Germline BAP1 Mutations Research Articles

PRAME Immunostaining in BAP-1-Inactivated Melanocytic Tumors: Unraveling Diagnostic Complexity and Exploring Germline Mutation Associations

Background: Cutaneous melanocytic tumors with BAP-1 inactivation (BIMTs), linked to mutations in the BAP-1 gene, present diagnostic challenges due to their morphological similarities with other melanocytic lesions. The search for reliable diagnostic markers, including PRAME, holds potential to significantly improve the accuracy of differential diagnoses. Methods: A retrospective analysis of 32 BIMTs from 25 patients, collected between 2018 and 2022, involved histologic examination and immunostaining for BAP-1 and PRAME. Results: Positive PRAME expression, defined as diffuse staining in at least 75% of nevic cells, was observed in 19% of cases. Variations in PRAME expression patterns were noted, particularly in biphasic lesions and those associated with germline BAP-1 mutations. Conclusions: The diagnostic complexities of BIMTs necessitate a comprehensive diagnostic strategy. While BAP-1 immunostaining remains pivotal, this study explored PRAME as a potential adjunctive diagnostic tool. PRAME antibody shows highly variable expression in BIMTs, limiting its utility as a supportive tool for the differential diagnosis with melanomas, especially in patients with biphasic lesions and germline mutations in BAP-1.

The Prevalence and Radiologic Features of Renal Cancers Associated with FLCN, BAP1, SDH, and MET Germline Mutations.

Purpose To investigate the prevalence of FLCN, BAP1, SDH, and MET mutations in an oncologic cohort and determine the prevalence, clinical features, and imaging features of renal cell carcinoma (RCC) associated with these mutations. Secondarily, to determine the prevalence of encountered benign renal lesions. Materials and Methods From 25 220 patients with cancer who prospectively underwent germline analysis with a panel of more than 70 cancer-predisposing genes from 2015 to 2021, patients with FLCN, BAP1, SDH, or MET mutations were retrospectively identified. Clinical records were reviewed for patient age, sex, race/ethnicity, and renal cancer diagnosis. If RCC was present, baseline CT and MRI examinations were independently assessed by two radiologists. Summary statistics were used to summarize continuous and categorical variables by mutation. Results A total of 79 of 25 220 (0.31%) patients had a germline mutation: FLCN, 17 of 25 220 (0.07%); BAP1, 22 of 25 220 (0.09%); SDH, 39 of 25 220 (0.15%); and MET, one of 25 220 (0.004%). Of these 79 patients, 18 (23%) were diagnosed with RCC (FLCN, four of 17 [24%]; BAP1, four of 22 [18%]; SDH, nine of 39 [23%]; MET, one of one [100%]). Most hereditary RCCs demonstrated ill-defined margins, central nonenhancing area (cystic or necrotic), heterogeneous enhancement, and various other CT and MR radiologic features, overlapping with the radiologic appearance of nonhereditary RCCs. The prevalence of other benign solid renal lesions (other than complex cysts) in patients was up to 11%. Conclusion FLCN, BAP1, SDH, and MET mutations were present in less than 1% of this oncologic cohort. Within the study sample size limits, imaging findings for hereditary RCC overlapped with those of nonhereditary RCC, and the prevalence of other associated benign solid renal lesions (other than complex cysts) was up to 11%. Keywords: Familial Renal Cell Carcinoma, Birt-Hogg-Dubé Syndrome, Carcinoma, Renal Cell, Paragangliomas, Urinary, Kidney © RSNA, 2024.

BAP1 is a novel regulator of HIF-1α

BAP1 is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline BAP1 mutations often develop mesothelioma, an aggressive malignancy of the serosal layers covering the lungs, pericardium, and abdominal cavity. Intriguingly, mesotheliomas developing in carriers of germline BAP1 mutations are less aggressive, and these patients have significantly improved survival. We investigated the apparent paradox of a tumor suppressor gene that, when mutated, causes less aggressive mesotheliomas. We discovered that mesothelioma biopsies with biallelic BAP1 mutations showed loss of nuclear HIF-1α staining. We demonstrated that during hypoxia, BAP1 binds, deubiquitylates, and stabilizes HIF-1α, the master regulator of the hypoxia response and tumor cell invasion. Moreover, primary cells from individuals carrying germline BAP1 mutations and primary cells in which BAP1 was silenced using siRNA had reduced HIF-1α protein levels in hypoxia. Computational modeling and co-immunoprecipitation experiments revealed that mutations of BAP1 residues I675, F678, I679, and L691 -encompassing the C-terminal domain-nuclear localization signal- to A, abolished the interaction with HIF-1α. We found that BAP1 binds to the N-terminal region of HIF-1α, where HIF-1α binds DNA and dimerizes with HIF-1β forming the heterodimeric transactivating complex HIF. Our data identify BAP1 as a key positive regulator of HIF-1α in hypoxia. We propose that the significant reduction of HIF-1α activity in mesothelioma cells carrying biallelic BAP1 mutations, accompanied by the significant reduction of HIF-1α activity in hypoxic tissues containing germline BAP1 mutations, contributes to the reduced aggressiveness and improved survival of mesotheliomas developing in carriers of germline BAP1 mutations.

Somatic BAP1 Loss in Ovarian Serous Borderline Tumor and Recurrent Low-grade Serous Carcinoma From a Germline BAP1 Mutation Carrier.

To the Editor: In a recent issue, Dr. Oliva and colleagues proposed the use of the immunohistochemical markers, Claudin-4 and BAP1, to distinguish between low-grade serous neoplasms and peritoneal mesothelioma 1. This article is of particular interest to us, as we have recently published on a cohort of 119 clinically annotated low-grade serous carcinomas, confirmed by central pathology review, with molecular profiling by targeted next-generation sequencing 2. In this cohort, we encountered 1 patient who represents an unusual exception to relying on loss of BAP1 expression to exclude the diagnosis of a low-grade serous neoplasm. This was a 59-yr-old female who underwent comprehensive surgical staging for bilateral ovarian masses. Final pathology revealed a stage IIIC serous borderline tumor involving bilateral ovaries (Fig. 1A), associated with noninvasive peritoneal implants and involvement of pelvic lymph nodes. After 7 yrs, she developed recurrent disease involving the sigmoid colon, in the form of metastatic low-grade serous carcinoma (Fig. 1B). Both primary and recurrent tumors showed a similar immunophenotype, characterized by strong diffuse expression of epithelial/Mullerian markers, including Claudin-4 (Fig. 1C), BerEP4, PAX8, ER, and PR, while negative for markers of mesothelial differentiation, namely, calretinin, and D2-40. Somatic mutational profiling by targeted next-generation sequencing revealed the low-grade serous carcinoma to harbor a BAP1 frameshift mutation (Y241Lfs*2). Germline testing further revealed a heterozygous BAP1 germline mutation (c.1110dupC, p.Met371Hisfs*27). Loss of BAP1 expression by immunohistochemistry in the low-grade serous carcinoma, as well as the prior serous borderline tumor (Fig. 1D), was consistent with bi-allelic inactivation of BAP1 as an early event in the molecular pathogenesis of this case.FIG. 1: Low-grade serous neoplasms associated with germline BAP1 mutation. (A) Ovarian serous borderline tumor showing characteristic hierarchical branching papillae lined by stratified columnar epithelium (inset: ciliated cells observed at high-magnification, consistent with tubal differentiation). (B) Recurrent invasive low-grade serous carcinoma involving muscularis propria of the sigmoid colon, showing infiltrating nests and micropapillae composed of tumor cells with small monotonous nuclei, and scattered psammoma bodies. Immunohistochemical analysis of the serous borderline tumor showing (C) diffuse expression of Claudin-4 and (D) loss of BAP1 expression in tumor cells with retained nuclear staining in non-neoplastic stromal cells.To our knowledge, this represents the first reported case of a BAP1-deficient low-grade serous neoplasm. It illustrates how genetic alterations of oncogenes and tumor suppressor genes are not tissue or disease-specific and emphasizes the importance of applying several cell lineage markers, along with morphologic correlation, for appropriate diagnostic classification of tumor type.

BAP1-Inactivated Melanoma Arising From BAP1-Inactivated Melanocytic Tumor in a Patient With BAP1 Germline Mutation: A Case Report and Review of the Literature.

BAP1-inactivated melanocytic tumors represent a subset of epithelioid melanocytic neoplasms resulting from biallelic inactivation of the BAP1 gene and by a driver mutation that activate the MAP kinase pathway, most commonly BRAFV600E. They occur sporadically or, less common, in the setting of BAP1 tumor predisposition syndrome caused by a BAP1 germline mutation that predisposes to several malignancies including cutaneous and uveal melanoma. To date, only few cases of BAP1-inactivated melanomas have been reported. We present a case of a 35-year-old woman presented with a melanocytic lesion microscopically composed of 3 distinct melanocytic populations, suggesting a stepwise progression model to melanoma from a conventional nevus through a melanocytoma stage. This progression was also supported from a molecular viewpoint given BRAFV600E, BAP1, and TERT-p hot spot mutations detected by targeted mutational analysis. Four atypical melanocytic lesions were removed from the patient's back, and the same A BAP1 c.856A>T, p.(Lys286Ter) mutation was detected on either tumoral or normal tissue samples. To the best of our knowledge, this is the first case of BAP1-inactivated melanoma with a documented TERT-p hot spot mutation manifesting as the first presentation of BAP1 tumor predisposition syndrome.

Novel insights into the BAP1-inactivated melanocytic tumor

BAP1-inactivated melanocytic tumor (BIMT) is a group of melanocytic neoplasms with epithelioid cell morphology molecularly characterized by the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21, and a mutually exclusive mitogenic driver mutation, more commonly BRAF. BIMTs can occur as a sporadic lesion or, less commonly, in the setting of an autosomal dominant cancer susceptibility syndrome caused by a BAP1 germline inactivating mutation. Owing to the frequent identification of remnants of a conventional nevus, BIMTs are currently classified within the group of combined melanocytic nevi. “Pure” lesions can also be observed. We studied 50 BIMTs from 36 patients. Most lesions were composed of epithelioid melanocytes of varying size and shapes, resulting extreme cytomorphological heterogeneity. Several distinctive morphological variants of multinucleated/giant cells were identified. Some hitherto underrecognized microscopic features, especially regarding nuclear characteristics included nuclear blebbing, nuclear budding, micronuclei, shadow nuclei, peculiar cytoplasmic projections (ant-bear cells) often containing micronuclei and cell-in-cell structures (entosis). In addition, there were mixed nests of conventional and BAP1-inactivated melanocytes and squeezed remnants of the original nevus. Of the 26 lesions studied, 24 yielded a BRAF mutation, while in the remaining two cases there was a RAF1 fusion. BAP1 biallelic and singe allele mutations were found in 4/22 and 16/24 neoplasms, respectively. In five patients, there was a BAP1 germline mutation. Six novel, previously unreported BAP1 mutations have been identified. BAP1 heterozygous loss was detected in 11/22 lesions. Fluorescence in situ hybridization for copy number changes revealed a related amplification of both RREB1 and MYC genes in one tumor, whereas the remaining 20 lesions studied were negative; no TERT-p mutation was found in 14 studied neoplasms. Tetraploidy was identified in 5/21 BIMTs. Of the 21 patients with available follow-up, only one child had a locoregional lymph node metastasis. Our results support a progression of BIMTs from a conventional BRAF mutated in which the original nevus is gradually replaced by epithelioid BAP1-inactivated melanocytes. Some features suggest more complex underlying pathophysiological events that need to be elucidated.

MAPK Pathway Genetic Alterations Are Associated with Prolonged Overall Survival in Low-Grade Serous Ovarian Carcinoma.

To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSC). Patients with LGSC tumors who underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations; copy-number alterations; and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected. Following central pathology rereview, 119 patients with LGSC were identified for analysis. Of these, 110 (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; MAPK pathway alterations were found in 60% (n = 71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis more than 50 years (P = 0.02) and platinum-sensitive disease (P = 0.03). On multivariate analysis, MAPK pathway alterations (P = 0.02) and platinum sensitivity (P = 0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; seven pathogenic germline mutations were identified: MUTYH (n = 2), BAP1 (n = 1), RB1 (n = 1), CHEK2 (n = 1), APC (n = 1), and FANCA (n = 1). There were no germline BRCA1/2 mutations. One germline MUTYH-associated LGSC harbored loss-of-heterozygosity at the MUTYH locus, and the patient with the germline BAP1 mutation also harbored a somatic BAP1 frameshift mutation. This study showed that MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC. See related commentary by Veneziani and Oza, p. 4357.

BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos

Carriers of heterozygous germline BAP1 mutations (BAP1+/-) are affected by the "BAP1 cancer syndrome." Although they can develop almost any cancer type, they are unusually susceptible to asbestos carcinogenesis and mesothelioma. Here we investigate why among all carcinogens, BAP1 mutations cooperate with asbestos. Asbestos carcinogenesis and mesothelioma have been linked to a chronic inflammatory process promoted by the extracellular release of the high-mobility group box 1 protein (HMGB1). We report that BAP1+/- cells secrete increased amounts of HMGB1, and that BAP1+/- carriers have detectable serum levels of acetylated HMGB1 that further increase when they develop mesothelioma. We linked these findings to our discovery that BAP1 forms a trimeric protein complex with HMGB1 and with histone deacetylase 1 (HDAC1) that modulates HMGB1 acetylation and its release. Reduced BAP1 levels caused increased ubiquitylation and degradation of HDAC1, leading to increased acetylation of HMGB1 and its active secretion that in turn promoted mesothelial cell transformation.

Meningiomas in Patients With Malignant Pleural Mesothelioma Harboring Germline BAP1 Mutations

BAP1 is a tumor suppressor gene implicated in DNA repair and cell growth. Individuals with germline BAP1 mutations are at a significantly increased risk for developing many different cancers including malignant mesothelioma, uveal melanomas, cutaneous melanomas and renal clear cell carcinomas. Meningiomas with absent BAP1 expression have been reported to be more aggressive and present often with rhabdoid features. Here, we report the co-occurrence of pleural mesotheliomas and meningiomas in patients with germline BAP1 mutations. We describe the cancer history, family pedigrees, clinical management, and outcomes of four BAP1 germline mutation carrier families with a history of malignant mesothelioma and meningioma.

Phase 2 Study of Olaparib in Malignant Mesothelioma and Correlation of Efficacy With Germline or Somatic Mutations in BAP1 Gene

IntroductionPARP inhibition may enhance antitumor responses in BAP1-associated mesothelioma by inducing synthetic lethality. MethodsA single-center, nonrandomized, phase 2 trial was conducted, in which patients with refractory mesothelioma were given olaparib 300 mg twice daily in a 21-day cycle until disease progression or intolerable toxicity. The primary objective was to determine the objective response rate on the basis of somatic or germline mutation status of DNA repair genes. The secondary objectives were to assess safety and tolerability and to determine progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing was performed on blood and tumor. ResultsA total of 23 previously treated patients with pleural and peritoneal mesothelioma were enrolled and treated (germline BAP1, n = 4; germline MRE11A, n = 1; somatic BAP1, n = 8 mutations). There was one (4%) partial response, 18 (78%) with stable disease at 6 weeks, and four (17%) with progressive disease. The median overall PFS and OS were 3.6 months (95% confidence interval [CI]: 2.7–4.2 mo) and 8.7 months (95% CI: 4.7 mo–not estimable), respectively. The median PFS of germline BAP1 mutants (n = 4) was 2.3 months (95% CI: 1.3–3.6 mo) versus 4.1 months (95% CI: 2.7–5.5 mo) for wild-type (n = 19; p = 0.019). The median OS was 4.6 months (95% CI: 3.1–4.9 mo) for germline BAP1 mutation versus 9.6 months (95% CI: 5.5 mo–not estimable) in no germline mutation (p = 0.0040). Olaparib was safe with no new safety concerns. ConclusionsOlaparib has limited activity in previously treated mesothelioma including patients with BAP1 mutations. Germline BAP1 mutations were associated with decreased PFS and OS.

Germline BAP1 Mutation in a Family With Multi-Generational Meningioma With Rhabdoid Features: A Case Series and Literature Review.

Meningioma is the most common primary brain tumor, and recurrence risk increases with increasing WHO Grade from I to III. Rhabdoid meningiomas are a subset of WHO Grade III tumors with rhabdoid cells, a high proliferation index, and other malignant features that follow an aggressive clinical course. Some meningiomas with rhabdoid features either only focally or without other malignant features are classified as lower grade yet still recur early. Recently, inactivating mutations in the tumor suppressor gene BAP1 have been associated with poorer prognosis in rhabdoid meningioma and meningioma with rhabdoid features, and germline mutations have been linked to a hereditary tumor predisposition syndrome (TPDS) predisposing patients primarily to melanoma and mesothelioma. We present the first report of a familial BAP1 inactivating mutation identified after multiple generations of a family presented with meningiomas with rhabdoid features instead of with previously described BAP1 loss-associated malignancies. A 24-year-old female presented with a Grade II meningioma with rhabdoid and papillary features treated with subtotal resection, adjuvant external beam radiation therapy, and salvage gamma knife radiosurgery six years later. Around that time, her mother presented with a meningioma with rhabdoid and papillary features managed with resection and adjuvant radiation therapy. Germline testing was positive for a pathogenic BAP1 mutation in both patients. Sequencing of both tumors demonstrated biallelic BAP1 inactivation via the combination of germline BAP1 mutation and either loss of heterozygosity or somatic mutation. No additional mutations implicated in oncogenesis were noted from either patient’s germline or tumor sequencing, suggesting that the inactivation of BAP1 was responsible for pathogenesis. These cases demonstrate the importance of routine BAP1 tumor testing in meningioma with rhabdoid features regardless of grade, germline testing for patients with BAP1 inactivated tumors, and tailored cancer screening in this population.

The Genetics of Uveal Melanoma: Overview and Clinical Relevance.

Over the last ten years, much has been learnt about the genetic characteristics and genetic evolution of uveal melanoma. It has been shown that uveal melanoma differs fundamentally from non-uveal melanoma and is an independent genetic subtype. Compared to other tumours, uveal melanoma has a low mutational burden. There are recurring chromosomal aberrations with losses of 1p, 6q, 8p and 16q, gains of 6p and 8q, and the presence of monosomy 3. GNAQ, GNA11, PLCB4, CYSLTR2, MAPKAPK5, as well as mutations in BAP1, SF3B1, SRSF2 and EIF1AX, the latter being linked to a higher risk of metastasis, have been identified as significantly mutated genes. In rare cases, a BAP1 germline mutation may also be present. In addition to higher risk of uveal melanoma, this variant is also linked with other tumours. In this case, additional work-up, genetic counselling and screening of family members should be offered. While the knowledge about the genetic characteristics of uveal melanoma is already routinely used for diagnostic and prognostic purposes, targeted genotype-dependent therapy of uveal melanoma is currently still missing.

Germ Line BAP1 Mutation in Patients with Uveal Melanoma and Renal Cell Carcinoma

Uveal melanoma (UM) and renal cell carcinoma (RCC) can occur sporadically and as a manifestation of BAP1 tumor predisposition syndrome. We aimed to understand the prevalence of germ line BAP1 pathogenic variants in patients with UM and RCC. We reviewed patients managed at Cleveland Clinic between November 2003 and November 2019 who were diagnosed with UM and RCC. Charts were reviewed for demographic and cancer-related characteristics. RCC samples were tested for BAP1 protein expression using immunohistochemical (IHC) staining, and testing for germ line BAP1 pathogenic variants was performed as part of routine clinical care. Thirteen patients were included in the study. The average age at diagnosis of UM was 61.3 years. Seven patients underwent fine-needle aspiration biopsy for prognostic testing of UM (low risk =5, high risk =2). Twelve patients were treated with plaque radiation therapy, and 3 patients developed metastatic disease requiring systemic therapy. The median time to diagnosis of RCC from time of diagnosis of UM was 0 months. RCC samples were available for 7 patients for BAP1 IHC staining (intact =6, loss =1). All patients underwent nephrectomy (total = 3, partial = 8, unknown =2), and 1 received systemic therapy for metastatic RCC. Six patients underwent germ line BAP1 genetic testing. Of these, 1 patient was heterozygous for a pathogenic variant of BAP1 gene: c.1781-1782delGG, p.Gly594Valfs*48. The overall prevalence of germ line BAP1 pathogenic variants in our study was high (1/6; 17%; 95% CI 0–46%). Patients with UM and RCC should be referred for genetic counseling to discuss genetic testing.

Inherited predisposition to malignant mesothelioma: germline BAP1 mutations and beyond.

Malignant mesothelioma (MM) is a rare aggressive neoplasm arising from mesothelial lining of body cavities, most commonly pleura and peritoneum. It is characterised by a poor prognosis and limited treatment options. A universally recognised risk factor for the development of MM is exposure to asbestos. However, evidence supporting a genetic susceptibility to the development of MM has been accumulating during the last decades. Intensive research for the identification of MM susceptibility genes has led to the discovery of BAP1 and to the definition of the so-called "BAP1-related tumour predisposition syndrome". Patients carrying germline BAP1 mutations have an increased risk for the early development of tumours, including MMs, uveal melanomas, cutaneous melanocytic lesions, clear cell renal cell carcinomas and basal cell carcinomas. Furthermore, pathogenic variants in tumour suppressor genes with a role in DNA repair have been recently described in families with clustered MM cases. These genetic alterations seem to confer exaggerate sensitivity to asbestos carcinogenic effect and, arguably, increased response to specific chemotherapeutic strategies. While the translational significance of BAP1 alterations is explored in the research field, the identification of families carrying germline BAP1 mutations is mandatory to start appropriate surveillance programs and guarantee the best clinical management to these patients.

NovelLRRK2mutations and other rare, non-BAP1-related candidate tumor predisposition gene variants in high-risk cancer families with mesothelioma and other tumors

There is irrefutable evidence that germline BRCA1-associated protein 1 gene (BAP1) mutations contribute to malignant mesothelioma (MM) susceptibility. However, BAP1 mutations are not found in all cases with evidence of familial MM or in other high-risk cancer families affected by various cancers, including MM. The goal of this study was to use whole genome sequencing (WGS) to determine the frequency and types of germline gene variants occurring in 12 MM patients who were selected from a series of 141 asbestos-exposed MM patients with a family history of cancer but without a germline BAP1 mutation. WGS was also performed on two MM cases, a proband and sibling, from a previously reported family with multiple cases of MM without the inheritance of a predisposing BAP1 mutation. Altogether, germline DNA sequencing variants were identified in 21 cancer-related genes in 10 of the 13 probands. Germline indel, splice site and missense mutations and two large deletions were identified. Among the 13 MM index cases, 6 (46%) exhibited one or more predicted pathogenic mutations. Affected genes encode proteins involved in DNA repair (ATM, ATR, BRCA2, BRIP1, CHEK2, MLH3, MUTYH, POLE, POLE4, POLQ and XRCC1), chromatin modification (ARID1B, DNMT3A, JARID2 and SETD1B) or other cellular pathways: leucine-rich repeat kinase 2 gene (LRRK2) (two cases) and MSH4. Notably, somatic truncating mutation or deletions of LRRK2 were occasionally found in MMs in The Cancer Genome Atlas, and the expression of LRRK2 was undetectable or downregulated in a majority of primary MMs and MM cell lines we examined, implying that loss of LRRK2 expression is a newly recognized tumor suppressor alteration in MM.

Roles and mechanisms of BAP1 deubiquitinase in tumor suppression.

The BAP1 gene has emerged as a major tumor suppressor mutated with various frequencies in numerous human malignancies, including uveal melanoma, malignant pleural mesothelioma, clear cell renal cell carcinoma, intrahepatic cholangiocarcinoma, hepatocellular carcinoma, and thymic epithelial tumors. BAP1 mutations are also observed at low frequency in other malignancies including breast, colorectal, pancreatic, and bladder cancers. BAP1 germline mutations are associated with high incidence of mesothelioma, uveal melanoma, and other cancers, defining the "BAP1 cancer syndrome." Interestingly, germline BAP1 mutations constitute an important paradigm for gene-environment interactions, as loss of BAP1 predisposes to carcinogen-induced tumorigenesis. Inactivating mutations of BAP1 are also identified in sporadic cancers, denoting the importance of this gene for normal tissue homeostasis and tumor suppression, although some oncogenic properties have also been attributed to BAP1. BAP1 belongs to the deubiquitinase superfamily of enzymes, which are responsible for the maturation and turnover of ubiquitin as well as the reversal of substrate ubiquitination, thus regulating ubiquitin signaling. BAP1 is predominantly nuclear and interacts with several chromatin-associated factors, assembling multi-protein complexes with mutually exclusive partners. BAP1 exerts its function through highly regulated deubiquitination of its substrates. As such, BAP1 orchestrates chromatin-associated processes including gene expression, DNA replication, and DNA repair. BAP1 also exerts cytoplasmic functions, notably in regulating Ca2+ signaling at the endoplasmic reticulum. This DUB is also subjected to multiple post-translational modifications, notably phosphorylation and ubiquitination, indicating that several signaling pathways tightly regulate its function. Recent progress indicated that BAP1 plays essential roles in multiple cellular processes including cell proliferation and differentiation, cell metabolism, as well as cell survival and death. In this review, we summarize the biological and molecular functions of BAP1 and explain how the inactivation of this DUB might cause human cancers. We also highlight some of the unresolved questions and suggest potential new directions.

Functional characterisation guides classification of novel BAP1 germline variants

We have identified six patients harbouring distinct germline BAP1 mutations. In this study, we functionally characterise known BAP1 pathogenic and likely benign germline variants out of these six patients to aid in the evaluation and classification of unknown BAP1 germline variants. We found that pathogenic germline variants tend to encode truncated proteins, show diminished expression of epithelial-mesenchymal transition (EMT) markers, are localised in the cytosol and have reduced deubiquitinase capabilities. We show that these functional assays are useful for BAP1 variant curation and may be added in the American College of Medical Genetics and Genomics (ACMG) criteria for BAP1 variant classification. This will allow clinicians to distinguish between BAP1 pathogenic and likely benign variants reliably and may aid to quickly benchmark newly identified BAP1 germline variants. Classification of novel BAP1 germline variants allows clinicians to inform predisposed patients and relevant family members regarding potential cancer risks, with appropriate clinical interventions implemented if required.

1897P Germline and somatic mutational landscape in a cohort of malignant pleural mesothelioma patients

Germline mutations in BAP1 and in other genes, such as BRCA2, CHEK2, CDKN2A or ATM, have been associated to hereditary predisposition to malignant pleural mesothelioma (MPM). We aim to characterize the genomic landscape in MPM patients at germline and somatic level.

Malignant Mesothelioma of the Peritoneum in Women: A Clinicopathologic Study of 164 Cases.

Malignant mesothelioma of the peritoneum in women is an uncommon tumor. In this study, we present the clinicopathologic features of 164 such cases seen in our institution over a period of 42 years (1974-2016). Clinical information, pathologic findings, immunohistochemical results, and follow-up were recorded. Hematoxylin and eosin-stained slides were reviewed in all cases. Patients ranged in age from 3 to 85 years, median: 49 years. Most patients presented with abdominal/pelvic pain, although some were asymptomatic, presented with paraneoplastic syndromes or cervical lymphadenopathy. Overall, 9% of patients had a history of direct or indirect exposure to asbestos. In total, 31% and 69% of patients had either a personal or family history of other tumors; most of these tumors are currently recognized as part of a syndrome. Genetic testing information was available in 5 patients: BAP-1 germline mutation (1), type 2 neurofibromatosis (1), Lynch syndrome (1), McCune-Albright syndrome (1), no BAP-1 or TP53 mutation (1). Most cases had gross and microscopic features typical of malignant mesothelioma of the peritoneum in women; however, some had confounding features such as gelatinous appearance, signet ring or clear cells, and well-differentiated papillary mesothelioma-like areas. Calretinin and WT-1 were the markers more frequently expressed, and up to 23% of the cases showed PAX-8 expression. Patients' treatments predominantly included: chemotherapy, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy. On multivariate analysis, the predominance of deciduoid cells, nuclear grade 3, and the absence of surgical treatment were associated with worse overall survival (OS). For all patients, the 3- and 5-year OS were 74.3% and 57.4%, respectively. The 3- and 5-year OS for patients treated with cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy were 88.9% and 77.8%, respectively.

Atypical nevi in a blaschkoid distribution in a patient with a germline BAP1 mutation

Atypical nevi in a blaschkoid distribution in a patient with a germline BAP1 mutation