Germline BRCA1-associated Protein-1 Research Articles

HAP1 cell utilization for accurate interpretation of germline BAP1 variants

Aims/Purpose: Pathogenic germline variants in BRCA1‐Associated Protein 1 (BAP1) gene cause a rare, dominant, life‐threatening tumour predisposition syndrome (BAP1‐TPDS). It increases risk for atypical cutaneous Spitz tumours and for several index cancers: uveal melanoma, malignant mesothelioma, cutaneous melanoma, clear cell renal cell carcinoma, and basal cell carcinoma. Because about 50% of variants in the public database CLINVAR are of unknown significance (VUS) and accurate interpretation of variants is crucial for screening cancer in carriers, improved tools for genomic BAP1 variant interpretation are needed. We aimed to create a mammalian cell based tool for this purpose.Methods: Four pathogenic BAP1 variants (c.67 + 1G > T, c.281A > G, c.680G > A, and c.1780_1781insT) and one VUS (c.1526C > T) were edited into the genome of near haploid HAP1 cells with CRISPR‐Cas9 and assayed for BAP1 expression and cell fitness. Proliferation and cell adhesion was quantified using xCelligence real‐time cell analysis system.Results: BAP1 loss reduces growth of HAP1 cells, which we exploited as phenotypic readout for pathogenicity of inserted variants. Three BAP1‐TPDS history‐associated variants c.67 + 1G > T, c.281A > G, and c.1780_1781insT reduced HAP1 adhesion and proliferation roughly by 70–80% whereas the c.680G > A missense variant, identified in a patient with UM without BAP1‐TPDS family history, reduced proliferation by 50%. VUS c.1526C > T behaved similarly to wild type.Conclusions: Qualitatively, the results of our in vitro tool for BAP1 variant interpretation agree with previous studies, validating the tool. The validated system has potential for scaling up for simultaneous analysis of multiple variants. Quantitatively, it might have potential for predicting higher or lower risk in family members.

Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome.

BRCA1-associated protein-1 (BAP1) is a recognised tumour suppressor gene. Germline BAP1 pathogenic/likely pathogenic variants are associated with predisposition to multiple tumours, including uveal melanoma, malignant pleural and peritoneal mesothelioma, renal cell carcinoma and specific non-malignant neoplasms of the skin, as part of the autosomal dominant BAP1-tumour predisposition syndrome. The overall lifetime risk for BAP1 carriers to develop at least one BAP1-associated tumour is up to 85%, although due to ascertainment bias, current estimates of risk are likely to be overestimated. As for many rare cancer predisposition syndromes, there is limited scientific evidence to support the utility of surveillance and, therefore, management recommendations for BAP1 carriers are based on expert opinion. To date, European recommendations for BAP1 carriers have not been published but are necessary due to the emerging phenotype of this recently described syndrome and increased identification of BAP1 carriers via large gene panels or tumour sequencing. To address this, the Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom invited European collaborators to collaborate to develop guidelines to harmonize surveillance programmes within Europe. Recommendations with respect to BAP1 testing and surveillance were achieved following literature review and Delphi survey completed by a core group and an extended expert group of 34 European specialists including Geneticists, Ophthalmologists, Oncologists, Dermatologists and Pathologists. It is recognised that these largely evidence-based but pragmatic recommendations will evolve over time as further data from research collaborations informs the phenotypic spectrum and surveillance outcomes.

Diagnostics of BAP1-Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience.

Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 (BAP1) lead to BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of BAP1-TPDS, along with a clinical update and cascade genetic testing of previously reported BAP1-TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected BAP1-TPDS and validated pathogenic variants (PVs) by assessing BAP1 somatic loss in matching tumor specimens. Overall, we identified seven patients (7/101, 6.9%) carrying six different germline BAP1 PVs, including one novel variant. Consistently, cascade testing revealed a total of seven BAP1 PV carriers. In addition, we explored the mutational burden of BAP1-TPDS tumors by targeted next-generation sequencing. Lastly, we found that certain tumors present in PV carriers retain a wild-type BAP1 allele, suggesting a sporadic origin of these tumors or a functional role of heterozygous BAP1 in neoplastic development. Altogether, our findings have important clinical implications for therapeutic response of BAP1-TPDS patients.

O10-5 BAP1 cancer syndrome

BRCA1 associated protein 1 (BAP1) is a member of ubiquitin C-terminal hydrolases (UCH) subfamily of deubiquitylating enzymes regulating transcription, DNA replication, DNA damage response etc. We discovered hereditary cancer syndrome “BAP1 cancer syndrome” where carriers of heterozygous germline BAP1 mutations are predisposed to various types of cancer, mainly malignant mesothelioma (MM), uveal melanoma, renal cell carcinoma, but also include breast cancer, cutaneous melanoma, basal cell carcinoma, meningioma, cholangiocarcinoma.

BAP1 germline variants in Finnish patients with malignant mesothelioma

ObjectivesAlthough 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 methods56 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. ResultsSanger 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. ConclusionThe 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.

MALIGNANT MESOTHELIOMA AND GERMLINE HETEROZYGOUS BAP1 MUTATION IN A YOUNG WOMAN PRESENTING WITH RECURRENT PLEURAL EFFUSIONS AND WORSENING PNEUMOTHORAX AFTER TALC PLEURODESIS

SESSION TITLE: Fellows Lung Cancer Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Germline BAP1 mutations are associated with a pattern of hereditary malignancies, namely uveal and cutaneous melanoma, malignant mesothelioma (MM), and renal cell carcinoma. We present a rare case of a young woman who was diagnosed with malignant pleural and peritoneal mesothelioma. CASE PRESENTATION: A 23 year-old woman with no known medical conditions or exposure to asbestos was referred to medical oncology after completing a video-assisted thoracoscopic surgery (VATS) followed by talc pleurodesis for recurrent pleural effusions of unknown etiology. Initial pleural fluid studies showed total protein 4.5 g/dL and LDH 150 U/L. Pleural fluid contained clusters of atypical mesothelial cells surrounded by inflammation suggestive of reactive mesothelial hyperplasia. VATS found abnormal reticulated surfaces and a white plaque-like tissue at the apex. Pleural biopsies showed atypical mesothelial proliferation suspicious for MM in a background of reactive changes, but ultimately results were considered non-diagnostic. Due to inconclusive pathology we recommended further evaluation with diagnostic laparoscopy because her CT scans also showed small volume ascites and pelvic fluid. Studding was noted on peritoneum, bowel, pelvic tissues, and omentum, and biopsies showed markedly atypical proliferation of epithelioid cells forming glandular and tubulopapillary structures with disorganized growth and focal invasion into adjacent adipose tissue. Immunostains of tumor cells were consistent with mesothelial differentiation. BAP-1 immunohistochemistry showed loss of expression only in tumor cells. Collectively these features supported a diagnosis of MM of epithelioid type. Peripheral blood testing for BAP1 tumor predisposition syndrome (BAP1-TPDS) was positive for a heterozygous germline BAP1 mutation, c.2050 C>T, p.Gln684* (Pilarski et al. 2013, Haugh et al. 2017). Staging scans prior to chemotherapy showed interval development of a pneumothorax in the right lung months after her talc pleurodesis. She was treated with cisplatin, pemetrexed, and bevacizumab with subsequent improvement of her pneumothorax. DISCUSSION: Our case report showed the clinical features of a patient with MM from BAP1-TPDS. Loss of BAP1 expression can help distinguish MM from reactive mesothelial cells (Cigognetti et al. 2015). Progression of her disease after having a talc pleurodesis manifested radiographically as a worsening pneumothorax, and chemotherapy was able to reverse this process. CONCLUSIONS: Unexplained pleural effusions or pleural or peritoneal biopsies showing atypical mesothelial cells should have immunohistochemistry testing for loss of BAP1 expression to evaluate for MM. MM due to BAP1-TPDS is responsive chemotherapy. Young MM patients without risk factors for MM should have germline testing for BAP1-TPDS. Reference #1: Pilarski, Robert, et al. “Expanding the Clinical Phenotype of hereditaryBAP1cancer Predisposition Syndrome, Reporting Three New Cases.” Genes, Chromosomes and Cancer, vol. 53, no. 2, 15 Nov. 2013, pp. 177–182., doi:10.1002/gcc.22129. Reference #2: Haugh, Alexandra M., et al. “Genotypic and Phenotypic Features of BAP1 Cancer Syndrome.” JAMA Dermatology, vol. 153, no. 10, 9 Aug. 2017, p. 999-1006., doi:10.1001/jamadermatol.2017.2330. Reference #3: Cigognetti, Marta, et al. “BAP1 (BRCA1-Associated Protein 1) Is a Highly Specific Marker for Differentiating Mesothelioma from Reactive Mesothelial Proliferations.” Modern Pathology, vol. 28, no. 8, 29 May 2015, pp. 1043–1057., doi:10.1038/modpathol.2015.65. DISCLOSURES: Speaker/Speaker's Bureau relationship with Daiichi Sankyo/AstraZeneca Please note: $1-$1000 Added 03/18/2020 by Blakely Kute, source=Web Response, value=Honoraria No relevant relationships by Eric Luk, source=Web Response

Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

Additional sex combs-like 1 (ASXL1) interacts with BRCA1-associated protein 1 (BAP1) deubiquitinase to oppose the polycomb repressive complex 1 (PRC1)-mediated histone H2A ubiquitylation. Germline BAP1 mutations are found in a spectrum of human malignancies, while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis. Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region, resulting in the production of C-terminally truncated mutant ASXL1 proteins. How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogenesis are unclear. Here, we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes. We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells, and lose the ability to interact with FOXK1/K2. Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes, particularly those involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling pathways. In addition to FOXK1/K2, we also identify other DNA-binding transcription regulators including transcription factors (TFs) which interact with wild-type ASXL1, but not C-terminally truncated mutant. Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.

Phase II study of olaparib in malignant mesothelioma (MM) to correlate efficacy with germline and somatic mutations in DNA repair genes.

9054 Background: BRCA1 associated protein 1 ( BAP1), a nuclear deubiquitinase involved in DNA double-strand break repair is frequently mutated in MM. Because poly(ADP-ribose) polymerase inhibitors (PARPIs) induce synthetic lethality in BRCA1/2 mutant cancers, we sought to evaluate efficacy of olaparib in patients with MM and correlate it with pathogenic germline and somatic mutations in DNA repair genes. Methods: Phase II single-center study (NCT03531840) enrolled patients with advanced pleural or peritoneal mesothelioma who had progressed on prior therapies, age >18 years, ECOG performance status <1, adequate organ and bone marrow function. Olaparib 300mg was given twice daily orally in 3 week cycles until disease progression or toxicity. Efficacy was assessed by CT scan every 6 weeks using RECIST criteria. Whole exome sequencing (WES) was performed on blood and tumor samples to identify pathogenic germline and somatic mutations in DNA repair genes. Primary objective was to determine response rate based on germline or somatic mutation status of DNA repair genes. Results: Between July 2018 to May 2019, 23 patients were enrolled, 15 pleural and 8 peritoneal MM [14 male; median age 63 (range 41-75 years); median number of prior treatments 3 (range 1-5)]. Median olaparib cycles received was 4 (2-21). WES to identify pathogenic mutations in the germline and tumor was performed in 23 and 17 patients respectively. Four patients had germline BAP1, 1 germline MRE11A, and 5 had somatic BAP1 mutations. Of 22 evaluable patients, 1(4%) had partial response (PR), 17 (77%) had stable disease at 6 weeks and 4 (18%) had progressive disease. Patient with PR had a germline mutation in MRE11A. Median progression free survival (PFS) and overall survival (OS) for all patients was 3.4 months (95% CI: 2.7 – 4.8 months) and 8.1 months (95% CI: 4.5 months – not estimable) respectively. Median PFS of germline BAP1 mutant patients (n = 4) was 2.3 months (95% CI: 1.3 – 3.6 months) compared to 4.1 months (95% CI: 2.7 – 5.5 months) for BAP1wild type patients (n = 18;P = 0.026). Median OS was 4.6 months (95% CI: 3.1 – 4.9 months) for patients with germline BAP1 mutation versus not reached for those without germline BAP1 mutation (P = 0.0058). The most common side effects of olaparib were anemia (16%), lymphopenia (24%), nausea (14%), and increased creatinine (9%). Conclusions: Olaparib has limited anti-tumor activity in previously treated MM patients including those with germline or somatic BAP1 mutations. Presence of germline BAP1 mutations was associated with decreased PFS and OS. Clinical trial information: NCT03531840.

Concurrent germline and somatic pathogenic BAP1 variants in a patient with metastatic bladder cancer

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.

BAP1: role in carcinogenesis and clinical implications.

BRCA-1 associated protein 1 (BAP1) is a tumor suppressor gene that has been implicated in the pathogenesis of several malignancies and is gaining more recognition as a crucial gene that could be amenable to therapeutic manipulation. There is a growing interest in prevention and establishing cancer screening guidelines in patients with germline BAP1 mutations to aid with early detection and treatment of associated malignancies. We aim to give a concise review of BAP1 and its role in carcinogenesis, the BAP1 cancer predisposition syndrome and discuss clinical implications including suggested screening guidelines, and potential targeted therapeutic options.

Families with BAP1-Tumor Predisposition Syndrome in The Netherlands: Path to Identification and a Proposal for Genetic Screening Guidelines.

Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1-tumor predisposition syndrome (BAP1-TPDS, OMIM 614327). BAP1-TPDS is associated with an increased risk of developing uveal melanoma (UM), cutaneous melanoma (CM), malignant mesothelioma (MMe), renal cell carcinoma (RCC), meningioma, cholangiocarcinoma, multiple non-melanoma skin cancers, and BAP1-inactivated nevi. Because of this increased risk, it is important to identify patients with BAP1-TPDS. The associated tumors are treated by different medical disciplines, emphasizing the need for generally applicable guidelines for initiating genetic analysis. In this study, we describe the path to identification of BAP1-TPDS in 21 probands found in the Netherlands and the family history at the time of presentation. We report two cases of de novo BAP1 germline mutations (2/21, 9.5%). Findings of this study combined with previously published literature, led to a proposal of guidelines for genetic referral. We recommend genetic analysis in patients with ≥2 BAP1-TPDS-associated tumors in their medical history and/or family history. We also propose to test germline BAP1 in patients diagnosed with UM <40 years, CM <18 years, MMe <50 years, or RCC <46 years. Furthermore, other candidate susceptibility genes for tumor types associated with BAP1-TPDS are discussed, which can be included in gene panels when testing patients.

Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations

IntroductionInherited mutations are easily detected factors that influence the disease courses and optimal treatment strategies of some cancers. Germline mutations in BRCA1 associated protein 1 (BAP1) are associated with unique disease profiles in mesothelioma, atypical spitz nevi, and uveal melanoma, but the patient characteristics of an unselected population of BAP1 carriers identified by an ascertainment prevalence study are unknown. MethodsWe collected blood samples, cancer histories, and occupational exposures from 183 unselected patients with BAP1-related diseases. Clinical information for each patient was obtained from medical records. Germline DNA was extracted from blood samples and sequenced using a next-generation sequencing assay. We tested screening criteria developed to identify patients with a possible germline BAP1 mutation. ResultsPathogenic or likely pathogenic germline BAP1 mutations were observed in 5 of 180 sequenced specimens and were exclusively found in patients identified by our screening criteria. Several patients with characteristics suspicious for a heritable deleterious mutation did not have a germline BAP1 mutation. The prevalence of pathogenic germline BAP1 mutations in patients with mesothelioma was 4.4% (95% confidence interval 1.1–11.1). ConclusionsResults from the first unselected prevalence ascertainment study of germline BAP1 alterations suggest that the frequency of this mutation is low among patients with mesothelioma. The proposed screening criteria successfully identified all patients with germline BAP1-mutant mesothelioma. These screening guidelines may assist physicians in selecting patients who would benefit from genetic testing. Future efforts should validate and refine these criteria and search for other germline mutations associated with mesothelioma and related diseases.

Population-based analysis of BAP1 germline variations in patients with uveal melanoma

Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (BAP1-TPDS) with increased risk of several cancers, the most frequent of which is uveal melanoma (UM). Pathogenicity of loss-of-function (LOF) BAP1 variants is clear, as opposed to that of missense and regulatory region variants. We sequenced the coding, promoter, untranslated region (UTR) and intronic regions of BAP1 and analyzed copy number variations (CNVs). In this nationwide study, the cohort comprised UM patients diagnosed between 2010 and 2017. These included 432 of 520 consecutive Finnish UM patients, 16 of whom were familial, and one additional patient from a Finnish-Swedish family. Twenty-one different rare variants were found: seven exonic, seven intronic, four 3' UTR and three promoter. We considered five variants likely to be pathogenic by effect on splicing, nuclear localization or deubiquitination activity. Intron 2 (c.67+1G>T) and exon 14 (c.1780_1781insT) LOF variants were presumed founder mutations, occurring in two and four families, respectively; both abolished nuclear localization in vitro. Intron 2, exons 5 (c.281A>G) and 9 (c.680G>A) missense variants markedly reduced deubiquitinating activity. A deep intronic 25 base pair deletion in intron 1 caused aberrant splicing in vitro. On the basis of functional studies and family cancer history, we classified four exon 13 missense variants as benign. No CNVs were found. The prevalence of pathogenic variants was 9/433 (2%) and 4/16 (25%) in Finnish UM families. Family cancer history and functional assays are indispensable when establishing the pathogenicity of BAP1 variants. Deep intronic variants can cause BAP1-TPDS.

Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.

The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors. We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided. The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001). This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research.

Clinical and dermoscopic features of cutaneous BAP1-inactivated melanocytic tumors: Results of a multicenter case-control study by the International Dermoscopy Society

Multiple BRCA1-associated protein 1 (BAP1)-inactivated melanocytic tumors (BIMTs) have been associated with a familial cancer syndrome involving germline mutations in BAP1. We sought to describe the clinical and dermoscopic features of BIMTs. This was a retrospective, multicenter, case-control study. Participating centers contributed clinical data, dermoscopic images, and histopathologic data of biopsy-proven BIMTs. We compared the dermoscopic features between BIMTs and control patients. The dataset consisted of 48 BIMTs from 31 patients (22 women; median age 37years) and 80 control patients. Eleven patients had a BAP1 germline mutation. Clinically, most BIMTs presented as pink, dome-shaped papules (n=24). Dermoscopically, we identified 5 patterns: structureless pink-to-tan with irregular eccentric dots/globules (n=14, 29.8%); structureless pink-to-tan with peripheral vessels (n=10, 21.3%); structureless pink-to-tan (n=7, 14.9%); a network with raised, structureless, pink-to-tan areas (n=7, 14.9%); and globular pattern (n=4, 8.5%). The structureless with eccentric dots/globules pattern and network with raised structureless areas pattern were only identified in BIMT and were more common in patients with BAP1 germline mutations (P<.0001 and P=.001, respectively). Limitations included our small sample size, retrospective design, the absence of germline genetic testing in all patients, and inclusion bias toward more atypical-looking BIMTs. Dome-shaped papules with pink-to-tan structureless areas and peripheral irregular dots/globules or network should raise the clinical suspicion for BIMT.

Histomorphologic spectrum of germline-related and sporadic BAP1-inactivated melanocytic tumors

BRCA1-associated protein 1 (BAP1)-inactivatedmelanocytic tumors (BIMTs) are often the earliest sign of the BAP1 tumor predisposition syndrome. Identification of BIMTs and selection of patients for germline testing affect the lives of patients with germline BAP1 mutations. To describe the spectrum of histomorphologic findings in BAP1-inactivated melanocytic lesions to improve their recognition. We determined the frequency of sporadic versus germline cases in our cohort, assessing whether any features were statistically linked to germline status. Histomorphologic features of BAP1-inactivated melanocytic lesions were analyzed by comparing cases with germline mutations with those with unknown or negative status. Available clinical follow-up data were reported. The histomorphologic spectrum of BAP1-inactivated melanocytic lesions is broad; it includes cases with spitzoid cytomorphology (69%), smaller epithelioid cells without spitzoid features (31%), and rhabdoid cytologic features (58%). BIMTs from patients with germline mutations were statistically more likely to have an extensive junctional component of BAP1-inactivated melanocytes (P=.0177). All 11 patients with suspected or confirmed germline mutations had a history of cutaneous melanoma or multiple BIMTs. The unknown germline status of 77 patients. Approximately 12% of patients with BIMTs have germline mutations. Extensive junctional involvement in a BIMT and a personal history of melanoma or previous BIMT may be additional indications for germline testing.

Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy

The germline BAP1 (BRCA1-associated protein-1) mutation and associated cancer pre-disposition syndrome was first described in 2011. Since then, physicians have considered this diagnosis for patients with a characteristic personal or family history of BAP1-associated tumours (mainly uveal and cutaneous melanoma, pleural/peritoneal mesothelioma, renal cell carcinoma and BAP1-deficient melanocytic lesions). However, a positive germline BAP1 mutation detection creates significant uncertainty in terms of appropriate cancer surveillance. A number of groups have proposed surveillance plans but important management dilemmas remain unresolved. The lifetime risk of developing cancer is not known and it is not clear if surveillance would lead to detecting cancer at an earlier stage or change survival outcomes. A consensus monitoring strategy was initially proposed at the Melanoma Institute Australia Melanoma Multidisciplinary Team meeting and later discussed with specialists in the field of cancer genetics, pathology, radiology, medical oncology, ophthalmology and dermatology. The objectives were to facilitate early diagnosis, incorporating where possible, clinically based and low/non-ionising radiation imaging modalities, applying the principles of a good screening test and a multidisciplinary focus.

A population-based analysis of germline BAP1 mutations in melanoma.

Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30 BAP1 variants in total, of which 27 were rare (ExAc allele frequency <0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and five in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants. Germline BAP1 alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in cutaneous melanoma.

Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas.

Patients with meningiomas have widely divergent clinical courses. Some entirely recover following surgery alone, while others have relentless tumor recurrences. This clinical conundrum is exemplified by rhabdoid meningiomas, which are designated in the World Health Organization Classification of Tumours as high grade, despite only a subset following an aggressive clinical course. Patient management decisions are further exacerbated by high rates of interobserver variability, biased against missing possibly aggressive tumors. Objective molecular determinants are needed to guide classification and clinical decision making. To define genomic aberrations of rhabdoid meningiomas, we performed sequencing of cancer-related genes in 27 meningiomas from 18 patients with rhabdoid features and evaluated breast cancer [BRCA]1-associated protein 1 (BAP1) expression by immunohistochemistry in 336 meningiomas. We assessed outcomes, germline status, and family history in patients with BAP1-negative rhabdoid meningiomas. The tumor suppressor gene BAP1, a ubiquitin carboxy-terminal hydrolase, is inactivated in a subset of high-grade rhabdoid meningiomas. Patients with BAP1-negative rhabdoid meningiomas had reduced time to recurrence compared with patients with BAP1-retained rhabdoid meningiomas (Kaplan-Meier analysis, 26 mo vs 116 mo, P < .001; hazard ratio 12.89). A subset of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, indicating that rhabdoid meningiomas can be a harbinger of the BAP1 cancer predisposition syndrome. We define a subset of aggressive rhabdoid meningiomas that can be recognized using routine laboratory tests. We implicate ubiquitin deregulation in the pathogenesis of these high-grade malignancies. In addition, we show that familial and sporadic BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management.

BAP1 germline mutations in uveal melanoma patients without family history of eye cancer

PurposeGermline pathogenic variants of the BRCA‐1 associated protein‐1 (BAP1) gene predispose to uveal melanoma and several other cancers. Testing for germline BAP1 mutations should be performed if typical BAP1 cancer predisposition syndrome tumors have been diagnosed in the family. We report the frequency of germline pathogenic variants of BAP1 in consecutive Finnish uveal melanoma patients without known history of eye cancer.MethodsIn Finland, uveal melanomas are treated centrally in the Ocular Oncology Service, Helsinki University Hospital. We collected clinical data and genomic DNA from 239 of 389 consecutive patients diagnosed from January 2010 to December 2015. Patients with verified family history of eye cancer were excluded. Fifteen patients had died before the study started and could not be sampled. The exons and exon‐intron junctions of BAP1 were sequenced.ResultsWe found only one probable pathogenic germline variant, a donor splice site mutation in a highly conserved region immediately after exon 2 in a 57‐year‐old male patient. Three of his family members had been diagnosed with typical BAP1‐related cancers (cutaneous melanoma, mesothelioma, and renal cell carcinoma). The mutation was not found in 61,486 controls from the ExAC (http://exac.broadinstitute.org). The frequency of germline BAP1 mutation in patients without any family history of eye cancer was 0.4% (1/239, 95% CI 0.01 to 2.2).ConclusionsThe frequency of BAP1 germline pathogenic variants in the Finnish patients with uveal melanoma without family history of ocular cancer is low. The family history of typical BAP1‐related cancers was informative, and should routinely be obtained to guide the BAP1 genetic testing.