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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...
September 14, 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...
October 6, 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
Yuhui Ding, Hongtao Rong, Tong Liu, Yi Wang, Jinhao Zhang, Sipeng Li, Tao Zhu
BACKGROUND: Malignant peripheral nerve sheath tumor(MPNST) is a kind of rare neurogenic malignancy which usually arises from nerve fibers in any tissue and organ that have nerve fiber distributions especially trunk and extremities but extremely rare in spinal canal. CASE DESCRIPTION: We report a 30-year-old woman, had a history of excision of intraspinal occupying lesions 5 times and the pathological diagnosis based on histomorphologic and immunohistochemistry was schwannomatosis which existed in her family history...
August 22, 2018: World Neurosurgery
Inga-Marie Schaefer, Jason L Hornick
Although some soft tissue and bone tumors can be identified based on histologic features alone, immunohistochemistry plays a critical diagnostic role for most mesenchymal tumor types. The discovery of recurrent genomic alterations in many benign and malignant mesenchymal neoplasms has added important biologic insights and expanded the spectrum of some diagnostic subgroups. Some tumors are defined by unique genomic alterations, whereas others share abnormalities that are not tumor-specific and can be observed in a sometimes broad range of biologically unrelated neoplasms...
November 2018: Advances in Anatomic Pathology
Nina Bögershausen, Bernd Wollnik
Mutations in genes that encode proteins of the SWI/SNF complex, called BAF complex in mammals, cause a spectrum of disorders that ranges from syndromic intellectual disability to Coffin-Siris syndrome (CSS) to Nicolaides-Baraitser syndrome (NCBRS). While NCBRS is known to be a recognizable and restricted phenotype, caused by missense mutations in SMARCA2 , the term CSS has been used lately for a more heterogeneous group of phenotypes that are caused by mutations in either of the genes ARID1B, ARID1A, ARID2, SMARCA4, SMARCB1, SMARCE1, SOX11 , or DPF2 ...
2018: Frontiers in Molecular Neuroscience
Aanchal Kakkar, Vijay Mariadas Antony, Raja Pramanik, Pirabu Sakthivel, Chirom Amit Singh, Deepali Jain
A significant proportion of sinonasal malignancies is comprised of poorly differentiated/undifferentiated carcinomas that defy accurate histological classification, and behave aggressively. Recent years have seen a refinement of this spectrum by inclusion of novel entities harboring specific genetic alterations, including SMARCB1 (INI1)-deficient sinonasal carcinoma (SDSC), characterized by inactivating alterations in SMARCB1 gene, as demonstrated by loss of INI1 immunoexpression. Cyclin D1 is a cell-cycle regulatory protein downstream of INI1...
August 15, 2018: Human Pathology
Dóra Mihály, Gergő Papp, Zsolt Mervai, Andrea Reszegi, Péter Tátrai, Gábor Szalóki, Johanna Sápi, Zoltán Sápi
MiR-206 is a remarkable miRNA because it functions as a suppressor miRNA in rhabdomyosarcoma while at the same time, as previously showed, it can act as an oncomiRNA in SMARCB1 immunonegative soft tissue sarcomas. The aim of this study was to investigate the effect of miR-206 on its several target genes in various human tumorous and normal cell lines. In the current work, we created miR-206-overexpressing cell lines (HT-1080, Caco2, iASC, and SS-iASC) using permanent transfection. mRNA expression of the target genes of miR-206 (SMARCB1, ACTL6A, CCND1, POLA1, NOTCH3, MET, and G6PD) and SMARCB1 protein expression were examined with quantitative real-time polymerase chain reaction, immunoblotting, immunocytochemistry, and flow cytometry...
August 15, 2018: Experimental Biology and Medicine
Johanna Kondelin, Kari Salokas, Lilli Saarinen, Kristian Ovaska, Heli Rauanheimo, Roosa-Maria Plaketti, Jiri Hamberg, Xiaonan Liu, Leena Yadav, Alexandra E Gylfe, Tatiana Cajuso, Ulrika A Hänninen, Kimmo Palin, Heikki Ristolainen, Riku Katainen, Eevi Kaasinen, Tomas Tanskanen, Mervi Aavikko, Minna Taipale, Jussi Taipale, Laura Renkonen-Sinisalo, Anna Lepistö, Selja Koskensalo, Jan Böhm, Jukka-Pekka Mecklin, Halit Ongen, Emmanouil T Dermitzakis, Outi Kilpivaara, Pia Vahteristo, Mikko Turunen, Sampsa Hautaniemi, Sari Tuupanen, Auli Karhu, Niko Välimäki, Markku Varjosalo, Esa Pitkänen, Lauri A Aaltonen
Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite-stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV Somatic point mutation data from the exome kit-targeted area from 24 exome-sequenced sporadic MSI CRCs and respective normals, and 12 whole-genome-sequenced sporadic MSI CRCs and respective normals were utilized...
September 2018: EMBO Molecular Medicine
Giovanny Soca-Chafre, Norma Hernández-Pedro, Alejandro Aviles-Salas, Carmen Alaez Versón, Karol Carrillo Sánchez, Andrés F Cardona, Federico Avila-Moreno, Pedro Barrios-Bernal, Diana Flores-Estrada, Oscar Arrieta
Background: Wood smoke exposure (WSE) has been associated with an increased risk of lung cancer development. WSE has been related with high frequency of EGFR mutations and low frequency of KRAS mutations. The aim of this study was to evaluate large scale genomic alterations in lung adenocarcinomas associated with WSE using targeted next generation sequencing. Methods: DNA multi-targeted sequencing was performed in 42 fresh-frozen samples of advanced lung adenocarcinomas...
July 17, 2018: Oncotarget
Neda Stjepanovic, Tracy L Stockley, Philippe L Bedard, Jeanna M McCuaig, Melyssa Aronson, Spring Holter, Kara Semotiuk, Natasha B Leighl, Raymond Jang, Monika K Krzyzanowska, Amit M Oza, Abha Gupta, Christine Elser, Lailah Ahmed, Lisa Wang, Suzanne Kamel-Reid, Lillian L Siu, Raymond H Kim
BACKGROUND: Matched tumor-normal sequencing, applied in precision cancer medicine, can identify unidentified germline Medically Actionable Variants (gMAVS) in cancer predisposition genes. We report patient preferences for the return of additional germline results, and describe various gMAV scenarios delivered through a clinical genetics service. METHODS: Tumor profiling was offered to 1960 advanced cancer patients, of which 1556 underwent tumor-normal sequencing with multigene hotspot panels containing 20 cancer predisposition genes...
August 9, 2018: BMC Medical Genomics
Kristina Khazeni, Hannah LaBove, Breelyn Wilky, Andrew E Rosenberg, Elizabeth Paulus, Harvey Chim, Joseph M Pearson, Danny Yakoub
INTRODUCTION: Myoepithelial carcinoma and proximal-type epithelioid sarcoma of the vulva are two rare malignancies with known aggressive behavior. In addition to a similar clinical course, these two disease entities also have significant histologic and pathologic overlap. Given the rarity of these malignancies, there is limited literature on the appropriate treatment regimen. Nevertheless, there is a consensus that early surgical resection is beneficial in both cases. PRESENTATION: We present a case of a patient who was initially diagnosed with myoepithelial carcinoma of the vulva with a differential later expanded to include possible epithelioid sarcoma...
2018: International Journal of Surgery Case Reports
Iikki Donner, Riku Katainen, Lauri J Sipilä, Mervi Aavikko, Eero Pukkala, Lauri A Aaltonen
OBJECTIVES: Although the primary cause of lung cancer is smoking, a considerable proportion of all lung cancers occur in never smokers. Gender influences the risk and characteristics of lung cancer and women are overrepresented among never smokers with the disease. Young age at onset and lack of established environmental risk factors suggest genetic predisposition. In this study, we used population-based sampling of young patients to discover candidate predisposition variants for lung adenocarcinoma in never-smoking women...
August 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Hildegard Kehrer-Sawatzki, Lan Kluwe, Reinhard E Friedrich, Anna Summerer, Eleonora Schäfer, Ute Wahlländer, Cordula Matthies, Isabel Gugel, Said Farschtschi, Christian Hagel, David N Cooper, Victor-Felix Mautner
Schwannomatosis and neurofibromatosis type 2 (NF2) are both characterized by the development of multiple schwannomas but represent different genetic entities. Whereas NF2 is caused by mutations of the NF2 gene, schwannomatosis is associated with germline mutations of SMARCB1 or LZTR1. Here, we studied 15 sporadic patients with multiple non-intradermal schwannomas, but lacking vestibular schwannomas and ophthalmological abnormalities, who fulfilled the clinical diagnostic criteria for schwannomatosis. None of them harboured germline NF2 or SMARCB1 mutations as determined by the analysis of blood samples but seven had germline LZTR1 variants predicted to be pathogenic...
July 13, 2018: Human Genetics
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