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Thomas P Howard, Taylor E Arnoff, Melinda R Song, Andrew O Giacomelli, Xiaofeng Wang, Andrew L Hong, Neekesh V Dharia, Su Wang, Francisca Vazquez, Minh-Tam Pham, Ann M Morgan, Franziska Wachter, Gregory H Bird, Guillaume Kugener, Elaine M Oberlick, Matthew G Rees, Hong L Tiv, Justin H Hwang, Katherine H Walsh, April Cook, John M Krill-Burger, Aviad Tsherniak, Prafulla C Gokhale, Peter J Park, Kimberly Stegmaier, Loren D Walensky, William C Hahn, Charles W M Roberts
Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. In this study, we screened several MRT cell lines with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to identify potential drug targets specific for these cancers. We discovered MDM2 and MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin (MDM2-specific) and ATSP-7041 (MDM2/4-dual), we show that MRT cells were more sensitive than other p53 wild-type cancer cell lines to inhibition of MDM2 alone as well as dual inhibition of MDM2/4...
February 12, 2019: Cancer Research
Alessandro Carugo, Rosalba Minelli, Luigi Sapio, Melinda Soeung, Federica Carbone, Frederick S Robinson, James Tepper, Ziheng Chen, Sara Lovisa, Maria Svelto, Samirkumar Amin, Sanjana Srinivasan, Edoardo Del Poggetto, Sara Loponte, Francesca Puca, Prasenjit Dey, Gabriel G Malouf, Xiaoping Su, Liren Li, Dolores Lopez-Terrada, Dinesh Rakheja, Alexander J Lazar, George J Netto, Priya Rao, Alessandro Sgambato, Anirban Maitra, Durga N Tripathi, Cheryl L Walker, Jose A Karam, Timothy P Heffernan, Andrea Viale, Charles W M Roberts, Pavlos Msaouel, Nizar M Tannir, Giulio F Draetta, Giannicola Genovese
Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19ARF -p53 axis...
February 11, 2019: Cancer Cell
Nadejda Beliakova-Bethell, Amey Mukim, Cory H White, Savitha Deshmukh, Hosiana Abewe, Douglas D Richman, Celsa A Spina
Histone deacetylase (HDAC) inhibitors (HDACi) have been widely tested in clinical trials for their ability to reverse HIV latency, but have yielded only limited success. One HDACi, suberoylanilide hydroxamic acid (SAHA), exhibits off-target effects on host gene expression predicted to interfere with induction of HIV transcription. Romidepsin (RMD) has higher potency and specificity for class I HDACs implicated in maintaining HIV provirus in the latent state. More robust HIV reactivation has indeed been achieved with RMD use ex vivo than with SAHA; however, reduction of viral reservoir size has not been observed in clinical trials...
February 11, 2019: Journal of Biological Chemistry
Yui Kojima, Mikiko Tanabe, Ikuma Kato, Toru Motoi, Mariko Kimura, Tomoe Sawazumi, Reiko Tanaka, Sawako Chiba, Masako Otani, Yoshiaki Inayama
Recently, a new entity "myoepithelioma-like tumor of the vulvar region (MELTVR)" was proposed as a rare mesenchymal neoplasm arising in vulvar regions of adult women. While MELTVRs morphologically resemble soft tissue myoepitheliomas and extraskeletal myxoid chondrosarcomas, they have a unique immunohistochemical profile (positive for epithelial membrane antigen and estrogen receptor, negative for S100 protein and glial fibrillary acidic protein, and loss of INI1/SMARCB1 expression), and lack EWSR1 and NR4A3 gene rearrangement, as seen by fluorescence in situ hybridization...
February 9, 2019: Pathology International
Anthony P Martinez, Karen J Fritchie
Recent work has revealed SMARCB1/INI1 loss by immunohistochemistry in a subset of epithelioid schwannomas and explored the significance of cytologic atypia and increased mitotic activity in these tumors. Additional studies have evaluated the utility and limitations of histone H3K27 trimethylation in diagnosis of high-grade and low-grade malignant peripheral nerve sheath tumors. New terminology regarding nerve sheath tumors in neurofibromatosis type 1 patients was proposed during a 2016 conference to better define guidelines for classification of this group of tumors...
March 2019: Surgical Pathology Clinics
Leandro Blas, Javier Roberti, Jorgelina Petroni, Liliana Reniero, Federico Cicora
PURPOSE OF THE REVIEW: We present an updated report of renal medullary carcinoma (RMC), a rare and aggressive condition. RECENT FINDINGS: There is a majority of male patients, of African descent, in the second or third decade of life. In differential diagnosis, other tumors, such as malignant rhabdoid tumor (MRT), vinculin-anaplastic lymphoma kinase (VCL-ALK) translocation renal cell carcinoma, and collecting duct carcinoma, may present difficulties. Abnormalities of tumor suppressor gene SMARCB1 have been found in RMC...
January 17, 2019: Current Urology Reports
Hideki Nagano, Toshimasa Izumi, Ei Kawahara, Takeru Oyama, Takanori Goi
BACKGROUND: Undifferentiated carcinoma of the esophagus with rhabdoid features is a very rare histologic finding that is occasionally associated with the loss of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1); however, until now, few survey reports of this type of tumor have been published. In this study, we describe a case of esophageal carcinoma with undifferentiated components and rhabdoid features that was exclusively positive for vimentin and SMARCB1 in a patient with prolonged survival...
January 16, 2019: Surgical Case Reports
Mrinal M Gounder, Guo Zhu, Lev Roshal, Eric Lis, Scott R Daigle, Stephen J Blakemore, Neil R Michaud, Meera Hameed, Travis J Hollmann
PURPOSE: We sought to determine the mechanism of an exceptional response in a patient diagnosed with a SMARCB1/INI1-negative chordoma treated with tazemetostat, an EZH2 inhibitor and followed by radiotherapy. EXPERIMENTAL DESIGN: In an attempt to investigate the mechanism behind this apparent abscopal effect, we interrogated tumor tissues obtained over the clinical course. We utilized next-generation sequencing, standard IHC and employed a novel methodology of multiplex immunofluorescence analysis...
January 14, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Thomas Schweiger, Sandra Liebmann-Reindl, Olaf Glueck, Patrick Starlinger, Johannes Laengle, Peter Birner, Walter Klepetko, Dietmar Pils, Berthold Streubel, Konrad Hoetzenecker
Background: Pulmonary metastasectomy is one of the cornerstones in the treatment of oligometastatic colorectal cancer (CRC). However, the selection of patients who benefit from a surgical resection is difficult. Mutational profiling has become an essential part of diagnosis and treatment of malignant disease. Despite this, comprehensive data on the mutational profile of CRC and its clinical impact in the context of pulmonary metastasectomy is sparse. We therefore aimed to provide a complete mutational status of CRC pulmonary metastases (PM) and corresponding primary tumors by targeted next-generation sequencing (tNGS), and correlate sequencing data with clinical outcome variables...
November 2018: Journal of Thoracic Disease
Serap Erkek, Pascal D Johann, Martina A Finetti, Yiannis Drosos, Hsien-Chao Chou, Marc Zapatka, Dominik Sturm, David T W Jones, Andrey Korshunov, Marina Rhyzova, Stephan Wolf, Jan-Philipp Mallm, Katja Beck, Olaf Witt, Andreas E Kulozik, Michael C Frühwald, Paul A Northcott, Jan O Korbel, Peter Lichter, Roland Eils, Amar Gajjar, Charles W M Roberts, Daniel Williamson, Martin Hasselblatt, Lukas Chavez, Stefan M Pfister, Marcel Kool
Biallelic inactivation of SMARCB1, encoding a member of the SWI/SNF chromatin remodeling complex, is the hallmark genetic aberration of atypical teratoid rhabdoid tumors (ATRT). Here, we report how loss of SMARCB1 affects the epigenome in these tumors. Using chromatin immunoprecipitation sequencing (ChIP-seq) on primary tumors for a series of active and repressive histone marks, we identified the chromatin states differentially represented in ATRTs compared with other brain tumors and non-neoplastic brain. Re-expression of SMARCB1 in ATRT cell lines enabled confirmation of our genome-wide findings for the chromatin states...
December 12, 2018: Cancer Cell
Yuhui Ding, Tao Zhu, Hongtao Rong, Yi Wang, Tong Liu, Jinhao Zhang, Sipeng Li, Zhe Wang, Ya Wang
BACKGROUND: Schwannomatosis is the third subtype of neurofibromatosis. Because the tumor is multiple and prone to recurrence, it often brings challenges to clinical diagnosis and treatment. In the past decade, researchers have come to realize the relationship between the SMARCB1 gene and schwannomatosis, which is expected to improve the current level of diagnosis and treatment. CASE DESCRIPTION: We collected the clinical data of a rare family of intraspinal schwannomatosis and carried out the genetic tests on three generations, totally 25 members, in this family...
December 18, 2018: World Neurosurgery
G Bellantoni, F Guerrini, M Del Maestro, R Galzio, S Luzzi
Background: Schwannomatosis is a genetic disorder that belongs to NF family. The mutation of SMARCB1 gene has been related to this entity and Coffin-Siris syndrome, as well. We reported a case of a female patient with SMARCB1 mutation who has developed a spontaneuous spleen rupture. Case description: A 28 years old female patient with a story of a Sjogren syndrome, celiac disease and a surgically treated schwannoma, presented to our observation in July 2013 for a pain on the left elbow, where a tumefation was present...
March 2019: ENeurologicalSci
Kunio Mochizuki, Masataka Kawai, Toru Odate, Ippei Tahara, Tomohiro Inoue, Kazunari Kasai, Tadao Nakazawa, Tetsuo Kondo
BACKGROUND/AIM: Switch/sucrose non-fermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), also named integrase interactor 1, is one of the core subunit proteins in the SWI/SNF ATP-dependent chromatin remodeling complex encoded at chromosomal position 22q11.2. Complete loss of SMARCB1 expression has been reported in various malignant tumors. Immunohistochemistry has demonstrated that SMARCB1 mutation/inactivation correlates well with loss of nuclear SMARCB1 expression...
December 2018: Anticancer Research
Yanming Ren, Chuanyuan Tao, Xiliang Wang, Yan Ju
Background: Rhabdoid tumors (RTs) are aggressive tumors that occur most frequently in children under 2 years old, which often invade kidney (KRTs) and Center Nervous System, named Atypical teratoid/rhabdoid tumors (AT/RTs). RTs often progress fast and lead to a high lethality. RTs have a low incidence, we can hardly accumulate enough samples to elicit the diagnosis. More importantly, histologically, RTs present a host of neural, epithelial, mesenchymal, or ependymal patterns, which makes them rather variable and difficult to diagnose...
2018: Cancer Cell International
Jo Elle G Peterson, Abhishek Bavle, Vidya P Mehta, Ronald A Rauch, William E Whitehead, Carrie A Mohila, Jack M Su, Adekunle M Adesina
Atypical teratoid/rhabdoid tumor (ATRT) is a high-grade central nervous system tumor, with poor prognosis despite intensive multimodal therapy. Loss of nuclear immunostaining for INI1 due to inactivation of the hSNF5/INI1 tumor suppressor gene is pathognomonic of ATRT. We present a patient with congenital ATRT, who had spontaneous tumor regression without therapy, and is disease-free 4 years later. Tumor histopathology showed rhabdoid cells characteristic of ATRT, but immunohistochemistry revealed heterogeneous loss of nuclear INI1 staining...
November 23, 2018: Pediatric and Developmental Pathology
Erfan Aref-Eshghi, Eric G Bend, Rebecca L Hood, Laila C Schenkel, Deanna Alexis Carere, Rana Chakrabarti, Sandesh C S Nagamani, Sau Wai Cheung, Philippe M Campeau, Chitra Prasad, Victoria Mok Siu, Lauren Brady, Mark A Tarnopolsky, David J Callen, A Micheil Innes, Susan M White, Wendy S Meschino, Andrew Y Shuen, Guillaume Paré, Dennis E Bulman, Peter J Ainsworth, Hanxin Lin, David I Rodenhiser, Raoul C Hennekam, Kym M Boycott, Charles E Schwartz, Bekim Sadikovic
Coffin-Siris and Nicolaides-Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes...
November 20, 2018: Nature Communications
Takashi Murakami, Yoichi Akazawa, Noboru Yatagai, Takafumi Hiromoto, Noriko Sasahara, Tsuyoshi Saito, Naoto Sakamoto, Akihito Nagahara, Takashi Yao
BACKGROUND: Colorectal sessile serrated adenoma/polyps (SSA/Ps) are considered early precursor lesions in the serrated neoplasia pathway. Recent studies have shown associations of SSA/Ps with lost MLH1 expression, a CpG island methylator phenotype, and BRAF mutations. However, the molecular biological features of SSA/Ps with early neoplastic progression have not yet been fully elucidated, owing to the rarity of cases of SSA/P with advanced histology such as cytologic dysplasia or invasive carcinoma...
November 20, 2018: Diagnostic Pathology
Raul Perret, Lara Chalabreysse, Sarah Watson, Isabelle Serre, Stephane Garcia, Fabien Forest, Violaine Yvorel, Daniel Pissaloux, Vincent Thomas de Montpreville, Julien Masliah-Planchon, Sylvie Lantuejoul, Marie Brevet, Jean-Yves Blay, Jean-Michel Coindre, Franck Tirode, Francois Le Loarer
SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS) is a recently described entity with an aggressive clinical course and specific genetic alterations of the BAF chromatin remodeling complex. In the present study, we reviewed the clinical and pathologic features of 30 cases of SMARCA4-DTS, discussed its main differential diagnoses and the challenging diagnostic scenarios that the average pathologist may face. In addition, we tested the specificity of the "SMARCA4-DTS immunohistochemical signature" (co-loss of SMARCA4 and SMARCA2 with overexpression of SOX2) in a large cohort of intrathoracic malignancies...
November 16, 2018: American Journal of Surgical Pathology
Isabel Tegeder, Katharina Thiel, Serap Erkek, Pascal D Johann, Johannes Berlandi, Venu Thatikonda, Michael C Frühwald, Marcel Kool, Astrid Jeibmann, Martin Hasselblatt
PURPOSE: Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly arising in infants. Mutations of SWI/SNF chromatin remodeling complex members SMARCB1/INI1 or (rarely) SMARCA4/Brg1 are the sole recurrent genetic lesions. Epigenetic studies revealed a large number of genes predicted to be affected by differential histone modifications in ATRT, but the role of these genes in the biology of ATRT remains uncertain. We therefore aimed at exploring the role of these genes in the detrimental effects of SMARCB1-deficiency...
November 16, 2018: Journal of Neuro-oncology
Alice S Wang, Ali O Jamshidi, Nathan Oh, Ronald Sahyouni, Behdokht Nowroozizadeh, Ronald Kim, Frank P K Hsu, Daniela Bota
Background: Multiple intracranial meningiomas account for <10% of all meningiomas. Familial multiple meningiomas have been linked to germline mutations in two genes: neurofibromatosis type 2 (NF2) and SWIch/Sucrose Non-Fermentable (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1). Sporadic multiple meningiomas have been associated with somatic NF2 mutations and, to date, there has been no case related to somatic SMARCB1 mutations. Here, we describe the first case...
2018: Frontiers in Neurology
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