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Published on: July 25, 2019
BAP1 germline variants in Finnish patients with malignant mesothelioma
Pauliina Repo1, Aleksandra Staskiewicz1, Eva Sutinen2
1Eye Genetics Group, Folkhälsan Research Center, Helsinki, Finland; Department of Ophthalmology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
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.
Insights
Genetic variants in the BAP1 gene predispose individuals to malignant mesothelioma (MM). This study found a 1.8% frequency of pathogenic BAP1 variants in Finnish MM patients, suggesting genetic testing for BAP1-TPDS is warranted.
Area of Science:
- Oncology
- Genetics
- Cancer Predisposition Syndromes
Background:
- Malignant mesothelioma (MM) is primarily linked to asbestos exposure, but genetic factors contribute in up to 7% of cases.
- Germline variants in the BRCA1-associated protein 1 (BAP1) gene cause BAP1 tumor predisposition syndrome (BAP1-TPDS), associated with MM, uveal melanoma, and other cancers.
- BAP1-inactivated nevi (BINs) can be an early indicator of BAP1-TPDS, sometimes preceding other tumor diagnoses.
Purpose of the Study:
- To determine the frequency of pathogenic germline BAP1 variants in Finnish patients diagnosed with malignant mesothelioma.
- To investigate the clinical presentation and genetic background of BAP1 variant carriers within the Finnish population.
Main Methods:
- Sequencing of germline DNA from 56 Finnish patients with MM to identify BAP1 variations.
- Immunohistochemistry and exome sequencing of benign nevi from a BAP1 variant carrier.
Main Results:
- One patient with MM carried the Finnish founder mutation c.1780_1781insT in BAP1, presenting with early-onset MM and multiple BINs, without asbestos exposure or family history.
- This founder mutation was subsequently identified in five Finnish BAP1-TPDS families.
- The frequency of pathogenic germline BAP1 variants in Finnish MM patients was found to be 1.8%.
Conclusions:
- The prevalence of pathogenic germline BAP1 variants in Finnish MM patients (1.8%) is similar to that observed in Finnish uveal melanoma patients (1.9%).
- Further research into the frequency of recurring BINs in BAP1-TPDS is recommended.
- Genetic testing for BAP1 variants should be considered in patients with two or more BAP1-TPDS core tumors, including BINs.
