Molecular analysis of an asbestos-exposed Belgian family with a high prevalence of mesothelioma


Familial clustering of malignant mesothelioma (MM) has been linked to the presence of germline mutations in BAP1. However, families with multiple MM patients, without segregating BAP1 mutation were described, suggesting the existence of other predisposing genetic factors. In this study, we report a previously undescribed Belgian family, in which BAP1 was found to be absent in the epithelial malignant mesothelial cells of the index patient. Whole exome analysis did not reveal a germline or somatic BAP1 variant. Also, no germline or somatic copy number changes in the BAP1 region could be identified. However, germline variants, predicted to be damaging, were detected in 11 other ‘Cancer census genes’ (i.e. MPL, RBM15, TET2, FAT1, HLA-A, EGFR, KMT2C, BRD3, NOTCH1, RB1 and MYO5A). Of these, the one in RBM15 seems to be the most interesting given its low minor allele frequency and absence in the germline DNA of the index patient’s mother. The importance of this ‘Cancer census gene’ in familial MM clustering needs to be evaluated further. Nevertheless, this study strengthens the suspicion that, next to germline BAP1 alterations, other genetic factors might predispose families to the development of MM.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Rake C, Gilham C, Hatch J, Darnton A, Hodgson J, Peto J (2009) Occupational, domestic and environmental mesothelioma risks in the British population: a case-control study. Br J Cancer 100(7):1175–1183.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Pass HI, Carbone M (2009) Current status of screening for malignant pleural mesothelioma. Semin Thorac Cardiovasc Surg 21(2):97–104.

    Article  PubMed  Google Scholar 

  3. 3.

    Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox NJ, Dogan AU, Pass HI, Trusa S, Hesdorffer M, Nasu M, Powers A, Rivera Z, Comertpay S, Tanji M, Gaudino G, Yang H, Carbone M (2011) Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet 43(10):1022–1025.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Wiesner T, Fried I, Ulz P, Stacher E, Popper H, Murali R, Kutzner H, Lax S, Smolle-Juttner F, Geigl JB, Speicher MR (2012) Toward an improved definition of the tumor spectrum associated with BAP1 germline mutations. J Clin Oncol 30(32):e337–e340.

    Article  PubMed  Google Scholar 

  5. 5.

    Cheung M, Talarchek J, Schindeler K, Saraiva E, Penney LS, Ludman M, Testa JR (2013) Further evidence for germline BAP1 mutations predisposing to melanoma and malignant mesothelioma. Cancer Genet 206(5):206–210.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Betti M, Casalone E, Ferrante D, Romanelli A, Grosso F, Guarrera S, Righi L, Vatrano S, Pelosi G, Libener R, Mirabelli D, Boldorini R, Casadio C, Papotti M, Matullo G, Magnani C, Dianzani I (2015) Inference on germline BAP1 mutations and asbestos exposure from the analysis of familial and sporadic mesothelioma in a high-risk area. Genes Chromosomes Cancer 54(1):51–62.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Ladanyi M, Zauderer MG, Krug LM, Ito T, McMillan R, Bott M, Giancotti F (2012) New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment. Clin Cancer Res 18(17):4485–4490.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P, Windpassinger C, Wackernagel W, Loy S, Wolf I, Viale A, Lash AE, Pirun M, Socci ND, Rutten A, Palmedo G, Abramson D, Offit K, Ott A, Becker JC, Cerroni L, Kutzner H, Bastian BC, Speicher MR (2011) Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet 43(10):1018–1021.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Abdel-Rahman MH, Pilarski R, Cebulla CM, Massengill JB, Christopher BN, Boru G, Hovland P, Davidorf FH (2011) Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet 48(12):856–859.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Njauw CN, Kim I, Piris A, Gabree M, Taylor M, Lane AM, DeAngelis MM, Gragoudas E, Duncan LM, Tsao H (2012) Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS ONE 7(4):e35295.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Wadt K, Choi J, Chung JY, Kiilgaard J, Heegaard S, Drzewiecki KT, Trent JM, Hewitt SM, Hayward NK, Gerdes AM, Brown KM (2012) A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma. Pigment Cell Melanoma Res 25(6):815–818.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Hoiom V, Edsgard D, Helgadottir H, Eriksson H, All-Ericsson C, Tuominen R, Ivanova I, Lundeberg J, Emanuelsson O, Hansson J (2013) Hereditary uveal melanoma: a report of a germline mutation in BAP1. Genes Chromosomes Cancer 52(4):378–384.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Popova T, Hebert L, Jacquemin V, Gad S, Caux-Moncoutier V, Dubois-d’Enghien C, Richaudeau B, Renaudin X, Sellers J, Nicolas A, Sastre-Garau X, Desjardins L, Gyapay G, Raynal V, Sinilnikova OM, Andrieu N, Manie E, de Pauw A, Gesta P, Bonadona V, Maugard CM, Penet C, Avril MF, Barillot E, Cabaret O, Delattre O, Richard S, Caron O, Benfodda M, Hu HH, Soufir N, Bressac-de Paillerets B, Stoppa-Lyonnet D, Stern MH (2013) Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet 92(6):974–980.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Pilarski R, Cebulla CM, Massengill JB, Rai K, Rich T, Strong L, McGillivray B, Asrat MJ, Davidorf FH, Abdel-Rahman MH (2014) Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases. Genes Chromosomes Cancer 53(2):177–182.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    de la Fouchardiere A, Cabaret O, Savin L, Combemale P, Schvartz H, Penet C, Bonadona V, Soufir N, Bressac-de Paillerets B (2015) Germline BAP1 mutations predispose also to multiple basal cell carcinomas. Clin Genet 88(3):273–277.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Wadt KA, Aoude LG, Johansson P, Solinas A, Pritchard A, Crainic O, Andersen MT, Kiilgaard JF, Heegaard S, Sunde L, Federspiel B, Madore J, Thompson JF, McCarthy SW, Goodwin A, Tsao H, Jonsson G, Busam K, Gupta R, Trent JM, Gerdes AM, Brown KM, Scolyer RA, Hayward NK (2015) A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma. Clin Genet 88(3):267–272.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Cheung M, Kadariya Y, Talarchek J, Pei J, Ohar JA, Kayaleh OR, Testa JR (2015) Germline BAP1 mutation in a family with high incidence of multiple primary cancers and a potential gene-environment interaction. Cancer Lett 369(2):261–265.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    McDonnell KJ, Gallanis GT, Heller KA, Melas M, Idos GE, Culver JO, Martin SE, Peng DH, Gruber SB (2016) A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer. Cancer Genet 209(3):75–81.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Cheung M, Kadariya Y, Pei J, Talarchek J, Facciolo F, Visca P, Righi L, Cozzi I, Testa JR, Ascoli V (2015) An asbestos-exposed family with multiple cases of pleural malignant mesothelioma without inheritance of a predisposing BAP1 mutation. Cancer Genet 208(10):502–507.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Ascoli V, Cozzi I, Vatrano S, Izzo S, Giorcelli J, Romeo E, Carnovale-Scalzo C, Grillo LR, Facciolo F, Visca P, Papotti M, Righi L (2016) Mesothelioma families without inheritance of a BAP1 predisposing mutation. Cancer Genet 209(9):381–387.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Bott M, Brevet M, Taylor BS, Shimizu S, Ito T, Wang L, Creaney J, Lake RA, Zakowski MF, Reva B, Sander C, Delsite R, Powell S, Zhou Q, Shen R, Olshen A, Rusch V, Ladanyi M (2011) The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat Genet 43(7):668–672.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Prins JB, Williamson KA, Kamp MM, Van Hezik EJ, Van der Kwast TH, Hagemeijer A, Versnel MA (1998) The gene for the cyclin-dependent-kinase-4 inhibitor, CDKN2A, is preferentially deleted in malignant mesothelioma. Int J Cancer 75(4):649–653

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Sekido Y, Pass HI, Bader S, Mew DJ, Christman MF, Gazdar AF, Minna JD (1995) Neurofibromatosis type 2 (NF2) gene is somatically mutated in mesothelioma but not in lung cancer. Cancer Res 55(6):1227–1231

    CAS  PubMed  Google Scholar 

  24. 24.

    Vandeweyer G, Van Laer L, Loeys B, Van den Bulcke T, Kooy RF (2014) VariantDB: a flexible annotation and filtering portal for next generation sequencing data. Genome Med 6(10):74.

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R, Rahman N, Stratton MR (2004) A census of human cancer genes. Nat Rev Cancer 4(3):177–183.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11(4):361–362.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC (2012) SIFT web server: predicting effects of amino acid substitutions on proteins. Nucl Acids Res 40 (Web Server issue):W452–W457.

    CAS  Article  Google Scholar 

  29. 29.

    Zerbino DR, Achuthan P, Akanni W, Amode MR, Barrell D, Bhai J, Billis K, Cummins C, Gall A, Giron CG, Gil L, Gordon L, Haggerty L, Haskell E, Hourlier T, Izuogu OG, Janacek SH, Juettemann T, To JK, Laird MR, Lavidas I, Liu Z, Loveland JE, Maurel T, McLaren W, Moore B, Mudge J, Murphy DN, Newman V, Nuhn M, Ogeh D, Ong CK, Parker A, Patricio M, Riat HS, Schuilenburg H, Sheppard D, Sparrow H, Taylor K, Thormann A, Vullo A, Walts B, Zadissa A, Frankish A, Hunt SE, Kostadima M, Langridge N, Martin FJ, Muffato M, Perry E, Ruffier M, Staines DM, Trevanion SJ, Aken BL, Cunningham F, Yates A, Flicek P (2017) Ensembl 2018. Nucl Acids Res.

    Article  PubMed  Google Scholar 

  30. 30.


  31. 31.

    Hylebos M, Van Camp G, Vandeweyer G, Fransen E, Beyens M, Cornelissen R, Suls A, Pauwels P, van Meerbeeck JP, Op de Beeck K (2017) Large-scale copy number analysis reveals variations in genes not previously associated with malignant pleural mesothelioma. Oncotarget 8(69):113673–113686.

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Exome Variant Server NHLBI GO Exome Sequencing Project (ESP). Accessed Jan 2018

  33. 33.

    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG, Exome Aggregation C (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536(7616):285–291.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Betti M, Casalone E, Ferrante D, Aspesi A, Morleo G, Biasi A, Sculco M, Mancuso G, Guarrera S, Righi L, Grosso F, Libener R, Pavesi M, Mariani N, Casadio C, Boldorini R, Mirabelli D, Pasini B, Magnani C, Matullo G, Dianzani I (2017) Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma. Cancer Lett 405:38–45.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Hassan R, Morrow B, Walsh T, Lee MK, Gao J, Mian I, Khan J, Raffeld M, Patel S, Xi L, Wei JS, Schrump D, Hesdorffer M, Zhang J, Calzone K, Padiernos E, Alewine C, Steinberg SM, Thomas A, King M-C (2018) Inherited predisposition to malignant mesothelioma (MM) due to mutations in DNA repair genes. [Abstract] ASCO June 1–5 2018, Chicago, USA

  36. 36.

    Panou V, Gadiraju M, Wolin A, Weipert CM, Skarda E, Husain AN, Patel JD, Rose B, Nelakuditi V, Knight Johnson A, Helgeson M, Fischer D, Sulai N, Turaga K, Huo D, Segal J, Kadri S, Li Z, Kindler HL, Churpek JE (2018) Frequency of germline mutations in cancer susceptibility genes in malignant mesothelioma. [Abstract] ASCO June 1–5 2018, Chicago, USA

  37. 37.

    Nasu M, Emi M, Pastorino S, Tanji M, Powers A, Luk H, Baumann F, Zhang YA, Gazdar A, Kanodia S, Tiirikainen M, Flores E, Gaudino G, Becich MJ, Pass HI, Yang H, Carbone M (2015) High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma. J Thorac Oncol 10(4):565–576.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Hiriart E, Gruffat H, Buisson M, Mikaelian I, Keppler S, Meresse P, Mercher T, Bernard OA, Sergeant A, Manet E (2005) Interaction of the Epstein-Barr virus mRNA export factor EB2 with human Spen proteins SHARP, OTT1, and a novel member of the family, OTT3, links Spen proteins with splicing regulation and mRNA export. J Biol Chem 280(44):36935–36945.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Raffel GD, Chu GC, Jesneck JL, Cullen DE, Bronson RT, Bernard OA, Gilliland DG (2009) Ott1 (Rbm15) is essential for placental vascular branching morphogenesis and embryonic development of the heart and spleen. Mol Cell Biol 29(2):333–341.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Ma Z, Morris SW, Valentine V, Li M, Herbrick JA, Cui X, Bouman D, Li Y, Mehta PK, Nizetic D, Kaneko Y, Chan GC, Chan LC, Squire J, Scherer SW, Hitzler JK (2001) Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28(3):220–221.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Mercher T, Coniat MB, Monni R, Mauchauffe M, Nguyen Khac F, Gressin L, Mugneret F, Leblanc T, Dastugue N, Berger R, Bernard OA (2001) Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia. Proc Natl Acad Sci USA 98(10):5776–5779.

    CAS  Article  PubMed  Google Scholar 

Download references


The human biological material of the index patient was provided by Biobank@UZA (Antwerp University Hospital, Belgium; ID: BE71030031000, funded by the Belgian National Cancer Plan). We also want to thank Sisca Kohl, nursing counselor at the Thoracic Oncology department of the Antwerp University Hospital, for helping with the collection of the peripheral blood samples of the family members.


This work was realized with an Emmanuel van der Schueren research grant from the Flemish League against Cancer and grant 2016/818 from the Belgian Foundation against Cancer.

Author information



Corresponding author

Correspondence to Jan P. van Meerbeeck.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 147 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hylebos, M., Op de Beeck, K., van den Ende, J. et al. Molecular analysis of an asbestos-exposed Belgian family with a high prevalence of mesothelioma. Familial Cancer 17, 569–576 (2018).

Download citation


  • Malignant mesothelioma
  • Familial cancer
  • Cancer predisposition
  • BAP1
  • Cancer census genes