Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer

Our plain-English summary of Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer, by M. Carbone, J.W. Harbour, J. Brugarolas, et al (Cancer Discovery, 2020).

The study

• Authors: M. Carbone, J.W. Harbour, J. Brugarolas, A. Bononi, I. Pagano, A. Dey, T. Krausz, H.I. Pass, H. Yang, G. Gaudino
• Journal: Cancer Discovery
• Published: 2020;10(8):1103-1120
• Type of article: Review
• Cited by: 252 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Among more than 200 BAP1-mutant families affected by the "BAP1 cancer syndrome," nearly all individuals inheriting a BAP1 mutant allele developed one or more malignancies during their lifetime, mostly uveal and cutaneous melanoma, mesothelioma, and clear-cell renal cell carcinoma. These cancer types are also those that, when they occur sporadically, are more likely to carry somatic biallelic BAP1 mutations. Mechanistic studies revealed that the tumor suppressor function of BAP1 is linked to its dual activity in the nucleus, where it is implicated in a variety of processes including DNA repair and transcription, and in the cytoplasm, where it regulates cell death and mitochondrial metabolism. BAP1 activity in tumor suppression is cell type- and context-dependent. BAP1 has emerged as a critical tumor suppressor across multiple cancer types, predisposing to tumor development when mutated in the germline as well as somatically. Moreover, BAP1 has emerged as a key regulator of gene-environment interaction.This article is highlighted in the In This Issue feature, p. 1079.

©2020 American Association for Cancer Research.

In plain English

This article was a review of research on BAP1, a gene that normally suppresses tumors. It covered mutations inherited by families (germline) and mutations acquired in tumors (somatic). It discussed how BAP1 works in cells and how BAP1 status bears on diagnosis, prognosis and therapy. The authors pooled 45 published articles covering 350 carriers of inherited BAP1 mutations from 140 families, including only carriers with a family history of BAP1-core cancers. Of these carriers, 295 (84.3%) had developed cancer, 442 cancers in total. The carriers without cancer were 50 years of age or younger. Among the studies reviewed, one reported that mice with an inherited Bap1 mutation given a low asbestos dose (0.5 mg in total) developed mesothelioma at a rate comparable to normal mice given ten times higher doses. Another cited study, of 385 mesothelioma patients at the NCI, reported median overall survival of 7.9 years in patients with inherited mutations versus 2.4 years in patients without them. The authors concluded that BAP1 is a potent tumor suppressor, since almost all carriers developed one or more cancers.

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: Review of published research on BAP1 mutations in human cancer, including the authors' pooled tally of published cases of inherited BAP1 mutation carriers
• Who was studied: The reviewed literature on BAP1. For the pooled tally: 350 carriers of germline BAP1 mutations (all ages) from 140 published families, drawn from 45 articles published up to September 30, 2019. Only carriers with a family history of BAP1-core cancers were included
• Exposure: Inherited (germline) and acquired (somatic) BAP1 mutations. The review also discussed gene–environment interaction, including erionite exposure in Cappadocia, Turkey, and a cited mouse study using very low doses of asbestos fibers (fiber type not specified in this article)
• Main results:
  • In the authors' pooled tally of carriers selected for a family history of BAP1-core cancers, 295 of 350 germline BAP1 carriers (84.3%) developed cancer, for a total of 442 cancers, in cases from 140 published families
  • Cancer-free carriers in the pooled tally were 50 years of age or younger
  • The review stated, citing other studies, that the overall cancer penetrance in germline BAP1 carriers is at least 85% and approaches 100% with increasing age
  • A cited mouse study reported that Bap1 heterozygous mice given 0.5 mg of asbestos developed mesothelioma at a rate comparable to wild-type mice exposed to ten times higher doses
  • A cited study by Baumann and colleagues reported 5-year survival of 47% (95% CI, 24–67) in mesothelioma patients with germline BAP1 mutations, versus 6.7% (95% CI, 6.2–7.3) in the comparison group, described as a 7-fold increase
  • A cited NCI study of 385 mesothelioma patients reported median overall survival of 7.9 years in patients with inherited mutations versus 2.4 years in patients without them (P = 0.001)
  • The review reported that acquired (somatic) BAP1 mutations are found in 60% to 70% of mesotheliomas
  • The review reported that acquired BAP1 mutations are found in approximately 45% of primary uveal melanomas
• The authors' conclusion: The authors concluded that all published data support BAP1 being a potent tumor suppressor, because almost all carriers of pathogenic germline BAP1 mutations developed one or more cancers during their lifetime
• Limitations the authors state:
  • The cell-death and DNA-damage mechanisms described were worked out in human fibroblasts and mesothelial cells; whether they apply to other cell types was not yet known
  • It was not yet known which BAP1 functions matter in each cancer type

Topics

Medical terms in this study, explained in our Lexicon: BAP1, BAP1 Tumor Predisposition Syndrome, Mesothelioma, Carcinoma.

Related studies

• Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations — M.G. Zauderer, G. Jayakumaran, et al. (2019)
• Dual Screen for Efficacy and Toxicity Identifies HDAC Inhibitor with Distinctive Activity Spectrum for BAP1-Mutant Uveal Melanoma — J.N. Kuznetsoff, D.A. Owens, et al. (2021)
• Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations — M. Carbone, H.I. Pass, et al. (2022)
• Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy — P. Star, A. Goodwin, et al. (2018)
• Ocular melanoma and the BAP1 hereditary cancer syndrome: implications for the dermatologist — L.M. Martorano, R.R. Winkelmann, et al. (2014)
• Re-evaluating the pathogenicity of the c.783+2T>C BAP1 germline variant — Y. Goldberg, Y. Laitman, et al. (2021)

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