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

Cheung, Mitchell; Kadariya, Yuwaraj; Talarchek, Jacqueline; Pei, Jianming; Ohar, Jill A.; Kayaleh, Omar; Testa, Joseph R.

doi:10.1016/j.canlet.2015.09.011

Cited by 41 publications

(39 citation statements)

References 29 publications

(37 reference statements)

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“…This tumor susceptibility disorder is inherited in an autosomal dominant manner, with BAP1 mutation carriers being at high risk for the development of a spectrum of tumor types, including atypical benign melanocytic lesions, malignant mesothelioma (MM), uveal melanoma, cutaneous melanoma, basal cell carcinoma, meningioma, paraganglioma and carcinomas of the kidney, lung, breast and potentially other organs (3–13). Genomic analysis of tumors from BAP1 mutation carriers often show loss of the remaining wild-type (WT) BAP1 allele as the second hit (4–6, 9), strongly suggesting that BAP1 acts as a classical 2-hit tumor suppressor gene (14).…”

Section: Introductionmentioning

confidence: 99%

Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations

Kadariya

Cheung

et al. 2016

Cancer Research

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Individuals harboring inherited heterozygous germline mutations in BAP1 are predisposed to a range of benign and malignant tumor types, including malignant mesothelioma, melanoma, and kidney carcinoma. However, evidence to support a tumor suppressive role for BAP1 in cancer remains contradictory. To test experimentally whether BAP1 behaves as a tumor suppressor, we monitored spontaneous tumor development in three different mouse models with germline heterozygous mutations in Bap1, including two models in which the knock-in mutations are identical to those reported in human BAP1 cancer syndrome families. We observed spontaneous malignant tumors in 54 of 93 Bap1-mutant mice (58%) versus 4 of 43 (9%) wild-type littermates. All three Bap1-mutant models exhibited a high incidence and similar spectrum of neoplasms, including ovarian sex cord stromal tumors, lung and mammary carcinomas, and spindle cell tumors. Notably, we also observed malignant mesotheliomas in two Bap1-mutant mice, but not in any wild-type animals. We further confirmed that the remaining wild-type Bap1 allele was lost in both spontaneous ovarian tumors and mesotheliomas, resulting in the loss of Bap1 expression. Additional studies revealed that asbestos exposure induced a highly significant increase in the incidence of aggressive mesotheliomas in the two mouse models carrying clinically relevant Bap1 mutations compared with asbestos-exposed wild-type littermates. Collectively, these findings provide genetic evidence that Bap1 is a bona fide tumor suppressor gene, and offer key insights into the contribution of carcinogen exposure to enhanced cancer susceptibility.

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Section: Introductionmentioning

confidence: 99%

Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations

Kadariya

Cheung

et al. 2016

Cancer Research

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“…Notably, other cancers observed in this family include MM, CM, and meningioma. Since then, numerous reports have expanded on the discovery of germline mutations in families or individuals with these and other cancers [BAP1 tumor predisposition syndrome (TPDS)] (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). In the OMIM (Online Mendelian Inheritance in Man) database, the disorder is now referred to as TPDS #614327 (http://www.…”

Section: Somatic and Germline Mutations Of Bap1mentioning

confidence: 99%

BAP1, a tumor suppressor gene driving malignant mesothelioma

Cheung

Testa

2017

Transl. Lung Cancer Res.

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Like cancer generally, malignant mesothelioma (MM) is a genetic disease at the cellular level. DNA copy number analysis of mesothelioma specimens has revealed a number of recurrent sites of chromosomal loss, including 3p21.1, 9p21.3, and 22q12.2. The key inactivated driver genes located at 9p21.1 and 22q12.2 were discovered two decades ago as being the tumor suppressor loci CDKN2A and NF2, respectively. Only relatively recently was the BAP1 gene determined to be the driver gene at 3p21.1 that is somatically inactivated. In 2011, we reported germline mutations in BAP1 in two families with a high incidence of mesothelioma and other cancers such as uveal melanoma (UM). As a result of a flurry of research activity over the last 5-6 years, the BAP1 gene is now firmly linked causally to a novel tumor predisposition syndrome (TPDS) characterized by increased susceptibility to mesothelioma, UM, cutaneous melanoma (CM) and benign melanocytic tumors, as well as several other cancer types. Moreover, results from recent in vivo studies with genetically engineered Bap1-mutant mouse models and new functional studies have provided intriguing biological insights regarding BAP1's role in tumorigenesis. These and other recent findings offer new possibilities for novel preventative and therapeutic strategies for MM patients.

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“…Investigators have examined BAP1 in families: i) with high incidence of MM [3,7,9,11,14]; ii) referred to genetic or cancer centers for uveal melanoma [9,12,15] or other melanocytic tumors [13,17]; iii) affected by basal cell carcinoma [16]; iv) having a family history suggestive of the BAP1 cancer syndrome [18]. Other families were examined as part of asbestos surveillance program [10].…”

Section: Case D-ii-3) Somatic Mutations In Exonmentioning

confidence: 99%

“…BAP1 regulates cell cycle control, target genes transcription, and DNA damage repair [2]. The germline mutation in the BAP1 gene is associated with a hereditary tumor predisposition syndrome (BAP1-TPDS, OMIM#614327) that occurs in family members with several cancer types: MM, uveal/cutaneous melanoma, renal cell carcinoma, basal cell carcinoma and other cancers [3][4][5][6][7][8][9][10][11][12][13][14][15][16]. As of March 2016, forty-six families with multiple cases of MM have been analyzed for BAP1 germline alterations.…”

Section: Introductionmentioning

confidence: 99%

Mesothelioma families without inheritance of a BAP1 predisposing mutation

et al. 2016

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (n=1), and unknown (n=1). These family units without inheritance of a BAP1 predisposing mutation expand the number of unmutated germline BAP1 families with multiple mesothelioma cases. This suggests that besides the exposure to asbestos other currently unknown genetic or epigenetic factors may be responsible for the high incidence of mesothelioma in BAP1-unmutated families.

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

Cited by 41 publications

References 29 publications

Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations

Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations

BAP1, a tumor suppressor gene driving malignant mesothelioma

Mesothelioma families without inheritance of a BAP1 predisposing mutation

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