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N.K. Hayward

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    MS 08 - BAP1 Cancer Syndrome and Mesothelioma (ID 26)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      MS08.03 - Screening for BAP1 in Danish Families (ID 1879)

      14:15 - 15:45  |  Author(s): N.K. Hayward

      • Abstract
      • Slides

      Background: BRCA1 associated protein-1 (BAP1) is a tumor suppressor gene that encodes a deubiquitinase involved in cell cycle regulation, cellular differentiation, and cell death (Carbone et al., 2013; Murali, Wiesner, & Scolyer, 2013). BAP1 is recruited to double-stand DNA breaks and promotes error-free DNA-repair (Yu et al., 2014). Germline BAP1 mutations have been identified in around 40 families with accumulation of mesothelioma, uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and basal cell carcinoma (BCC) (Carbone et al., 2013; Wadt et al., 2014; Wiesner et al., 2011). Speculation exists as to whether BAP1 germline mutation carriers with mesothelioma, UM or RCC have different prognosis compared to non-carriers with the same types of cancer. Somatic BAP1 mutations have been identified in approximately 20% of pleural malignant mesotheliomas (Zauderer MG, Bott M, McMillan R, Sima CS, Rusch V, Krug LM, Ladanyi M, 2013), with most studies reporting no significant differences in the histopathological features or survival of patients with BAP1 mutant compared to wild-type tumors. A recent study of Portuguese siblings discovered a germline BAP1 mutation as the possible cause of the only known familial clustering of well-differentiated papillary mesothelioma (WDPM), a rare subtype of epithelioid mesothelioma (Ribeiro et al., 2013), and there has since been another report of WDPM in a carrier of a germline BAP1 mutation (Pilarski et al., 2014). Previously, some patients with germline BAP1 mutations and malignant mesotheliomas have been reported as long-term survivors, which is very rare for mesotheliomas, raising the possibility that such tumors may be associated with more favorable prognosis (Ribeiro et al., 2013; Wiesner T, Fried I, Ulz P, Stacher E, Popper H, Murali R, Kutzner H, Lax S, Smolle-Jüttner F, Geigl JB, 2014). In contrast, somatic BAP1 mutations or loss of BAP1 have been associated with high-grade tumors or disseminated disease in sporadic RCC and UM patients, which could indicate a worse prognosis for carriers of germline BAP1 mutations with these tumor types. Clearly, further studies are necessary to clarify whether BAP1 germline mutation carriers with various cancers have altered prognosis relative to individuals who acquire somatic mutations in BAP1. Here, we sought to determine the frequency of germline BAP1 mutations in cancer prone families with accumulation of mesothelioma, UM, CM and RCC. Methods: Families were collected through the Danish melanoma registry and through Clinical Genetic Departments in Denmark. Families, who previously had received genetic counselling regarding mesothelioma, CM, UM, and RCC, were contacted. Results: In total we analysed 152 Danish families and found five with BAP1 mutations, which are described in Table 1. We analysed 127 CM patients, who were either young onset (<40 years), had multiple primary CM, or had a family history of melanoma, and found no BAP1 mutation. We analysed 22 sporadic cases of UM or familial cases of CM, with one case of UM in the family and found no BAP1 mutation. However, in 6 melanoma families with two cases of UM, we found 4 families with BAP1 mutation, and 2 of 3 families analysed with 2 or more cases of mesothelioma carried BAP1 mutations. We found that the strongest indicator of a germline BAP1 mutation, were families with two or more cases of mesotheliomas or UM. In 40% of families with the occurrence of mesothelioma and CM we also found BAP1 mutations but did not find BAP1 mutations in families with only CM or RCC, or families with CM and RCC. Table 1: Characterization of Danish BAP1 mutation-positive families

      Family Mutation Cases of UM/No. of mutation carriers Cases of mesothelioma/ No. of mutation carriers Cases of CM/No. of mutation carriers Other types of cancer in mutation carriers
      A c.1708C>G p.L570V 3/14 2/14 1/14 Paraganglioma, Sarcoma
      B c.581-2A>G Splice defect 7/9 0/9 1/9 Lung
      C c.1209_1210dupT p.D404X 0/8 3/8 2/8 BCC, Breast, unknown primary
      D c.178C>T p.R60X 3/10 0/10 2/10 BCC, ovary
      E c.178C>T p.R60X 2/4 1/4 0/4 BCC
      Total 15/45(33%) 6/45(13%) 6/45(13%)
      13% of BAP1 mutation carries developed mesothelioma, 33% developed UM, and 13% developed CM. There were no cases of RCC in the 5 Danish BAP1 mutation-positive families. Conclusion: In the Danish BAP1 mutation carriers we observed rare tumor types (pericardial paraganglioma and malignant fibrous histiocytoma) and three cases of unknown primary tumors. At present there is no international consensus about a surveillance program for BAP1 mutation carriers. Since BAP1 contributes to a rare, recently discovered cancer syndrome, there is as yet no documented reduction of morbidity or mortality to persons following surveillance. To obtain such empirical data we offer persons carrying a pathogenic BAP1 mutation a surveillance program consisting of yearly ophthalmological and dermatological examination from the age of 15. In addition, from the age of 25, we offer ultrasound examination of the kidneys every second year. We inform the patient and their general practitioners of the increased cancer risk, and signs which should prompt further symptom-related investigations. At the moment, we have not established a surveillance program for mesothelioma. References: Carbone, M., Yang, H., Pass, H. I., Krausz, T., Testa, J. R., & Gaudino, G. (2013). BAP1 and cancer. Nature Reviews. Cancer, 13, 153–9. doi:10.1038/nrc3459 Murali, R., Wiesner, T., & Scolyer, R. a. (2013). Tumours associated with BAP1 mutations. Pathology, 45, 116–26. doi:10.1097/PAT.0b013e32835d0efb Pilarski, R., Cebulla, C. M., Massengill, J. B., Rai, K., Rich, T., Strong, L., … Abdel-Rahman, M. H. (2014). Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases. Genes Chromosomes and Cancer, 53, 177–182. doi:10.1002/gcc.22129 Ribeiro, C., Campelos, S., Moura, C. S., Machado, J. C., Justino, A., & Parente, B. (2013). Well-differentiated papillary mesothelioma: Clustering in a Portuguese family with a germline BAP1 mutation. Annals of Oncology, 24, 2147–2150. doi:10.1093/annonc/mdt135 Wadt, K. A. W., Aoude, L. G., Johansson, P., Solinas, A., Pritchard, A., Crainic, O., … Hayward, N. K. (2014). A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma. Clinical Genetics. doi:10.1111/cge.12501 Wiesner T, Fried I, Ulz P, Stacher E, Popper H, Murali R, Kutzner H, Lax S, Smolle-Jüttner F, Geigl JB, S. M. (2014). J OURNAL OF C LINICAL O NCOLOGY Toward an Improved Definition of the Tumor Spectrum Associated With BAP1. Journal of Clinical Oncology, 30(32), 2012–2015. Wiesner, T., Obenauf, A. C., Murali, R., Fried, I., Griewank, K. G., Ulz, P., … Speicher, M. R. (2011). Germline mutations in BAP1 predispose to melanocytic tumors. Nature Genetics, 43(10), 1018–21. doi:10.1038/ng.910 Yu, H., Pak, H., Hammond-Martel, I., Ghram, M., Rodrigue, A., Daou, S., … Affar, E. B. (2014). Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proceedings of the National Academy of Sciences of the United States of America, 111, 285–90. doi:10.1073/pnas.1309085110 Zauderer MG, Bott M, McMillan R, Sima CS, Rusch V, Krug LM, Ladanyi M. (2013). Clinical Characteristics of Patients with Malignant Pleural. Journal of Thoracic Oncology, 8(11), 1430–1433.

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