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Genomic profiling of malignant peritoneal mesothelioma reveals recurrent
alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X
#MMPMID27813512
Joseph NM
; Chen YY
; Nasr A
; Yeh I
; Talevich E
; Onodera C
; Bastian BC
; Rabban JT
; Garg K
; Zaloudek C
; Solomon DA
Mod Pathol
2017[Feb]; 30
(2
): 246-254
PMID27813512
show ga
Malignant mesothelioma is a rare cancer that arises from the mesothelial cells
that line the pleural cavity and less commonly from the peritoneal lining of the
abdomen and pelvis. Most pleural mesotheliomas arise in patients with a history
of asbestos exposure, whereas the association of peritoneal mesotheliomas with
exposure to asbestos and other potential carcinogens is less clear, suggesting
that the genetic alterations that drive malignant peritoneal mesothelioma may be
unique from those in pleural mesothelioma. Treatment options for all malignant
mesotheliomas are currently limited, with no known targeted therapies available.
To better understand the molecular pathogenesis of malignant peritoneal
mesothelioma, we sequenced 510 cancer-related genes in 13 patients with malignant
mesothelioma arising in the peritoneal cavity. The most frequent genetic
alteration was biallelic inactivation of the BAP1 gene, which occurred in 9/13
cases, with an additional two cases demonstrating monoallelic loss of BAP1. All
11 of these cases demonstrated loss of BAP1 nuclear staining by
immunohistochemistry, whereas two tumors without BAP1 alteration and all 42 cases
of histologic mimics in peritoneum (8 multilocular peritoneal inclusion cyst, 6
well-differentiated papillary mesothelioma of the peritoneum, 16 adenomatoid
tumor, and 12 low-grade serous carcinoma of the ovary) demonstrated intact BAP1
nuclear staining. Additional recurrently mutated genes in this cohort of
malignant peritoneal mesotheliomas included NF2 (3/13), SETD2 (2/13), and DDX3X
(2/13). While these genes are known to be recurrently mutated in pleural
mesotheliomas, the frequencies are distinct in peritoneal mesotheliomas, with
nearly 85% of peritoneal tumors harboring BAP1 alterations versus only 20-30% of
pleural tumors. Together, these findings demonstrate the importance of epigenetic
modifiers including BAP1, SETD2, and DDX3X in mesothelial tumorigenesis and
suggest opportunities for targeted therapies.
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