Families with BAP1-Tumor Predisposition Syndrome in The Netherlands: Path to Identification and a Proposal for Genetic Screening Guidelines

Our plain-English summary of Families with BAP1-Tumor Predisposition Syndrome in The Netherlands: Path to Identification and a Proposal for Genetic Screening Guidelines, by C. Chau, R. van Doorn, N.M. van Poppelen, et al (Cancers, 2019).

The study

• Authors: C. Chau, R. van Doorn, N.M. van Poppelen, N. van der Stoep, A.R. Mensenkamp, R.H. Sijmons, B.W. van Paassen, A.M.W. van den Ouweland, N.C. Naus, A.H. van der Hout, T.P. Potjer, F.E. Bleeker, M.R. Wevers, L.P. van Hest, M.C.J. Jongmans, M. Marinkovic, J.C. Bleeker, M.J. Jager, G.P.M. Luyten, M. Nielsen
• Journal: Cancers
• Published: 2019;11(8)
• Cited by: 57 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1-tumor predisposition syndrome (BAP1-TPDS, OMIM 614327). BAP1-TPDS is associated with an increased risk of developing uveal melanoma (UM), cutaneous melanoma (CM), malignant mesothelioma (MMe), renal cell carcinoma (RCC), meningioma, cholangiocarcinoma, multiple non-melanoma skin cancers, and BAP1-inactivated nevi. Because of this increased risk, it is important to identify patients with BAP1-TPDS. The associated tumors are treated by different medical disciplines, emphasizing the need for generally applicable guidelines for initiating genetic analysis. In this study, we describe the path to identification of BAP1-TPDS in 21 probands found in the Netherlands and the family history at the time of presentation. We report two cases of de novo BAP1 germline mutations (2/21, 9.5%). Findings of this study combined with previously published literature, led to a proposal of guidelines for genetic referral. We recommend genetic analysis in patients with ≥2 BAP1-TPDS-associated tumors in their medical history and/or family history. We also propose to test germline BAP1 in patients diagnosed with UM <40 years, CM <18 years, MMe <50 years, or RCC <46 years. Furthermore, other candidate susceptibility genes for tumor types associated with BAP1-TPDS are discussed, which can be included in gene panels when testing patients.

In plain English

This multicenter retrospective case series described 22 families in the Netherlands in which germline variants in the BAP1 gene (changes in a person's own DNA, not only in a tumor) had been found, and how each family came to be tested. One family, whose variant was of uncertain significance, was left out of the family analyses, leaving 72 carriers in 21 families. Testing was most often started because of BAP1-inactivated nevi, a type of skin lesion (8 of 22 families). Malignant mesothelioma occurred in 8 of the 72 carriers (11%), at a median age of 60 years, compared with a median of 74 years in the general Dutch population. Six of these were pleural and two peritoneal. Nine more mesotheliomas were reported in untested relatives, and 14 of these 17 cases were in three families. Two of 21 probands (9.5%) had probable new (de novo) mutations. No asbestos-exposure assessment was reported. The authors raised a gene–environment interaction only as a hypothesis. The authors proposed referral guidelines for genetic testing, including testing in mesothelioma diagnosed before age 50. They noted selection bias and small numbers.

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: Multicenter retrospective case series of families with germline BAP1 variants (the authors also call it a cohort study), with a proposal for genetic referral guidelines based on the findings and published literature
• Who was studied: 22 families with germline BAP1 variants identified in the Netherlands. After excluding one family with a variant of unknown significance, 21 families remained, with clinical information on 727 individuals. These included 72 carriers: 21 probands, 41 tested relatives who carried the variant, and 10 obligate carriers.
• Exposure: Germline pathogenic or likely pathogenic BAP1 gene variants. No asbestos-exposure assessment was reported for these patients. The authors discussed a gene–environment interaction (BAP1 variant plus asbestos) only as a hypothesis that has not been proven in BAP1-TPDS.
• Main results:
  • Malignant mesothelioma was found in 8 of the 72 BAP1-TPDS carriers (11%).
  • Among the 8 carriers with mesothelioma, the median age of onset was 60 years (range 39 to 71). This was earlier than the median age of 74 years at diagnosis in the general Dutch population.
  • Of the 8 mesotheliomas in carriers, 6 were pleural (75%) and 2 were peritoneal (25%).
  • Nine further mesotheliomas (5 pleural, 4 peritoneal) were reported in untested relatives. Of all 17 mesothelioma patients, 14 were in three families.
  • Two of 21 probands (9.5%) had probable de novo BAP1 mutations.
  • Genetic testing was most often started because of BAP1-inactivated nevi (BINs) in the proband: 8 of the 22 families (36%).
  • Two of the 72 carriers (3%) developed renal cell carcinoma, and both of these patients also had mesothelioma.
  • The estimated cumulative proportion free of mesothelioma at age 65 was 0.74 (95% CI 0.54 to 0.95). The article does not state clearly whether this figure is for non-proband carriers only or for all carriers.
• The authors' conclusion: The authors concluded that the cohort showed a high cancer risk, in line with previous reports. Combining their findings with published literature, they proposed referral guidelines for germline BAP1 testing. These include testing patients diagnosed with uveal melanoma before 40, cutaneous melanoma before 18, malignant mesothelioma before 50, or renal cell carcinoma before 46, and patients with two or more BAP1-TPDS-associated tumors in their own and/or family history.
• Limitations the authors state:
  • Tumors were not examined with immunohistochemistry or genetic analysis, so it is uncertain whether the tumors found were related to the BAP1 variant.
  • Patients were highly selected and testing bias was likely, so tumor frequencies are probably influenced by bias.
  • The number of non-proband carriers was small, which gave wide confidence intervals, and follow-up data after age 65 were unreliable.
  • The cohort was too small to draw conclusions about associations with other tumor types.
  • The patient population was relatively young, which may explain lower tumor frequencies than in international cohorts.

Topics

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

Related studies

• Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome — F. Lalloo, A. Kulkarni, et al. (2023)
• Novel LRRK2 mutations and other rare, non-BAP1-related candidate tumor predisposition gene variants in high-risk cancer families with mesothelioma and other tumors — M. Cheung, Y. Kadariya, et al. (2021)
• Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases — K. Rai, R. Pilarski, et al. (2016)
• The Importance of Multidisciplinary Approach in Early Detection of BAP1 Tumor Predisposition Syndrome: Clinical Management and Risk Assessment — A. Battaglia (2014)
• Diagnostics of BAP1-Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience — M. Sculco, M. La Vecchia, et al. (2022)
• Malignant Peripheral Nerve Sheath Tumor in a Patient With BAP1 Tumor Predisposition Syndrome — M.C. Kaszuba, J.S. Pulido, et al. (2018)

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