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BAP1 mutations in high-grade meningioma: implications for patient care.

ABSTRACT: We have recently shown that the breast cancer (BRCA)1-associated protein-1 tumor suppressor gene (BAP1) is inactivated in a subset of clinically aggressive meningiomas that display rhabdoid histomorphology. Immunohistochemistry for BAP1 protein provides a rapid and inexpensive method for screening suspected cases. Notably, some patients with BAP1-mutant meningiomas have germline BAP1 mutations and BAP1 tumor predisposition syndrome (TPDS). It appears that nearly all patients with germline BAP1 mutations develop malignancies by age 55, most frequently uveal melanoma, cutaneous melanoma, pleural or peritoneal malignant mesothelioma, or renal cell carcinoma, although other cancers have also been associated with BAP1 TPDS. Therefore, when confronted with a patient with a potentially high-grade rhabdoid meningioma, it is important that neuropathologists assess the BAP1 status of the tumor and that the patient's family history of cancer is carefully ascertained. In the appropriate clinical setting, genetic counseling and germline BAP1 DNA sequencing should be performed. A cancer surveillance program for individuals who carry germline BAP1 mutations may help identify tumors such as uveal melanoma, cutaneous melanoma, and renal cell carcinoma at early and treatable stages. Because BAP1-mutant meningiomas are rare tumors, multi-institutional efforts will be needed to evaluate therapeutic strategies and to further define the clinicopathologic features of these tumors.

SUBMITTER: Shankar GM

PROVIDER: S-EPMC5737364 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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BAP1 mutations in high-grade meningioma: implications for patient care.

Shankar Ganesh M GM Santagata Sandro S

Neuro-oncology 20171001 11

We have recently shown that the breast cancer (BRCA)1-associated protein-1 tumor suppressor gene (BAP1) is inactivated in a subset of clinically aggressive meningiomas that display rhabdoid histomorphology. Immunohistochemistry for BAP1 protein provides a rapid and inexpensive method for screening suspected cases. Notably, some patients with BAP1-mutant meningiomas have germline BAP1 mutations and BAP1 tumor predisposition syndrome (TPDS). It appears that nearly all patients with germline BAP1 m ...[more]

PMID: 28482042

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Project description:Mullerian adenosarcoma is an uncommon mesenchymal tumor of the gynecologic tract. Most cases are low-grade, while high-grade adenosarcomas are rare and not well studied. Herein, we characterize the clinicopathologic and molecular features of 27 adenosarcomas of gynecologic origin, enriched for high-grade tumors subjected to targeted panel sequencing. Sarcomatous overgrowth was more frequently seen in high-grade compared to low-grade tumors (12/17, 71%, vs 1/10, 10%, p = 0.004) and heterologous elements were exclusive to high-grade cases (n = 7, p = 0.03). All deaths were from high-grade disease (advanced primary, n = 2, or recurrence, n = 5). Genetic alterations specific to high-grade adenosarcomas have known associations with chromosome instability, including TP53 mutations (n = 4) and amplifications of MDM2 (n = 2) and CCNE1 (n = 2). Somatic ATRX frameshift mutations were found in 2 patients with high-grade recurrences following a primary low-grade adenosarcoma and ATRX deletion in 1 high-grade adenosarcoma with an adjacent low-grade component. The fraction of genome altered by copy number alterations was significantly higher in high-grade compared to low-grade adenosarcomas (P = 0.001). Other recurrent genetic alterations across the entire cohort included BAP1 homozygous deletions (n = 4), DICER1 mutations (n = 4), ARID1A mutations (n = 3), TERT promoter mutations (n = 2) and amplification (n = 1), as well as alterations involving members of the PI3K and MAPK signaling pathways. One tumor harbored an ESR1-NCOA3 fusion and another had an MLH1 homozygous deletion. Immunohistochemical analysis for BAP1 revealed loss of nuclear expression in 6/24 (25%) cases, including all four tumors with BAP1 deletions. Notably, out of 196 mesenchymal neoplasms of gynecologic origin, BAP1 homozygous deletion was only found in adenosarcomas (P = 0.0003). This study demonstrates that high-grade adenosarcomas are heterogeneous at the molecular level and are characterized by genomic instability and TP53 mutations; ATRX loss may be involved in high-grade transformation of low-grade adenosarcoma; and BAP1 inactivation appears to be a specific pathogenic driver in a subset of adenosarcomas.

Dataset Information

BAP1 mutations in high-grade meningioma: implications for patient care.

Publications

BAP1 mutations in high-grade meningioma: implications for patient care.

Similar Datasets

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