BAP1 germline variants in Finnish patients with malignant mesothelioma

Pauliina Repo; Aleksandra Staskiewicz; Eva Sutinen; Mikko Rönty; Tero T Kivelä; Marjukka Myllärniemi; Joni A Turunen

doi:10.1016/j.lungcan.2022.01.017

BAP1 germline variants in Finnish patients with malignant mesothelioma

Lung Cancer. 2022 Mar:165:102-107. doi: 10.1016/j.lungcan.2022.01.017. Epub 2022 Jan 24.

Authors

Pauliina Repo¹, Aleksandra Staskiewicz², Eva Sutinen³, Mikko Rönty⁴, Tero T Kivelä⁵, Marjukka Myllärniemi³, Joni A Turunen²

Affiliations

¹ Eye Genetics Group, Folkhälsan Research Center, Helsinki, Finland; Department of Ophthalmology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland. Electronic address: pauliina.e.repo@hus.fi.
² Eye Genetics Group, Folkhälsan Research Center, Helsinki, Finland; Department of Ophthalmology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
³ Department of Pulmonary Medicine, Heart and Lung Center, Helsinki University Hospital and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁴ Department of Pathology, HUSLAB, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁵ Department of Ophthalmology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

PMID: 35114507
DOI: 10.1016/j.lungcan.2022.01.017

Abstract

Objectives: Although asbestos exposure is the most common cause of malignant mesothelioma (MM), an aggressive cancer of the pleura or peritoneum, up to 7% of patients harbor a genetic predisposition to MM. Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause a dominantly inherited tumor predisposition syndrome, BAP1-TPDS, in which MM is the second most common associated cancer. Other frequent cancers in BAP1-TPDS are uveal melanoma (UM), cutaneous melanoma and renal cell carcinoma. Additionally patients can exhibit benign skin lesions, BAP1-inactivated nevi (BIN). Most BINs arise sporadically, but patients with BAP1-TPDS may harbor multiple BINs before other tumors or as the only indication of the syndrome. Our objective was to establish the frequency of pathogenic germline BAP1 variants in Finnish patients with MM.

Materials and methods: 56 DNA samples archived in the Helsinki Biobank from Finnish patients with MM were sequenced for germline BAP1 variations. Formalin fixed paraffin embedded nevi from a pathogenic variant carrier were subjected to immunohistochemistry and exome sequencing.

Results: Sanger sequencing identified one patient with Finnish founder mutation c.1780_1781insT, p.(G549Vfs*49) in BAP1. The carrier was diagnosed with MM over fifteen years before the cohorts mean onset age (mean 68, range 27 to 82) although the patient had no asbestos exposure or family history of BAP1-TPDS. However, the patient had three BINs removed prior to the MM. The c.1780_1781insT is now found from five Finnish BAP1-TPDS families with unknown common ancestor.

Conclusion: The frequency of pathogenic germline BAP1 variants in Finnish patients with MM is 1.8 % (95 % CI, 0.04 to 9.2), comparable to the frequency in Finnish patients with UM (1.9 %). The frequency of recurring BINs in patients with BAP1-TPDS should be studied further and genetic testing for BAP1 variants considered if the patient has ≥ 2 BAP1-TPDS core tumors, including BINs.

Keywords: BAP1; BAP1-TPDS; BAP1-inactivated nevus; Malignant mesothelioma; Tumor predisposition.