Abstract
Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (TPDS). BAP1 TPDS is associated with an increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma, and several other cancer subtypes. Here, we report a germline nonsense BAP1 variant (c.850G>T, p.Glu284Ter) in a patient with bladder cancer and a strong family history of malignancy. Concurrently, we identified a somatic frameshift BAP1 variant, and as expected, immunostaining validated the loss of BAP1 protein in patient-derived tumor specimens. Together, these data provide strong evidence of pathogenicity in this case. With the addition of bladder cancer to the tumor types reported with germline BAP1 mutations, our understanding of the BAP1 TPDS continues to evolve, and may affect future screening and surveillance guidelines.
Highlights
Bladder cancer is the most common malignancy of the urinary tract, with an estimated 549,000 new cases diagnosed worldwide in 2018.1 It is characterized by one of the highest somatic mutation frequencies of any studied cancer, third only to melanoma and lung.[2]
Germline pathogenic variants in the BRCA1-associated protein 1 (BAP1) tumor suppressor gene are the genetic cause of the BAP1 tumor predisposition syndrome (TPDS; OMIM: 614327; known as the BAP1 cancer syndrome5)
BAP1 TPDS is associated with an increased risk of uveal melanoma, cutaneous melanoma, mesothelioma, renal cell carcinoma, and several other cancer subtypes.[6,7,8,9]
Summary
Bladder cancer is the most common malignancy of the urinary tract, with an estimated 549,000 new cases diagnosed worldwide in 2018.1 It is characterized by one of the highest somatic mutation frequencies of any studied cancer, third only to melanoma and lung.[2]. A greater understanding of the molecular alterations and subtypes that define bladder cancer has resulted in a new wave of targeted therapies.[3]. In bladder cancer clinical research most next-generation sequencing (NGS) tests are aimed at identifying potentially targetable somatic alterations. Germline pathogenic variants in the BRCA1-associated protein 1 (BAP1) tumor suppressor gene are the genetic cause of the BAP1 tumor predisposition syndrome (TPDS; OMIM: 614327; known as the BAP1 cancer syndrome[5]). BAP1 TPDS is associated with an increased risk of uveal melanoma, cutaneous melanoma, mesothelioma, renal cell carcinoma, and several other cancer subtypes.[6,7,8,9]
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