Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome

Our plain-English summary of Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome, by F. Lalloo, A. Kulkarni, C. Chau, et al (European Journal of Human Genetics, 2023).

The study

• Authors: F. Lalloo, A. Kulkarni, C. Chau, M. Nielsen, M. Sheaff, J. Steele, R. van Doorn, K. Wadt, M. Hamill, B. Torr, M. Tischkowitz, Delphi respondents, H. Hanson
• Journal: European Journal of Human Genetics
• Published: 2023;31(11):1261-1269
• Cited by: 55 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

BRCA1-associated protein-1 (BAP1) is a recognised tumour suppressor gene. Germline BAP1 pathogenic/likely pathogenic variants are associated with predisposition to multiple tumours, including uveal melanoma, malignant pleural and peritoneal mesothelioma, renal cell carcinoma and specific non-malignant neoplasms of the skin, as part of the autosomal dominant BAP1-tumour predisposition syndrome. The overall lifetime risk for BAP1 carriers to develop at least one BAP1-associated tumour is up to 85%, although due to ascertainment bias, current estimates of risk are likely to be overestimated. As for many rare cancer predisposition syndromes, there is limited scientific evidence to support the utility of surveillance and, therefore, management recommendations for BAP1 carriers are based on expert opinion. To date, European recommendations for BAP1 carriers have not been published but are necessary due to the emerging phenotype of this recently described syndrome and increased identification of BAP1 carriers via large gene panels or tumour sequencing. To address this, the Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom invited European collaborators to collaborate to develop guidelines to harmonize surveillance programmes within Europe. Recommendations with respect to BAP1 testing and surveillance were achieved following literature review and Delphi survey completed by a core group and an extended expert group of 34 European specialists including Geneticists, Ophthalmologists, Oncologists, Dermatologists and Pathologists. It is recognised that these largely evidence-based but pragmatic recommendations will evolve over time as further data from research collaborations informs the phenotypic spectrum and surveillance outcomes.

© 2023. The Author(s).

In plain English

This article is a clinical practice guideline, not a study of patients. It set out recommendations for people carrying germline pathogenic or likely pathogenic variants in the BAP1 gene. A core group of 10 members reviewed the literature and drafted statements. An extended group of 34 European specialists scored them in up to two Delphi rounds, with 80% agreement counting as consensus. All but four statements reached consensus. Respondents agreed (100%) that mesothelioma, peritoneal and pleural, is part of the core syndrome. They also agreed (81%) that genetic testing may be considered in isolated mesothelioma before age 60 when there was no asbestos exposure. Because no data suggested that mesothelioma screening detects early disease, they agreed (81%) it should be done only within research studies. The guideline recommended annual kidney imaging from age 30, plus yearly eye and skin examinations. Separately from the Delphi vote, the core group considered that carriers should be advised to avoid occupations with asbestos exposure. The authors called the guidelines pragmatic. They noted limited evidence and likely overestimated risk figures, and stated that the guidelines are not a legal standard of care.

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: Clinical practice guideline developed from a literature review and a modified electronic Delphi consensus survey (two rounds, 80% agreement required)
• Who was studied: Expert panel: a core group of 10 members and an extended group of 34 European specialists (geneticists, ophthalmologists, oncologists, dermatologists, pathologists), convened by the UK CanGene-CanVar project. Work ran from November 2020 to June 2022. Individual statements were scored by 36 to 42 respondents.
• Exposure: Carriers of germline pathogenic or likely pathogenic BAP1 variants. Asbestos exposure was not measured. Its absence appears as a factor in deciding whether to test people with isolated mesothelioma.
• Main results:
  • In Delphi round 1, 29 statements reached consensus and 13 did not. After round 2, consensus was reached on all but four statements.
  • Mesothelioma (peritoneal and pleural), uveal melanoma, cutaneous melanoma, renal carcinoma and BAP1-inactivated melanocytic tumours were agreed to be core tumours. For mesothelioma: n = 42; 31 strongly agree, 11 agree; 100% consensus; strong recommendation.
  • Prevalence of germline BAP1 pathogenic variants in people with isolated mesothelioma was agreed to be low, less than 3% (n = 37; 7 strongly agree, 23 agree; 81% consensus; strong).
  • Testing may be considered in isolated mesothelioma diagnosed before 60 years without asbestos exposure (n = 37; 9 strongly agree, 21 agree; 81% consensus; moderate).
  • No data suggest that mesothelioma surveillance (chest X-ray or MRI) detects early-stage disease. Surveillance should be done only in research studies (n = 37; 6 strongly agree, 24 agree; 81% consensus; moderate).
  • Annual renal imaging should be offered to all carriers (n = 40; 85% consensus; weak). The guideline set the start at age 30 (80% consensus; weak) and named MRI as the preferred method.
  • Annual dilated eye examination by an ocular oncologist or a uveal melanoma expert should be offered to all carriers (n = 40; 98% consensus; moderate).
  • Annual dermatological review with full body examination and photography should be offered to all carriers (n = 41; 83% consensus; moderate).
  • Outside the Delphi process, the core group considered that carriers should be advised to avoid occupations with asbestos exposure and residential exposure during renovations, not to smoke, and to limit UV exposure.
• The authors' conclusion: The authors described the guidelines as a pragmatic approach based on the best currently available evidence along with expert opinion. They recommended long-term prospective observation of carriers under surveillance, because randomised trials will never be possible.
• Limitations the authors state:
  • Each individual clinician has limited experience with families carrying BAP1 variants.
  • There was scant evidence on surveillance in this patient group.
  • Current risk estimates are likely overestimated because of ascertainment bias.
  • The guidelines do not represent a legal standard of care and should not replace clinical judgement.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Peritoneal Mesothelioma, Carcinoma, Neoplasm.

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• Post-thoracotomy neuralgic amyotrophy in a patient with BAP1 tumor predisposition syndrome: Multimodality longitudinal follow-up — N. Jazebi, N. Dargah-Zada, et al. (2021)
• Histomorphologic spectrum of BAP1 negative melanocytic neoplasms in a family with BAP1-associated cancer susceptibility syndrome — Z. Marušić, M. Buljan, et al. (2015)
• Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases — K. Rai, R. Pilarski, et al. (2016)
• 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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