BAP1 and cancer

Our plain-English summary of BAP1 and cancer, by M. Carbone, H. Yang, H.I. Pass, et al (Nature Reviews. Cancer, 2013).

The study

• Authors: M. Carbone, H. Yang, H.I. Pass, T. Krausz, J.R. Testa, G. Gaudino
• Journal: Nature Reviews. Cancer
• Published: 2013;13(3):153-9
• Cited by: 530 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

BAP1 is a deubiquitylase that is found associated with multiprotein complexes that regulate key cellular pathways, including the cell cycle, cellular differentiation, cell death, gluconeogenesis and the DNA damage response (DDR). Recent findings indicate that germline BAP1 mutations cause a novel cancer syndrome that is characterized, at least in the affected families that have been studied so far, by the onset at an early age of benign melanocytic skin tumours with mutated BAP1, and later in life by a high incidence of mesothelioma, uveal melanoma, cutaneous melanoma and possibly additional cancers.

In plain English

This was a review by researchers who had earlier linked inherited (germline) BAP1 gene mutations to mesothelioma in two US families. The authors reviewed published reports on families carrying these mutations and laboratory studies of what the BAP1 protein does in cells. Their table pooled published data on people tested and found to carry germline BAP1 mutations. Of 76 carriers, 53 had developed cancer, and 13 of those 53 had two or more cancers. Malignant mesothelioma was found in 22 of 76 carriers (28.95%, 95% CI 19.96 to 39.96), uveal (eye) melanoma in 21 of 76, and skin melanoma in 11 of 76. Benign skin growths the authors call MBAITs were found in 19 of 35 carriers examined. The authors noted that earlier studies found minimal or no evidence of asbestos or erionite exposure among the mesothelioma patients in these families. They said that they could not yet tell whether the links to other cancers were causal, that family-based estimates may overstate risk, and that large population studies were needed. The authors concluded that carriers need close monitoring for early cancer detection.

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 (a 'Progress' article) of published reports on families with germline BAP1 mutations and of laboratory studies of BAP1 function, including a table that pools published data on mutation carriers
• Who was studied: 76 individuals described in published reports who were genetically tested and found to carry germline BAP1 mutations. These included the authors' own Louisiana ('L') and Wisconsin ('W') families and families reported by other groups. Not all cancer types were assessed in all 76: for example, breast and ovarian cancer were assessed in 43 carriers and MBAITs in 35.
• Exposure: Germline (inherited) BAP1 mutations. Mineral fibres (asbestos, erionite) are discussed as possible co-factors. The authors note that earlier studies (their own and Wiesner and colleagues') found minimal or no evidence of asbestos or erionite exposure among the family members who developed mesothelioma.
• Main results:
  • In the pooled published data, 53 of 76 BAP1 germline mutation carriers had developed malignancies, and 13 of these 53 developed two or more cancers.
  • Overall cancer incidence among the 76 mutation carriers was 69.74%.
  • Malignant mesothelioma occurred in 22 of 76 carriers: 28.95% (95% CI 19.96 to 39.96). Age at diagnosis ranged from 37 to 85 years (mean 55.2), compared with a US general-population median age of 74.
  • Uveal melanoma occurred in 21 of 76 carriers: 27.63% (95% CI 18.84 to 38.37).
  • Cutaneous melanoma occurred in 11 of 76 carriers: 14.47% (95% CI 7.79 to 24.84).
  • Among the 53 carriers with malignancies, 13 (24.53%, 95% CI 14.94 to 37.57%) had two or more malignant tumours. The authors compared this with 8% in the United States.
  • Of 35 carriers examined for the benign skin lesions the authors call MBAITs, 19 had one or more lesions.
• The authors' conclusion: The authors concluded that the apparent ability of BAP1 mutations to cause multiple tumour types suggests the gene has a major role in cancer cell growth. In their view, BAP1-mutation carriers require close monitoring for early detection and curative removal of uveal and cutaneous melanoma, mesothelioma and other malignancies.
• Limitations the authors state:
  • Carcinomas are relatively common in the general population, so the authors could not yet say with certainty whether the association with carcinomas is causal.
  • Risk estimates drawn from families with multiple tumours may be higher than the true risk for mutation carriers in the general population.
  • Large population-based studies will be required to validate the association.
  • All carriers without cancer were younger than 55 and may still develop cancer later in life.
  • Some of the most recent studies on BAP1 function had not yet been independently verified.

Topics

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

Related studies

• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)
• Roles and mechanisms of BAP1 deubiquitinase in tumor suppression — L. Masclef, O. Ahmed, et al. (2021)
• BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos — F. Novelli, A. Bononi, et al. (2021)
• BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation — A. Bononi, C. Giorgi, et al. (2017)
• High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma — M. Nasu, M. Emi, et al. (2015)
• Germline BAP1 mutations induce a Warburg effect — A. Bononi, H. Yang, et al. (2017)

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