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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
Ji Yoon Han, Woori Jang, Joonhong Park, Myungshin Kim, Yonggoo Kim, In Goo Lee
The child with global developmental delay (GDD)/intellectual disability (ID) is deserving of the appropriate evaluation available for improving the health and well-being of patients and their families. To better elucidate the diagnostic approach of genetic tests for patients with GDD and/or ID, we evaluated the results in a cohort of 75 patients with clinical features of GDD and/or ID who were referred for diagnostic workup. A total of 75 children were investigated for GDD or ID in the pediatric neurology department...
November 6, 2018: Annals of Human Genetics
Brittany C Michel, Andrew R D'Avino, Seth H Cassel, Nazar Mashtalir, Zachary M McKenzie, Matthew J McBride, Alfredo M Valencia, Qianhe Zhou, Michael Bocker, Luis M M Soares, Joshua Pan, David I Remillard, Caleb A Lareau, Hayley J Zullow, Nora Fortoul, Nathanael S Gray, James E Bradner, Ho Man Chan, Cigall Kadoch
Mammalian SWI/SNF chromatin remodelling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF and a newly characterized non-canonical complex (ncBAF). However, their complex-specific targeting on chromatin, functions and roles in disease remain largely undefined. Here, we comprehensively mapped complex assemblies on chromatin and found that ncBAF complexes uniquely localize to CTCF sites and promoters. We identified ncBAF subunits as synthetic lethal targets specific to synovial sarcoma and malignant rhabdoid tumours, which both exhibit cBAF complex (SMARCB1 subunit) perturbation...
December 2018: Nature Cell Biology
William J Anderson, Jason L Hornick
Sarcomas encompass a broad group of malignant mesenchymal neoplasms, whose accurate diagnosis and classification relies on the integration of clinical, histopathological and molecular features. Our understanding of the latter has increased dramatically in recent years with the widespread application of high-throughput sequencing. Concomitantly, the role of immunohistochemistry has continued to expand, as many genomic alterations have been exploited by the development of novel diagnostic markers that act as surrogates for their detection...
November 1, 2018: Genes, Chromosomes & Cancer
Erik A Williams, Julie J Miller, Shilpa S Tummala, Tristan Penson, A John Iafrate, Tareq A Juratli, Daniel P Cahill
TERT promoter (TERTp) mutations are found in the majority of World Health Organization (WHO) grade IV adult IDH wild-type glioblastoma (IDH-wt GBM). Here, we characterized the subset of IDH-wt GBMs that do not have TERTp mutations. In a cohort of 121 adult grade IV gliomas, we identified 109 IDH-wt GBMs, after excluding 11 IDH-mutant cases and one H3F3A -mutant case. Within the IDH-wt cases, 16 cases (14.7%) were TERTp wild-type (TERTp-wt). None of the 16 had BRAF V600E or H3F3A G34 hotspot mutations. When compared to TERTp mutants, patients with TERTp-wt GBMs, were significantly younger at first diagnosis (53...
October 17, 2018: Acta Neuropathologica Communications
Theodoros Karantanos, Lisa Rooper, Youme Kang, Cheng Ting Lin, Pawla Wenga, Sarah Sagorsky, Josh Lauring, Hyunseok Kang
Integrase interactor 1 (INI-1)-deficient carcinoma is a rare cancer characterized by the loss of the SWItch/Sucrose Non-Fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene ( SMARCB1 ) and tends to follow an aggressive clinical course. There is no currently available standard therapy option, although a few promising treatment strategies, including enhancer of zeste homolog 2 (EZH2) inhibition, are under active investigation. This report describes a 30-year-old woman with INI-1-deficient carcinoma who progressed on combination chemotherapy and an EZH2 inhibitor...
October 8, 2018: Oncologist
Michael A Paolini, Benjamin R Kipp, William R Sukov, Sarah M Jenkins, Emily G Barr Fritcher, Derick Aranda, Karen S SantaCruz, Sadeq Al-Dandan, Pete Fisher, William C McDonald, Charles P Bondurant, Grant Van Dyke Darkow, Caterina Giannini, Joseph E Parisi, Mark E Jentoft, Aditya Raghunathan
Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant CNS neoplasms that typically occur in children <2 years of age. These are characterized by high-grade histologic features and mutations of the INI1/SMARCB1 gene readily detected by loss of expression by immunohistochemistry. Among adults, the majority of AT/RTs occurs in the cerebral hemispheres. A small number of adult AT/RTs involving the sellar and suprasellar region reported in the literature suggest a distinct clinical course for this group...
December 1, 2018: Journal of Neuropathology and Experimental Neurology
Paweł Gajdzis, Marick Laé, Jerzy Klijanienko
BACKGROUND: Epithelioid sarcoma (ES) is a rare mesenchymal tumor that is divided into 2 types: classic and proximal. To the authors' knowledge, ES has been poorly studied in cytology, with fewer than 50 cases reported to date. The objective of the current study was to analyze the cytological and immunohistochemical information regarding 5 cases of ES. METHODS: Five cases of ES were analyzed: 4 of proximal type and 1 of classic type. The cases were taken from 4 female patients and 1 male patient...
November 2018: Cancer Cytopathology
Irina Alimova, Angela Pierce, Etienne Danis, Andrew Donson, Diane K Birks, Andrea Griesinger, Nicholas K Foreman, Mariarita Santi, Laura Soucek, Sujatha Venkataraman, Rajeev Vibhakar
Loss of SMARCB1 is the hallmark genetic event that characterizes rhabdoid tumors in children. Rhabdoid tumors of the brain (ATRT) occur in young children and are particularly challenging with poor long term survival. SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. The mechanisms by which SMARCB1 deletion results in tumorigenesis remain unclear. Recent studies demonstrate that ATRT consists of 3 genomic sub-groups with a subset of poor outcome tumors expressing high BMP and MYC pathway activation...
September 19, 2018: International Journal of Cancer. Journal International du Cancer
Susan Sammak, Mark D Allen, Najoua Hamdani, Mark Bycroft, Giovanna Zinzalla
c-MYC and the SWI/SNF chromatin remodeling complex act as master regulators of transcription, and play a key role in human cancer. Although they are known to interact, the molecular details of their interaction are lacking. We have determined the structure of the RPT1 region of the INI1/hSNF5/BAF47/SMARCB1 subunit of the SWI/SNF complex that acts as a c-MYC-binding domain, and have localized the interaction regions on both INI1 and on the c-MYC:MAX heterodimer. c-MYC interacts with a highly conserved groove on INI1, while INI1 binds to the c-MYC helix-loop-helix region...
September 17, 2018: FEBS Journal
Yuuki Nishimura, Akihiko Yoshida, Kan Yonemori, Noriko Motoi, Kenji Tamura, Nobuyoshi Hiraoka, Taisuke Mori
SMARCB1-deficiency has been found in a variety of tumors. Here, we report a SMARCB1-deficient squamous cell carcinoma of a mediastinal cyst. A 53-year-old man was diagnosed with a cyst of the pericardial region in his twenties. As a symptom at this time, he complained of severe pain and dyspnea in the right chest. Following investigation using imaging and histological examination of the biopsy specimen, he was diagnosed with a SMARCB1 deficient malignant neoplasm. As tumor cells showed positive immunostaining for p40 and CK5/6, the immunophenotype of the tumor was consistent with squamous cell carcinoma (SCC)...
October 2018: Pathology International
Monika M Golas, Sakthidasan Jayaprakash, Le T M Le, Zongpei Zhao, Violeta Heras Huertas, Ida S Jensen, Juan Yuan, Bjoern Sander
The human tumor suppressor SMARCB1/INI1/SNF5/BAF47 (SNF5) is a core subunit of the multi-subunit ATP-dependent chromatin remodeling complex SWI/SNF, also known as Brahma/Brahma-related gene 1 (BRM/BRG1)-associated factor (BAF). Experimental studies of SWI/SNF are currently considerably limited by the low cellular abundance of this complex; thus, recombinant protein production represents a key to obtain the SWI/SNF proteins for molecular and structural studies. While the expression of mammalian proteins in bacteria is often difficult, the baculovirus/insect cell expression system can overcome limitations of prokaryotic expression systems and facilitate the co-expression of multiple proteins...
November 2018: Molecular Biotechnology
Sabrina Rossi, Monica Brenca, Lucia Zanatta, Elena Trincia, Angela Guerriero, Cristina Pizzato, Alessandro Fiorindi, Elisabetta Viscardi, Felice Giangaspero, Roberta Maestro, Angelo Paolo Dei Tos, Caterina Giannini
SMARCB1 inactivation is a well-established trigger event in atypical teratoid/rhabdoid tumor. Recently, a role for SMARCB1 inactivation has emerged as a mechanism of clonal evolution in other tumor types, including rare brain tumors. We describe an unusual malignant intra-axial SMARCB1-deficient spindle cell desmoplastic neoplasm, occurring in a 6-year-old child with meningioangiomatosis and a long history of seizures. Striking features of the tumor were a storiform pattern and strong CD34 expression. Undifferentiated round cell areas with isolated rhabdoid cells showing high mitotic index and focal necrosis with INI1 expression loss were present...
October 1, 2018: Journal of Neuropathology and Experimental Neurology
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