Genotypic and Phenotypic Features of BAP1 Cancer Syndrome

Abstract

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 PARTICIPANTSPatients 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 MEASURESAll 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 RELEVANCEOur 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.

Genomics and Functional Genomics of Malignant Pleural Mesothelioma

“…To further expand the knowledge on MPM biology, various research groups have conducted in silico analyses on TCGA and other open access multi-institutional MPM datasets. These efforts have identified novel genetic aberrations and confirmed the earlier findings on recurrent alterations [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. The data suggest that commonly detected novel variations are related to cellular processes such as DNA repair, histone methylation, RNA metabolism, and angiogenesis.…”

“…Furthermore, BAP1 interacts with a number of nuclear proteins, such as BRCA1 (Breast Cancer Type 1) and BARD1 (BRCA1-associated RING domain protein 1), and assembles an active multiprotein complex that promotes homologous recombination and double-strand break repair, thereby maintaining genomic stability and functioning as a tumor suppressor [ 37 ]. Recently, heterozygous germline mutations eventually resulting in biallelic inactivation of the BAP1 gene have been implicated in a rare condition named “BAP1 cancer syndrome”, which is characterized by the increased susceptibility to multiple cancers, primarily familial MPM, and uveal melanomas, and less frequently cutaneous melanomas, breast carcinomas, cholangiocarcinomas, sarcomas, basal cell carcinomas, renal cell carcinomas, and various types of CNS tumors [ 38 , 39 , 40 , 41 , 42 ]. It is of particular interest to mention here that germline mutations in DNA damage sensing and repair genes, and other tumor suppressor genes may also increase the risk of MPM development.…”

Detecting germline BAP1 mutations in patients with peritoneal mesothelioma: benefits to patient and family members

“…Inheritance is autosomal dominant with high penetrance. Other malignancies often reported in carriers of germline BAP1 mutations include most types of skin cancers [ 20 – 22 ], breast cancer, cholangiocarcinoma, non-small cell lung adenocarcinoma, meningioma, sarcomas, peripheral nerve sheath tumor, and neuroendocrine carcinoma [ 1 – 6 , 9 , 11 , 23 , 24 ].…”

“…Carriers of germline BAP1 mutations can also develop characteristic benign melanocytic skin lesions that were initially called as “atypical Spitz tumors” [ 25 ], and later when the unique histological and molecular characteristics of these lesions were elucidated, named as “melanocytic BAP1 mutated atypical intradermal tumors” (MBAITs) [ 6 , 22 ].…”

Clinical, dermoscopic, histological and molecular analysis of BAP1-inactivated melanocytic naevus/tumour in two familial cases of BAP1 syndrome

“…Dear Editor , BRCA1‐associated protein (BAP)1‐inactivated melanocytic naevus/tumours (BIMN/Ts) are specific skin tumours that appear during the first two decades of life . These lesions must be recognized by dermatologists and pathologists as an early predictive marker of BAP1 cancer syndrome, as they may precede the development of uveal and cutaneous melanomas, mesotheliomas, lung adenocarcinomas, renal cell carcinomas and meningiomas by several years . The dermoscopic characteristics of these tumours have not been described.…”