Germline BAP1 Mutations Research Articles

Germline BAP1 mutation in a family with high incidence of multiple primary cancers and a potential gene–environment interaction

We report a high-risk cancer family with multiple mesotheliomas, cutaneous melanomas, basal cell carcinomas, and meningiomas segregating with a germline nonsense mutation in BAP1 (c.1938T>A; p.Y646X). Notably, most (four of five) mesotheliomas were peritoneal rather than the usually more common pleural form of the disease, and all five mesothelioma patients also developed second or third primary cancers, including two with meningiomas. Another family member developed both cutaneous melanoma and breast cancer. Two family members had basal cell carcinomas, and six others had melanocytic tumors, including four cutaneous melanomas, one uveal melanoma, and one benign melanocytic tumor. The family resides in a subtropical area, and several members had suspected exposure to asbestos either occupationally or in the home. We hypothesize that the concurrence of a genetic predisposing factor and environmental exposure to asbestos and UV irradiation contributed to the high incidence of multiple cancers seen in this family, specifically mesothelioma and various uveal/skin tumors, respectively.

Uveal melanoma and renal cell carcinoma both metastatic to the liver

PurposeGermline mutations in the BRCA1‐associated protein‐1 gene (BAP1) predispose carriers to several types of cancer, including uveal and cutaneous melanoma, mesothelioma, renal cell cancer, and possibly other diverse tumor types. Approximately 2% of consecutive Finnish uveal melanoma patients harbor a germline mutation in BAP1.MethodsCase report.ResultsA 53‐year‐old man was diagnosed with renal cancer in 2006. No metastasis was detected during a 5‐year follow‐up after surgery. In 2011, he noted decreased vision in his left eye. Ophthalmological examination revealed a suspicious choroidal mass and the patient was referred to the ocular Oncology service, Helsinki University Eye Clinic. A choroidal melanoma with a largest basal dimension of 15.5 mm and thickness of 11.1 mm and no metastases was detected (T3aN0M0, stage IIB). He received brachytherapy with an iodine plaque. Three years later he had liver metastases, and biopsies indicated the presence of both uveal melanoma and renal carcinoma metastases. Further, a sister of his father also has had uveal melanoma. Given that the patient was a candidate to harbor a germline BAP1 mutation we sequenced the gene. No mutation was found in the coding regions or adjacent intronic sequences. Further, we carried out whole exome sequencing, and no mutations or mosaicism were found in BAP1, BRCA1, SF3B1, or EIF1AX.ConclusionsNot all familial uveal melanoma patients even with history of renal cell cancer harbor an obvious BAP1 germline mutation. Currently, we are analyzing histological samples to further investigate the possible role of BAP1 in tumor tissue and genetic data to find or exclude indirect effect on BAP1 function.

Clinical Characteristics of Uveal Melanoma in Patients With GermlineBAP1Mutations

Somatic mutations in BAP1 (BRCA1-associated protein 1 gene) are frequently identified in uveal melanoma. To date, the role of germline BAP1 mutations in uveal melanoma has not been characterized. To characterize the clinical phenotype of uveal melanoma in patients with germline BAP1 mutations. Retrospective cohort study at an academic ophthalmology referral center among 507 patients with uveal melanoma who consented for collection of blood samples. The study dates were June 22, 1992, to December 14, 2010. Clinical characteristics of uveal melanoma and the development of metastases. BAP1 gene sequencing from blood samples of patients with uveal melanoma was correlated with clinical characteristics. Of 507 blood samples analyzed, 25 patients (4.9%) exhibited 18 BAP1 polymorphisms, of which 9 were novel. Computational analyses predicted that 8 BAP1 mutations in 8 patients (1.6%) were likely to result in damaged BAP1 protein. Five of these 8 mutations were novel. These 8 patients were compared with 482 patients in whom no BAP1 polymorphisms were identified. In univariate analyses, patients with germline BAP1 mutations exhibited larger tumor diameters (mean, 15.9 vs 12.3 mm; P = .004) and higher rates of ciliary body involvement (75.0% vs 21.6%, P = .002) and metastases (71.4% vs 18.0%, P = .003) compared with control subjects. Patients with germline BAP1 mutations exhibited increased frequency of family history of cancer (100% vs 65.9%, P = .06), particularly cutaneous melanoma (62.5% vs 9.9%, P < .001) and ocular melanoma (25.0% vs 1.9%, P = .01). No differences were identified in age at diagnosis, sex, history of other malignant neoplasm, presenting visual acuity, distance of the tumor from the optic nerve or fovea, iris involvement, extrascleral extension, or tumor pigmentation. Germline BAP1 mutations increased risk of metastasis independent of ciliary body involvement (P = .02). Germline BAP1 mutation approached significance as an independent risk factor for metastasis (P = .09). These data suggest that germline BAP1 mutations occur infrequently in uveal melanoma and are associated with larger tumors and higher rates of ciliary body involvement, 2 known risk factors for metastasis.

Abstract LB-220: Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma

Abstract Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma (MM). MM pathogenesis is generally associated to professional exposure to asbestos. However, to date we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after even minimal exposure. In a set of short-term experiments, we intraperitoneally injected BAP1+/- and wild-type littermates with low doses of asbestos fibers and analyzed the inflammatory response both at a cellular and humoral level. In a long-term experiment following a similar protocol, we assessed the incidence of MM in mice with and without germline BAP1 mutations and their survival. We found that, compared to their wild type littermates, BAP1+/- mice exposed to low doses of asbestos fibers showed significant alterations of the peritoneal inflammatory response. In particular, we observed significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1+/- mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, and shorter survival. Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response. Citation Format: A. Napolitano, L. Pellegrini, A. Dey, D. Larson, M. Tanji, E. G. Flores, B. Kendrick, D. Lapid, A. Powers, S. Kanodia, S. Pastorino, H. I. Pass, V Dixit, H. Yang, M. Carbone. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-220. doi:10.1158/1538-7445.AM2015-LB-220

Abstract 2752: Prevalence of BAP1 germline mutations in asbestos-exposed malignant mesothelioma cases and controls

Abstract Malignant mesothelioma (MM) is an uncommon but aggressive cancer that has been linked with asbestos exposure. Contributing genetic factors appear to play a role because familial clustering of MM has been observed and that only a small percentage of asbestos-exposed individuals have been documented to develop MM. Germline mutation of BAP1 has been identified as one such predisposing factor. However, the frequency of germline BAP1 mutations in MM cases is debatable due to small sampling sizes of studies from previous publications. Therefore, we decided to determine the prevalence of germline BAP1 mutations in a large set of asbestos-exposed MM cases and controls, the biggest such population study to date. BAP1 mutation status was compared between 150 MM cases with a family history of cancer and 153 asbestos-exposed controls without indications of familial cancers. Although no alterations of BAP1 were discovered in the controls, BAP1 mutations were identified in 9 of the MM cases (6%). These alterations included 2 splice site changes, 4 insertion/deletions, and 3 missense mutations. In vitro enzymatic assays showed decreased deubiquitinase activity for each of the three BAP1 missense mutant proteins. We observed a statistically significant lower age of MM onset as well as a higher incidence of peritoneal MMs among the 9 BAP1 mutation cases compared to the non-mutated MM cases. The other tumors identified in family members of the 9 individuals included additional MMs, ocular and cutaneous melanomas, renal, breast, lung, and gastric carcinomas, and lymphomas. Interestingly, six of the nine MM cases with a germline BAP1 mutation had two or more primary cancers, suggesting a widespread targeting of tissues of multiple organs caused by the mutation. In summary, these findings suggest that patients presenting with MM and a family history of cancer should be considered for BAP1 mutation testing to identify those who might benefit from screening and regular monitoring of family members to enable early detection and intervention. Citation Format: Mitchell Cheung, Jacqueline Talarchek, Suzanne E. Howard, Timothy Howard, Hongzhuang Peng, Mary Hesdorffer, Frank J. Rauscher, Jill A. Ohar, Joseph Testa. Prevalence of BAP1 germline mutations in asbestos-exposed malignant mesothelioma cases and controls. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2752. doi:10.1158/1538-7445.AM2015-2752

Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma.

Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated with professional exposure to asbestos. However, to date, we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after minimal exposure. Using a BAP1(+/-) mouse model, we found that, compared with their wild-type littermates, BAP1(+/-) mice exposed to low-dose asbestos fibers showed significant alterations of the peritoneal inflammatory response, including significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1(+/-) mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, doses that rarely induced mesothelioma in wild-type mice. Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response.

BAP1 missense mutation c.2054 A>T (p.E685V) completely disrupts normal splicing through creation of a novel 5' splice site in a human mesothelioma cell line.

BAP1 is a tumor suppressor gene that is lost or deleted in diverse cancers, including uveal mela¬noma, malignant pleural mesothelioma (MPM), clear cell renal carcinoma, and cholangiocarcinoma. Recently, BAP1 germline mutations have been reported in families with combinations of these same cancers. A particular challenge for mutation screening is the classification of non-truncating BAP1 sequence variants because it is not known whether these subtle changes can affect the protein function sufficiently to predispose to cancer development. Here we report mRNA splicing analysis on a homozygous substitution mutation, BAP1 c. 2054 A&T (p.Glu685Val), identified in an MPM cell line derived from a mesothelioma patient. The mutation occurred at the 3rd nucleotide from the 3’ end of exon 16. RT-PCR, cloning and subsequent sequencing revealed several aberrant splicing products not observed in the controls: 1) a 4 bp deletion at the end of exon 16 in all clones derived from the major splicing product. The BAP1 c. 2054 A&T mutation introduced a new 5’ splice site (GU), which resulted in the deletion of 4 base pairs and presumably protein truncation; 2) a variety of alternative splicing products that led to retention of different introns: introns 14–16; introns 15–16; intron 14 and intron 16; 3) partial intron 14 and 15 retentions caused by activation of alternative 3’ splice acceptor sites (AG) in the introns. Taken together, we were unable to detect any correctly spliced mRNA transcripts in this cell line. These results suggest that aberrant splicing caused by this mutation is quite efficient as it completely abolishes normal splicing through creation of a novel 5’ splice site and activation of cryptic splice sites. These data support the conclusion that BAP1 c.2054 A&T (p.E685V) variant is a pathogenic mutation and contributes to MPM through disruption of normal splicing.

Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma

Malignant mesothelioma (MM) is a uniformly fatal tumour caused predominantly by exposure to asbestos. It is not known why some exposed individuals get mesothelioma and others do not. There is some epidemiological evidence of host susceptibility. BAP1 gene somatic mutations and allelic loss are common in mesothelioma and recently a BAP1 cancer syndrome was described in which affected individuals and families had an increased risk of cancer of multiple types, including MM. To determine if BAP1 mutations could underlie any of the sporadic mesothelioma cases in our cohort of patients, we performed targeted deep sequencing of the BAP1 exome on the IonTorrent Proton sequencer in 115 unrelated MM cases. No exonic germline BAP1 mutations of known functional significance were observed, further supporting the notion that sporadic germline BAP1 mutations are not relevant to the genetic susceptibility of MM.

A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma

We report four previously undescribed families with germline BRCA1-associated protein-1 gene (BAP1) mutations and expand the clinical phenotype of this tumor syndrome. The tumor spectrum in these families is predominantly uveal malignant melanoma (UMM), cutaneous malignant melanoma (CMM) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported by the finding of loss of BAP1 protein expression by immunochemistry in two BCCs from individuals with germline BAP1 mutations and no loss of BAP1 staining in 53 of sporadic BCCs consistent with somatic mutations and loss of heterozygosity of the gene in the BCCs occurring in mutation carriers. Lastly, we identify the first reported recurrent mutation in BAP1 (p.R60X), which occurred in three families from two different continents. In two of the families, the mutation was inherited from a common founder but it arose independently in the third family.

Abstract 3522: A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid and pancreatic cancers

Abstract BRCA1 associated protein-1 (BAP1) functions as a tumor suppressor gene by modulating fundamental cellular mechanisms such as cell cycle progression and cell growth. Inactivating germline mutations of BAP1 predispose to multiple cancers including uveal and cutaneous melanoma as well as malignant mesothelioma. In the present study we document a family with a novel germline mutation of BAP1 (g.1777C&amp;gt;T) that results in expression of a truncated BAP1 protein. Family members with this mutation demonstrated a primary clinical phenotype of autosomal dominant, early-onset melanocytic neoplasms with immunohistochemistry (IHC) of these tumors demonstrating lack of BAP1 protein expression. In addition, family members harboring the BAP1 germline mutation developed other neoplastic disease such as thyroid cancer and pancreatic cancer. IHC analysis of these cancers also demonstrated loss of BAP1 protein expression. Our investigation identifies a new BAP1 mutation, further underscores the relevance of BAP1 as a clinically important tumor suppressor gene and broadens the range of cancers associated with BAP1 inactivation. Further study will be required to understand the full scope of BAP1-associated neoplastic disease. Citation Format: Gregory T. Gallanis, Kathleen A. Heller, Eleni-Marina Melas, Stephen B. Gruber. A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid and pancreatic cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3522. doi:10.1158/1538-7445.AM2014-3522

Inference on germline BAP1 mutations and asbestos exposure from the analysis of familial and sporadic mesothelioma in a high‐risk area

Inherited loss-of-function mutations in the BAP1 oncosuppressor gene are responsible for an inherited syndrome with predisposition to malignant mesothelioma (MM), uveal and keratinocytic melanoma, and other malignancies. Germline mutations that were inherited in an autosomal dominant fashion were identified in nine families with multiplex MM cases and 25 families with multiple melanoma, renal cell carcinoma, and other tumors. Germline mutations were also identified in sporadic MM cases, suggesting that germline mutations in BAP1 occur frequently. In this article, we report the analysis of BAP1 in five multiplex MM families and in 103 sporadic cases of MM. One family carried a new truncating germline mutation. Using immunohistochemistry, we show that BAP1 is not expressed in tumor tissue, which is in accordance with Knudson's two hits hypothesis. Interestingly, whereas the three individuals who were possibly exposed to asbestos developed MM, the individual who was not exposed developed a different tumor type, that is, mucoepidermoid carcinoma. This finding suggests that the type of carcinogen exposure may be important for the cancer type that is developed by mutation carriers. On the contrary, the other families or the 103 sporadic patients did not show germline mutations in BAP1. Our data show that BAP1 mutations are very rare in patients with sporadic MM, and we report a new BAP1 mutation, extend the cancer types associated with these mutations, and suggest the existence of other yet unknown genes in the pathogenesis of familial MM.

Prevalence of germline BAP1 mutations in patients with malignant mesothelioma (MM).

e18542 Background: Somatic BAP1 mutations are found in nearly a quarter of MM tumors and germline BAP1 mutations define a new cancer syndrome characterized by familial mesothelioma, uveal melanoma,...

Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases

The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma. However, the frequency of the syndrome in patients with UM and the association with other cancers are still not clear. In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1. We also studied four additional patients with a personal or family history suggestive of BAP1 hereditary cancer syndrome. We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1. Two of these three patients presented with UM and the third with a metastatic adenocarcinoma likely from a hepatic cholangiocarcinoma. Reported family histories included UM, mesothelioma, RCC, CM, and several other internal malignancies. The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC. However, other cancers, such as cholangiocarcinoma and breast carcinoma may be part of the phenotype of this hereditary cancer predisposition syndrome. In addition, the results support the existence of other candidate genes in addition to BAP1 contributing to hereditary predisposition to UM.

BAP1 germline mutation in two first grade family members with uveal melanoma

BackgroundUveal melanoma (UM) is the most common primary cancer of the eye in adults. About half of the patients are at risk of developing metastatic disease resulting in a poor...

Well-differentiated papillary mesothelioma: clustering in a Portuguese family with a germline BAP1 mutation

BackgroundWell-differentiated papillary mesothelioma (WDPM) is a rare variant of epithelioid mesothelioma and is considered to be associated with good prognosis due to its clinically indolent behavior and long survival. Most reported cases involve the peritoneum of women at reproductive age with no history of exposure to asbestos, with pleural involvement being less common. The optimal management, including the role of chemotherapy in the treatment of WDPM, remains unsettled. Patients and methodsThe authors describe two cases of WDPM in women of the same family (siblings); the elder with WDPM of the pleura and peritoneum with a 12-year survival period and the younger with a WDPM of the peritoneum diagnosed in 2011 and uveal melanoma diagnosed in 2012. Neither patient had any known exposure to asbestos fibers or any other mineral carcinogens. ResultsAfter the concurrent diagnosis of WDPM and uveal melanoma, genetic diagnosis was carried out taking into consideration that these two malignancies were recently associated with hereditary BAP1 gene mutations and it was positive for both the patients. ConclusionsTo our knowledge, this is the first description of WDPM in two siblings who also presented with a germline BAP1 mutation. This article provides evidence of the wide clinical spectrum of cancer susceptibility associated with a BAP1 germline mutation.

Germline BAP1 Mutations Predispose to Renal Cell Carcinomas

The genetic cause of some familial nonsyndromic renal cell carcinomas (RCC) defined by at least two affected first-degree relatives is unknown. By combining whole-exome sequencing and tumor profiling in a family prone to cases of RCC, we identified a germline BAP1 mutation c.277A>G (p.Thr93Ala) as the probable genetic basis of RCC predisposition. This mutation segregated with all four RCC-affected relatives. Furthermore, BAP1 was found to be inactivated in RCC-affected individuals from this family. No BAP1 mutations were identified in 32 familial cases presenting with only RCC. We then screened for germline BAP1 deleterious mutations in familial aggregations of cancers within the spectrum of the recently described BAP1-associated tumor predisposition syndrome, including uveal melanoma, malignant pleural mesothelioma, and cutaneous melanoma. Among the 11 families that included individuals identified as carrying germline deleterious BAP1 mutations, 6 families presented with 9 RCC-affected individuals, demonstrating a significantly increased risk for RCC. This strongly argues that RCC belongs to the BAP1 syndrome and that BAP1 is a RCC-predisposition gene.

BAP1 and cancer

BAP1 is a deubiquitylase that is found associated with multiprotein complexes that regulate key cellular pathways, including the cell cycle, cellular differentiation, cell death, gluconeogenesis and the DNA damage response (DDR). Recent findings indicate that germline BAP1 mutations cause a novel cancer syndrome that is characterized, at least in the affected families that have been studied so far, by the onset at an early age of benign melanocytic skin tumours with mutated BAP1, and later in life by a high incidence of mesothelioma, uveal melanoma, cutaneous melanoma and possibly additional cancers.

Hereditary uveal melanoma: A report of a germline mutation in BAP1

Melanoma of the eye is a rare and distinct subtype of melanoma, which only rarely are familial. However, cases of uveal melanoma (UM) have been found in families with mixed cancer syndromes. Here, we describe a comprehensive search for inherited genetic variation in a family with multiple cases of UM but no aggregation of other cancer diagnoses. The proband is a woman diagnosed with UM at 16 years who within 6 months developed liver metastases. We also identified two older paternal relatives of the proband who had died from UM. We performed exome sequencing of germline DNA from members of the affected family. Exome-wide analysis identified a novel loss-of-function mutation in the BAP1 gene, previously suggested as a tumor suppressor. The mutation segregated with the UM phenotype in this family, and we detected a loss of the wild-type allele in the UM tumor of the proband, strongly supporting a causative association with UM. Screening of BAP1 germline mutations in families predisposed for UM may be used to identify individuals at increased risk of disease. Such individuals may then be enrolled in preventive programs and regular screenings to facilitate early detection and thereby improve prognosis.

Germline mutations in BAP1 predispose to melanocytic tumors

Germline mutations in BAP1 predispose to melanocytic tumors

The ASXL–BAP1 axis: new factors in myelopoiesis, cancer and epigenetics

The recent identification of germline and somatic mutations in BAP1 as well as in multiple members of the ASXL (additional sex combs-like) family of genes has highlighted the role of these proteins in a diverse array of biological functions. A diverse number of possible functions have previously been ascribed to ASXL1 in non-hematopoietic contexts, including physical co-operativity with HP1a and LSD1. Here we discuss new evidence for a BAP1-independent function of ASXL1 in regulating histone H3 lysine 27 methylation through interactions with the Polycomb-repressive complex 2 (PRC2). BAP1, a nuclear-localized deubiquitinase, has been shown to interact with a number of proteins, including ASXL1 and/or ASXL2, but the functional importance of this interaction has remained elusive. Here, we highlight recent work revealing the critical function of BAP1 in restricting myelopoiesis and in regulating hematopoietic stem cell function. These data provide evidence that BAP1 and ASXL1 function as a novel class of tumor suppressors in myeloid malignancies. BAP1 functions through effects on stability of host cell factor-1, and O-GlcNAcylation, and ASXL1 impacts histone post-translational modifications through interaction with PRC2. Future studies investigating the mechanism of transformation by loss of BAP1 and ASXL1 may result in new therapeutic approaches to treat hematological malignancies.