Genotypic and Phenotypic Features of BAP1 Cancer Syndrome: A Report of 8 New Families and Review of Cases in the Literature | Genetics and Genomics | JAMA Dermatology | JAMA Network
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Original Investigation
October 2017

Genotypic and Phenotypic Features of BAP1 Cancer Syndrome: A Report of 8 New Families and Review of Cases in the Literature

Author Affiliations
  • 1Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  • 2Massachusetts General Hospital Cancer Center, Boston
  • 3Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, Boston
  • 4Department of Dermatology, University of Iowa Hospitals and Clinics, and Iowa City VAMC, Iowa City
  • 5Dana Farber Cancer Institute, Boston, Massachusettss
  • 6Section of Dermatology, University of Chicago Medicine, Chicago, Illinois
  • 7The Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois
JAMA Dermatol. 2017;153(10):999-1006. doi:10.1001/jamadermatol.2017.2330
Key Points

Question  How are patients with germline mutations in BAP1 most likely to present, and how are dermatologists involved in their care?

Findings  Among the 10 patients presented in this series, as well as the additional 205 patients identified in a review of the literature, melanocytic BAP1–mutated atypical intradermal tumors (MBAITs) had a significantly earlier median age of onset (32 years) compared with other BAP1-associated tumors and were present in 40 of 53 patients (75%) with documented skin examinations.

Meaning  Dermatologists play a crucial role in identifying patients with the BAP1 syndrome by screening patients diagnosed with MBAITs.


Importance  Patients with germline mutations in BAP1 may develop several flesh-colored melanocytic BAP1–mutated atypical intradermal tumors (MBAITs). These tumors generally develop earlier than other BAP1–associated tumors, highlighting an important role for dermatologists in identifying and screening patients with a history suggestive of a germline mutation.

Objective  To describe 8 new families with germline mutations in BAP1 and provide a comprehensive review of reported cases.

Design, Settings and Participants  Patients were identified in an outpatient dermatology clinical setting over a 6-month period (10 mutation carriers from 8 families) and through a literature review using PubMed (205 patients).

Exposures  Mutations were identified through next-generation sequencing of saliva or blood samples, and RNA was extracted from fibroblasts cultured from a patient with an intronic variant to determine the impact of the mutation on the coding sequence.

Main Outcomes and Measures  All 215 patients were assessed for personal and/or family history and genotype. These findings were compiled and assessed for any association between genotype and phenotype.

Results  Overall, this study included 215 patients (108 women, 91 men, and 16 gender unspecified; median [range] age, 46.5 [10.0-79.0] years). Nine of the 10 patients who were identified in the outpatient dermatology setting were found to have MBAITs on clinical examination. Forty of 53 patients (75%) identified in the literature review who underwent total-body skin examinations (TBSE) were found to have MBAITs, suggesting a high penetrance in patients who have undergone TBSE. The most prevalent malignancies among BAP1 mutation carriers were uveal melanoma (n =  60 [28%]), mesothelioma (n = 48 [22%]), cutaneous melanoma (n = 38 [18%]), and renal cell carcinoma (n = 20 [9%]). A total of 71 unique mutations in BAP1 have been reported.

Conclusions and Relevance  Our results indicate that germline mutations in both coding and noncoding regions throughout the BAP1 gene can impair protein function, leading to an increased risk for several associated malignancies. Four of the 8 probands we present had no history of BAP1-associated malignancies and were assessed for germline mutations when found to have MBAITs on dermatologic examination. Dermatologists can identify patients with a high likelihood of the BAP1 cancer syndrome through personal and family history and TBSE for the presence of possible MBAITs.