(+/-) knockout mouse model to assess its susceptibility to mesothelioma upon chronic exposure to asbestos. Bap1(+/-) mice exhibited a significantly higher incidence of asbestos-induced mesothelioma than wild-type (WT) littermates (73% vs. 32%, respectively). Furthermore, mesotheliomas arose at an accelerated rate in Bap1(+/-) mice than in WT animals (median survival, 43 weeks vs. 55 weeks after initial exposure, respectively) and showed increased invasiveness and proliferation. No spontaneous mesotheliomas were seen in unexposed Bap1(+/-) mice followed for up to 87 weeks of age. Mesothelioma cells from Bap1(+/-) mice showed biallelic inactivation of Bap1, consistent with its proposed role as a recessive cancer susceptibility gene. Unlike in WT mice, mesotheliomas from Bap1(+/-) mice did not require homozygous loss of Cdkn2a. However, normal mesothelial cells and mesothelioma cells from Bap1(+/-) mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1(+/-) mice to mesothelioma may be facilitated, in part, by cooperation between Bap1 and Rb. Drawing parallels to human disease, these unbiased genetic findings indicate that BAP1 mutation carriers are predisposed to the tumorigenic effects of asbestos and suggest that high penetrance of mesothelioma requires such environmental exposure.

©2014 American Association for Cancer Research.

In plain English

This was an animal experiment in mice. The authors bred mice with one inactivated copy of the Bap1 gene (Bap1+/- mice), a mouse counterpart of the inherited BAP1 mutations seen in some families with mesothelioma. Male Bap1+/- mice and normal (wild-type) littermates, 25 per group, were injected into the abdomen with crocidolite asbestos four times, 21 days apart, for 3.2 mg per mouse in total. Peritoneal mesothelioma caused death in 73% of the Bap1+/- mice that could be evaluated, compared with 32% of wild-type mice. Median survival after the first injection was 43 weeks for Bap1+/- mice and 55 weeks for wild-type mice. Tumors in Bap1+/- mice often invaded the pancreas, liver or intestinal muscle. Their tumor cells had lost the normal copy of Bap1 and showed reduced levels of Rb, a tumor-suppressor protein. Among unexposed Bap1+/- mice followed long term, one spontaneous tumor was seen, a mammary squamous cell carcinoma. The authors concluded that BAP1 mutation carriers are predisposed to the tumor-causing effects of asbestos. They noted that more spontaneous tumors might appear as the unexposed mice age.

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: animal experiment (genetically modified knockout mouse model compared with wild-type littermates)
• Who was studied: Male mice carrying one inactivated Bap1 copy (Bap1+/-) and wild-type littermates, 25 per group, aged 8 to 10 weeks at first asbestos injection. A separate group of 27 Bap1+/- and 30 wild-type mice was followed long term without asbestos to look for spontaneous tumors.
• Exposure: UICC crocidolite asbestos fibers injected into the abdomen (intraperitoneally), 800 micrograms per injection every 21 days for 4 injections (total 3.2 mg per mouse)
• Main results:
  • Deaths from peritoneal mesothelioma occurred in 73% of asbestos-exposed Bap1+/- mice that could be pathologically evaluated, versus 32% of asbestos-exposed wild-type mice (Fisher exact test, P less than 0.01).
  • Median survival from the first asbestos injection was 43 weeks in Bap1+/- mice versus 55 weeks in wild-type mice (Wilcoxon 2-sample test, P less than 0.0001).
  • All asbestos-exposed Bap1+/- mice had died of mesothelioma or other asbestos-related disease by 57 weeks. At that point, 69 weeks after first exposure according to the article, 5 (20%) wild-type mice were still alive and without symptoms.
  • Mesotheliomas in Bap1+/- mice were consistently larger and more aggressive than in wild-type mice, often invading the pancreas, liver and/or intestinal smooth muscle. Occasional spread to the lungs was seen.
  • Tumor cells from Bap1+/- mice had lost the remaining normal (wild-type) Bap1 copy and lacked Bap1 protein.
  • Expression of Cdkn2a and Cdkn2b was absent in tumor cells from wild-type mice but present in tumor cells from Bap1+/- mice.
  • Rb1 mRNA levels in tumor cells from Bap1+/- mice were less than half those in tumor cells from wild-type mice. Rb was also reduced in normal mesothelial cells from Bap1+/- mice.
  • Among unexposed mice followed long term, only 1 spontaneous tumor was found in Bap1+/- mice, a squamous cell carcinoma of mammary origin. One tumor, a thymic lymphoma, was seen in wild-type littermates.
• The authors' conclusion: The authors concluded that their genetic findings indicate BAP1 mutation carriers are predisposed to the tumor-causing effects of asbestos. They suggested that high penetrance of mesothelioma requires such environmental exposure.
• Limitations the authors state:
  • Most unexposed Bap1+/- mice were still only 11 to 20 months old, so the authors could not rule out spontaneous mesotheliomas or other tumors arising as the mice age further.
  • Whether the Rb finding in mice applies to humans had not been studied and was left for future investigation.

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: Germline Mutation, BAP1, Malignant Mesothelioma, Mesothelioma, Median Survival, CDKN2A, Mesothelial Cells, Environmental Exposure.

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• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)
• Intrahepatic cholangiocarcinoma development in a patient with a novel BAP1 germline mutation and low exposure to asbestos — G. Brandi, M. Deserti, et al. (2020)
• Germline BAP1 mutations predispose also to multiple basal cell carcinomas — A. de la Fouchardière, O. Cabaret, et al. (2015)
• Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer — J.A. Ohar, M. Cheung, et al. (2016)
• A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma — K.A. Wadt, L.G. Aoude, et al. (2015)

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