Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations

Our plain-English summary of Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations, by Y. Kadariya, M. Cheung, J. Xu, et al (Cancer Research, 2016).

The study

• Authors: Y. Kadariya, M. Cheung, J. Xu, J. Pei, E. Sementino, C.W. Menges, K.Q. Cai, F.J. Rauscher, A.J. Klein-Szanto, J.R. Testa
• Journal: Cancer Research
• Published: 2016;76(9):2836-44
• Cited by: 90 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Individuals harboring inherited heterozygous germline mutations in BAP1 are predisposed to a range of benign and malignant tumor types, including malignant mesothelioma, melanoma, and kidney carcinoma. However, evidence to support a tumor-suppressive role for BAP1 in cancer remains contradictory. To test experimentally whether BAP1 behaves as a tumor suppressor, we monitored spontaneous tumor development in three different mouse models with germline heterozygous mutations in Bap1, including two models in which the knock-in mutations are identical to those reported in human BAP1 cancer syndrome families. We observed spontaneous malignant tumors in 54 of 93 Bap1-mutant mice (58%) versus 4 of 43 (9%) wild-type littermates. All three Bap1-mutant models exhibited a high incidence and similar spectrum of neoplasms, including ovarian sex cord stromal tumors, lung and mammary carcinomas, and spindle cell tumors. Notably, we also observed malignant mesotheliomas in two Bap1-mutant mice, but not in any wild-type animals. We further confirmed that the remaining wild-type Bap1 allele was lost in both spontaneous ovarian tumors and mesotheliomas, resulting in the loss of Bap1 expression. Additional studies revealed that asbestos exposure induced a highly significant increase in the incidence of aggressive mesotheliomas in the two mouse models carrying clinically relevant Bap1 mutations compared with asbestos-exposed wild-type littermates. Collectively, these findings provide genetic evidence that Bap1 is a bona fide tumor suppressor gene and offer key insights into the contribution of carcinogen exposure to enhanced cancer susceptibility. Cancer Res; 76(9); 2836-44. ©2016 AACR.

©2016 American Association for Cancer Research.

In plain English

This animal experiment tested whether mice with one inherited faulty Bap1 copy develop more tumors. The authors studied three mouse models, two with mutations identical to those in human BAP1 cancer syndrome families. Without asbestos, mice were followed for up to 31 months. Malignant tumors were found in 54 of 93 (58%) Bap1-mutant mice and 4 of 43 (9%) normal littermates. Ovarian tumors were most common: 38 of 60 mutant females had them, and no normal females did. Two mutant mice developed malignant mesothelioma (one pleural, one peritoneal) and no normal mice did; this difference was not statistically significant. Separately, male mice received four abdominal injections of crocidolite asbestos. Peritoneal mesothelioma occurred in 74% and 71% of the two mutant groups versus 35% of normal mice. Median survival, counted from the first asbestos injection, was 48 and 46 weeks in the mutant groups versus 60 weeks. The authors noted that tumor types in the mice generally differed from those seen in humans. They concluded the findings are consistent with BAP1 mutation carriers having elevated mesothelioma risk that rises greatly after exposure to carcinogenic fibers.

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: tumor monitoring in three genetically modified mouse models (heterozygous germline Bap1 mutations) compared with wild-type littermates, plus an asbestos-injection experiment in two of the models
• Who was studied: 93 Bap1-mutant mice from three models (a knockout of Bap1 exons 6 and 7, and knock-in models W and L matching human BAP1 families W and L) and 43 wild-type littermates, in an FVB genetic background, at Fox Chase Cancer Center, Philadelphia. Separate asbestos-exposed cohorts of Bap1+/W and Bap1+/L male mice and wild-type littermates were also studied. The text does not give group sizes for these cohorts.
• Exposure: Inherited (germline) heterozygous Bap1 mutations. In the asbestos experiment, male mice aged 10 weeks were injected into the abdominal cavity (i.p.) with 800 μg of crocidolite every 21 days, for four injections in total.
• Main results:
  • Without asbestos, malignant tumors occurred in 54 of 93 (58%) Bap1-mutant mice versus 4 of 43 (9%) wild-type littermates.
  • Ovarian sex cord stromal tumors were the most frequent tumors in Bap1-mutant mice. They were found in 38 of 60 (63%) mutant females and in no wild-type females.
  • Two spontaneous malignant mesotheliomas, both sarcomatous (1 pleural, 1 peritoneal), occurred in Bap1-mutant mice and none in the 43 wild-type mice. The difference was not statistically significant (p greater than 0.05).
  • Three of four ovarian tumors tested had lost one copy of chromosome 14, where Bap1 lies, and had lost Bap1 expression. One spontaneous mesothelioma showed markedly reduced signal for the remaining normal Bap1 copy.
  • After crocidolite injection, peritoneal mesothelioma occurred in 74% of Bap1+/W mice and 71% of Bap1+/L mice versus 35% of wild-type mice (p less than 0.005 for wild-type vs Bap1+/W; p less than 0.01 for wild-type vs Bap1+/L).
  • Median survival from the time of the first asbestos injection was 48 weeks in Bap1+/W mice and 46 weeks in Bap1+/L mice, versus 60 weeks in wild-type mice.
  • Asbestos-induced mesotheliomas in both knock-in models were consistently larger and more aggressive than those in wild-type littermates.
• The authors' conclusion: The authors concluded that the overall findings are consistent with BAP1 mutation carriers being inherently at elevated risk of malignant mesothelioma, and with that risk increasing greatly upon exposure to carcinogenic fibers.
• Limitations the authors state:
  • The tumor types seen in the mutant mice generally differed from those in the human BAP1 cancer syndrome. The authors attribute this to differences in tissue susceptibility between mice and humans.
  • There was not enough tissue from the spontaneous mesotheliomas for genome-wide copy-number analysis.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, BAP1 Tumor Predisposition Syndrome, Germline Mutation, Malignant Mesothelioma, Carcinoma, Neoplasm, Spindle Cell, Mesothelioma.

Related studies

• Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma — J. Xu, Y. Kadariya, et al. (2014)
• 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)
• Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma — A. Napolitano, L. Pellegrini, et al. (2016)
• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)
• Germline BAP1 mutations predispose also to multiple basal cell carcinomas — A. de la Fouchardière, O. Cabaret, et al. (2015)
• Clinical Implications of Real-time Integrative Sequencing in Management of Patients With Suspected Germline BAP1 Mutations — S. Sengupta, A.C. Weyand, et al. (2019)

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