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David A Solomon - One of the best experts on this subject based on the ideXlab platform.
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well differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in traf7 and cdc42
Modern Pathology, 2019Co-Authors: Meredith Stevers, Courtney Onodera, Boris C Bastian, Joseph T Rabban, Karuna Garg, Charles Zaloudek, Jessica Van Ziffle, James P Grenert, David A SolomonAbstract:Well-differentiated papillary mesothelioma is an uncommon mesothelial neoplasm that most frequently arises in the peritoneal cavity of women of reproductive age. Whereas malignant mesothelioma is an aggressive Tumor associated with poor outcome, well-differentiated papillary mesothelioma typically exhibits indolent behavior. However, histologically differentiating between these two entities can be challenging, necessitating the development of distinguishing biomarkers. While the genetic alterations that drive malignant mesothelioma have recently been determined, the molecular pathogenesis of well-differentiated papillary mesothelioma is unknown. Here we performed genomic profiling on a cohort of ten well-differentiated papillary mesothelioma of the peritoneum. We identified that all Tumors harbored somatic missense mutations in either the TRAF7 or CDC42 genes, and lacked alterations involving BAP1, NF2, CDKN2A, DDX3X, SETD2, and ALK that are frequent in malignant mesothelioma. We recently identified that another mesothelial neoplasm, Adenomatoid Tumor of the genital tract, is genetically defined by somatic missense mutations in the TRAF7 gene, indicating a shared molecular pathogenesis between well-differentiated papillary mesothelioma and Adenomatoid Tumors. To the best of our knowledge, well-differentiated papillary mesothelioma is the first human Tumor type found to harbor recurrent mutations in the CDC42 gene, which encodes a Rho family GTPase. Immunohistochemistry demonstrated intact BAP1 expression in all cases of well-differentiated papillary mesothelioma, indicating that this is a reliable marker for distinguishing well-differentiated papillary mesothelioma from malignant mesotheliomas that frequently display loss of expression. Additionally, all well-differentiated papillary mesothelioma demonstrated robust expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation, similar to that observed in Adenomatoid Tumors. In contrast, we have previously shown that L1CAM staining is not observed in normal mesothelial cells and malignant mesotheliomas of the peritoneum. Together, these studies demonstrate that well-differentiated papillary mesothelioma is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 that molecularly distinguish this entity from malignant mesothelioma.
Charles Zaloudek - One of the best experts on this subject based on the ideXlab platform.
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well differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in traf7 and cdc42
Modern Pathology, 2019Co-Authors: Meredith Stevers, Courtney Onodera, Boris C Bastian, Joseph T Rabban, Karuna Garg, Charles Zaloudek, Jessica Van Ziffle, James P Grenert, David A SolomonAbstract:Well-differentiated papillary mesothelioma is an uncommon mesothelial neoplasm that most frequently arises in the peritoneal cavity of women of reproductive age. Whereas malignant mesothelioma is an aggressive Tumor associated with poor outcome, well-differentiated papillary mesothelioma typically exhibits indolent behavior. However, histologically differentiating between these two entities can be challenging, necessitating the development of distinguishing biomarkers. While the genetic alterations that drive malignant mesothelioma have recently been determined, the molecular pathogenesis of well-differentiated papillary mesothelioma is unknown. Here we performed genomic profiling on a cohort of ten well-differentiated papillary mesothelioma of the peritoneum. We identified that all Tumors harbored somatic missense mutations in either the TRAF7 or CDC42 genes, and lacked alterations involving BAP1, NF2, CDKN2A, DDX3X, SETD2, and ALK that are frequent in malignant mesothelioma. We recently identified that another mesothelial neoplasm, Adenomatoid Tumor of the genital tract, is genetically defined by somatic missense mutations in the TRAF7 gene, indicating a shared molecular pathogenesis between well-differentiated papillary mesothelioma and Adenomatoid Tumors. To the best of our knowledge, well-differentiated papillary mesothelioma is the first human Tumor type found to harbor recurrent mutations in the CDC42 gene, which encodes a Rho family GTPase. Immunohistochemistry demonstrated intact BAP1 expression in all cases of well-differentiated papillary mesothelioma, indicating that this is a reliable marker for distinguishing well-differentiated papillary mesothelioma from malignant mesotheliomas that frequently display loss of expression. Additionally, all well-differentiated papillary mesothelioma demonstrated robust expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation, similar to that observed in Adenomatoid Tumors. In contrast, we have previously shown that L1CAM staining is not observed in normal mesothelial cells and malignant mesotheliomas of the peritoneum. Together, these studies demonstrate that well-differentiated papillary mesothelioma is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 that molecularly distinguish this entity from malignant mesothelioma.
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genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes bap1 setd2 and ddx3x
Modern Pathology, 2017Co-Authors: Nancy M Joseph, Yunnyi Chen, Anthony Nasr, Iwei Yeh, Eric Talevich, Courtney Onodera, Boris C Bastian, Joseph T Rabban, Karuna Garg, Charles ZaloudekAbstract: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.
Chenchin Sun - One of the best experts on this subject based on the ideXlab platform.
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malignant mesothelioma of the tunica vaginalis testis diagnostic studies and differential diagnosis
Archives of Pathology & Laboratory Medicine, 2012Co-Authors: Seble S Chekol, Chenchin SunAbstract:Malignant mesothelioma of the tunica vaginalis testis is an extremely rare Tumor representing 0.3% to 5% of all malignant mesotheliomas. Gross examination of testicular mesotheliomas typically reveals Tumor nodules studding the thickened tunica vaginalis and, in some cases, infiltrating the testicular parenchyma, leading to diagnostic challenges. Microscopically, the Tumor is characterized by epithelioid cells arising from the tunica vaginalis with papillary, tubulopapillary, or solid architectural patterns. The papillae are usually lined by a single layer of cells with relatively bland cytologic features. An epithelial cell phenotype admixed with a sarcomatoid pattern has also been described in a few cases. Immunohistochemically, the Tumor is usually positive for calretinin, Wilms Tumor-1, epithelial membrane antigen, D2-40, thrombomodulin, cytokeratin 7, and cytokeratin 5/6. Electron microscopic studies reveal epithelial cells joined by tight junctions, forming lumina, and displaying long microvilli with length to width ratios often greater than 10. The most important differential diagnostic considerations include florid mesothelial hyperplasia, Adenomatoid Tumor, carcinoma of the rete testis, and serous papillary Tumors. In addition, the various types of testicular germ cell Tumors should be considered, including seminomas, embryonal carcinomas, and intratubular germ cell Tumors, particularly in Tumors with testicular parenchymal involvement. Pleomorphic sarcomas should also be considered, particularly when dealing with the biphasic variant. The prognosis for this entity is grave, with a median survival of 23 months. Aggressive therapy with radical orchiectomy remains the mainstay of treatment.
Courtney Onodera - One of the best experts on this subject based on the ideXlab platform.
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well differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in traf7 and cdc42
Modern Pathology, 2019Co-Authors: Meredith Stevers, Courtney Onodera, Boris C Bastian, Joseph T Rabban, Karuna Garg, Charles Zaloudek, Jessica Van Ziffle, James P Grenert, David A SolomonAbstract:Well-differentiated papillary mesothelioma is an uncommon mesothelial neoplasm that most frequently arises in the peritoneal cavity of women of reproductive age. Whereas malignant mesothelioma is an aggressive Tumor associated with poor outcome, well-differentiated papillary mesothelioma typically exhibits indolent behavior. However, histologically differentiating between these two entities can be challenging, necessitating the development of distinguishing biomarkers. While the genetic alterations that drive malignant mesothelioma have recently been determined, the molecular pathogenesis of well-differentiated papillary mesothelioma is unknown. Here we performed genomic profiling on a cohort of ten well-differentiated papillary mesothelioma of the peritoneum. We identified that all Tumors harbored somatic missense mutations in either the TRAF7 or CDC42 genes, and lacked alterations involving BAP1, NF2, CDKN2A, DDX3X, SETD2, and ALK that are frequent in malignant mesothelioma. We recently identified that another mesothelial neoplasm, Adenomatoid Tumor of the genital tract, is genetically defined by somatic missense mutations in the TRAF7 gene, indicating a shared molecular pathogenesis between well-differentiated papillary mesothelioma and Adenomatoid Tumors. To the best of our knowledge, well-differentiated papillary mesothelioma is the first human Tumor type found to harbor recurrent mutations in the CDC42 gene, which encodes a Rho family GTPase. Immunohistochemistry demonstrated intact BAP1 expression in all cases of well-differentiated papillary mesothelioma, indicating that this is a reliable marker for distinguishing well-differentiated papillary mesothelioma from malignant mesotheliomas that frequently display loss of expression. Additionally, all well-differentiated papillary mesothelioma demonstrated robust expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation, similar to that observed in Adenomatoid Tumors. In contrast, we have previously shown that L1CAM staining is not observed in normal mesothelial cells and malignant mesotheliomas of the peritoneum. Together, these studies demonstrate that well-differentiated papillary mesothelioma is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 that molecularly distinguish this entity from malignant mesothelioma.
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genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes bap1 setd2 and ddx3x
Modern Pathology, 2017Co-Authors: Nancy M Joseph, Yunnyi Chen, Anthony Nasr, Iwei Yeh, Eric Talevich, Courtney Onodera, Boris C Bastian, Joseph T Rabban, Karuna Garg, Charles ZaloudekAbstract: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.
Boris C Bastian - One of the best experts on this subject based on the ideXlab platform.
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well differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in traf7 and cdc42
Modern Pathology, 2019Co-Authors: Meredith Stevers, Courtney Onodera, Boris C Bastian, Joseph T Rabban, Karuna Garg, Charles Zaloudek, Jessica Van Ziffle, James P Grenert, David A SolomonAbstract:Well-differentiated papillary mesothelioma is an uncommon mesothelial neoplasm that most frequently arises in the peritoneal cavity of women of reproductive age. Whereas malignant mesothelioma is an aggressive Tumor associated with poor outcome, well-differentiated papillary mesothelioma typically exhibits indolent behavior. However, histologically differentiating between these two entities can be challenging, necessitating the development of distinguishing biomarkers. While the genetic alterations that drive malignant mesothelioma have recently been determined, the molecular pathogenesis of well-differentiated papillary mesothelioma is unknown. Here we performed genomic profiling on a cohort of ten well-differentiated papillary mesothelioma of the peritoneum. We identified that all Tumors harbored somatic missense mutations in either the TRAF7 or CDC42 genes, and lacked alterations involving BAP1, NF2, CDKN2A, DDX3X, SETD2, and ALK that are frequent in malignant mesothelioma. We recently identified that another mesothelial neoplasm, Adenomatoid Tumor of the genital tract, is genetically defined by somatic missense mutations in the TRAF7 gene, indicating a shared molecular pathogenesis between well-differentiated papillary mesothelioma and Adenomatoid Tumors. To the best of our knowledge, well-differentiated papillary mesothelioma is the first human Tumor type found to harbor recurrent mutations in the CDC42 gene, which encodes a Rho family GTPase. Immunohistochemistry demonstrated intact BAP1 expression in all cases of well-differentiated papillary mesothelioma, indicating that this is a reliable marker for distinguishing well-differentiated papillary mesothelioma from malignant mesotheliomas that frequently display loss of expression. Additionally, all well-differentiated papillary mesothelioma demonstrated robust expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation, similar to that observed in Adenomatoid Tumors. In contrast, we have previously shown that L1CAM staining is not observed in normal mesothelial cells and malignant mesotheliomas of the peritoneum. Together, these studies demonstrate that well-differentiated papillary mesothelioma is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 that molecularly distinguish this entity from malignant mesothelioma.
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genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes bap1 setd2 and ddx3x
Modern Pathology, 2017Co-Authors: Nancy M Joseph, Yunnyi Chen, Anthony Nasr, Iwei Yeh, Eric Talevich, Courtney Onodera, Boris C Bastian, Joseph T Rabban, Karuna Garg, Charles ZaloudekAbstract: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.