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. 2019 Aug 4;11(8):1114.
doi: 10.3390/cancers11081114.

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

Cindy Chau  1 , Remco van Doorn  2 , Natasha M van Poppelen  3   4 , Nienke van der Stoep  5 , Arjen R Mensenkamp  6 , Rolf H Sijmons  7 , Barbara W van Paassen  3 , Ans M W van den Ouweland  3 , Nicole C Naus  4 , Annemieke H van der Hout  7 , Thomas P Potjer  5 , Fonnet E Bleeker  8 , Marijke R Wevers  6 , Liselotte P van Hest  9 , Marjolijn C J Jongmans  6   10 , Marina Marinkovic  1 , Jaco C Bleeker  1 , Martine J Jager  1 , Gregorius P M Luyten  1 , Maartje Nielsen  11
Affiliations

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

Cindy Chau et al. Cancers (Basel). .

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.

Keywords: BAP1; BAP1 tumor predisposition syndrome; germline; referral guidelines.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Venn diagrams of BAP1-tumor predisposition syndrome (BAP1-TPDS)-associated core malignancies found in BAP1-TPDS probands (a) and in the 21 BAP1-TPDS families (b). Eight probands were genetically analyzed as a result of the diagnosis of BINs and are, therefore, missing in Figure 1a.
Figure 2
Figure 2
Disease-free Kaplan–Meier curves for proven/obligate non-proband BAP1 variant carriers excluding probands (red) of uveal melanoma (a), cutaneous melanoma (b), malignant mesothelioma (c), and renal cell carcinoma (d). Individuals with BAP1-TPDS including probands are illustrated with the gray dotted line.
See this image and copyright information in PMC

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