BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas

Leblay, Noémie; Leprêtre, Frédéric; Stang, Nolwenn Le; Gautier‐Stein, Amandine; Villeneuve, Laurent; Isaac, Sylvie; Maillet, Denis; Galateau-Sallé, Françoise; Villenet, Céline; Sebda, Shéhérazade; Goracci, Alexandra; Byrnes, Graham; McKay, James; Figeac, Martin; Gléhen, Olivier; Gilly, François-Noël; Foll, Matthieu; Fernández-Cuesta, Lynnette; Brevet, Marie

doi:10.1016/j.jtho.2016.12.019

Cited by 73 publications

(53 citation statements)

References 36 publications

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“…11,12 The BAP1 mutation in our case was not a truncating but a missense mutation, which is in line with previous reports. 12,13 In keeping with these data, we observed a selective loss of BAP1 expression in the tumor cells that may be explained by somatic ploidy including loss of the wild-type allele. Coverage data support this hypothesis.…”

Section: Discussionsupporting

confidence: 81%

Integrated Histogenetic Analysis Reveals BAP1 -Mutated Epithelioid Mesothelioma in a Patient With Cancer of Unknown Primary

Bochtler

Endris

Reiling

et al. 2018

J Natl Compr Canc Netw

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This case report presents a male patient with epithelioid mesothelioma that was initially misdiagnosed as cancer of unknown primary (CUP) and correctly identified using molecular panel sequencing. The patient had a prior history of colon and breast cancer. To assess the enlarged mediastinal lymph nodes, retrosternal lymphadenectomy was performed in 2016. The lymph nodes were histologically deemed unrelated to the known breast cancer by the reference pathologist, thus leading to the diagnosis of a CUP syndrome. When the patient presented to our center, targeted deep sequencing of both breast cancer and presumed CUP was performed to address the clonal relationship between both malignancies. A missense mutation in was revealed in both samples, with coverage data indicating a germline event. The patient was subsequently counseled by a human geneticist and underwent genetic testing, which confirmed the germline nature of this mutation. Collectively, these data led to the diagnosis of (-associated protein-1) tumor predisposition syndrome (TPDS). With the knowledge of an underlying mutation and its known frequent association with epithelioid mesothelioma, the histology was reassessed and the diagnosis was revised to epithelioid mesothelioma. At this point, peritoneal involvement of mesothelioma could be diagnosed and histologically confirmed. This case illustrates the potential of integrated histopathologic and molecular diagnostics in helping to decipher CUP syndromes and establish the correct diagnosis. Additionally, this case highlights typical features of TPDS with its general susceptibility to cancers, with pleural and peritoneal mesotheliomas as most prevalent clinical entities and the typically more benign course of these epithelioid mesotheliomas compared with -unrelated cases of mesotheliomas.

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Section: Discussionsupporting

confidence: 81%

Integrated Histogenetic Analysis Reveals BAP1 -Mutated Epithelioid Mesothelioma in a Patient With Cancer of Unknown Primary

Bochtler

Endris

Reiling

et al. 2018

J Natl Compr Canc Netw

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“…This idea must be viewed in light of the fact that 13 of the 23 subjects (56%) had a second malignancy, so the apparent longer survivals may reflect a lead time bias for subjects undergoing frequent medical surveillance. However, studies on mesotheliomas with somatic BAP-1 mutations (eg, Leblay et al 111 ) have also found that such tumors are associated with longer survival, so loss of BAP-1 may in fact confer a better prognosis.…”

Section: Bap-1 Cancer-predisposition Syndromementioning

confidence: 99%

Malignant Mesothelioma and Its Non-Asbestos Causes

Attanoos

Churg

Galateau-Salle

et al. 2018

Archives of Pathology & Laboratory Medicine

177

129

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- Currently, most pleural mesotheliomas (70% to 90%) in men in Europe and North America are attributable to asbestos exposure; for peritoneal mesothelioma the proportion is lower. In North America few mesotheliomas in women at any site are attributable to asbestos exposure, but in Europe the proportion is higher and varies considerably by locale. In certain geographic locations other types of mineral fibers (erionite, fluoro-edenite, and probably balangeroite) can induce mesothelioma. Therapeutic radiation for other malignancies is a well-established cause of mesothelioma, with relative risks as high as 30. Carbon nanotubes can also induce mesotheliomas in animals but there are no human epidemiologic data that shed light on this issue. Chronic pleural inflammation may be a cause of mesothelioma but the data are scanty. Although SV40 can induce mesotheliomas in animals, in humans the epidemiologic data are against a causative role. A small number of mesotheliomas (probably in the order of 1%) are caused by germline mutations/deletions of BRCA1-associated protein-1 ( BAP1) in kindreds that also develop a variety of other cancers. All of these alternative etiologies account for a small proportion of tumors, and most mesotheliomas not clearly attributable to asbestos exposure are spontaneous (idiopathic).

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“…In addition, inactivating mutations of neurofibromin 2 ( NF2 ) and cyclin-dependent kinase inhibitor 2A ( CDKN2A ) are also relatively common, while other mutations are rare. Previous studies in PeM [11–18] have only focused on genomic information; therefore, the downstream consequences of these genomic alterations are not well understood. Genome information coupled with transcriptome and proteome information is more likely to be successful in revealing potential therapeutic modalities.…”

Section: Introductionmentioning

confidence: 99%

BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma

Nabavi²,

et al. 2019

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Background Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis. Methods To search for novel therapeutic targets for PeM, we performed a comprehensive integrative multi-omics analysis of the genome, transcriptome, and proteome of 19 treatment-naïve PeM, and in particular, we examined BAP1 mutation and copy number status and its relationship to immune checkpoint inhibitor activation. Results We found that PeM could be divided into tumors with an inflammatory tumor microenvironment and those without and that this distinction correlated with haploinsufficiency of BAP1 . To further investigate the role of BAP1 , we used our recently developed cancer driver gene prioritization algorithm, HIT’nDRIVE, and observed that PeM with BAP1 haploinsufficiency form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies. Conclusions Our findings reveal BAP1 to be a potential, easily trackable prognostic and predictive biomarker for PeM immunotherapy that refines PeM disease classification. BAP1 stratification may improve drug response rates in ongoing phases I and II clinical trials exploring the use of immune checkpoint blockade therapies in PeM in which BAP1 status is not considered. This integrated molecular characterization provides a comprehensive foundation for improved management of a subset of PeM patients. Electronic supplementary material The online version of this article (10.1186/s13073-019-0620-3) contains supplementary material, which is available to authorized users.

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BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas

Abstract: As in pleural mesothelioma, inactivation of BAP1 is frequent in peritoneal mesotheliomas. We found that BAP1 protein nuclear expression is a good prognostic factor and a more reliable marker for the complete loss of BAP1 activity than mutation or copy number loss.

Cited by 73 publications

References 36 publications

Integrated Histogenetic Analysis Reveals BAP1 -Mutated Epithelioid Mesothelioma in a Patient With Cancer of Unknown Primary

Integrated Histogenetic Analysis Reveals BAP1 -Mutated Epithelioid Mesothelioma in a Patient With Cancer of Unknown Primary

Malignant Mesothelioma and Its Non-Asbestos Causes

BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma

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