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Christopher A. French - One of the best experts on this subject based on the ideXlab platform.
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pediatric NUT Midline Carcinoma therapeutic success employing a sarcoma based multimodal approach
Pediatric Hematology and Oncology, 2017Co-Authors: Simone Storck, Steven G Dubois, Bruno Märkl, Alyssa L Kennedy, Karen J Marcus, Lisa A Teot, Jennifer Vaughn, Astrid Gnekow, Ivo Leuschner, Christopher A. FrenchAbstract:A subset of poorly differentiated squamous cell Carcinomas, NUT Midline Carcinomas (NMC) are characterized by a translocation t(15;19)(q13;p13) [1]. The prognosis is generally dismal [2] and therap...
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NUT Midline Carcinoma of the larynx an international series and review of the literature
Histopathology, 2017Co-Authors: Henrik Hellquist, Christopher A. French, Justin A Bishop, Andres Cocapelaz, Evan J Propst, Antonio Paiva Correia, Boyee Ngan, Ronald Grant, Nicole A Cipriani, David VokesAbstract:Aims NUT Midline Carcinoma (NMC) is a rare undifferentiated and aggressive Carcinoma that locates characteristically to the Midline of the head and neck, and mediastinum. NMC is characterized by chromosomal rearrangements of the gene NUT, at 15q14. The BRD4 gene on 19q13 is the most common translocation partner forming a fusion oncogene, BRD4–NUT. By the end of 2014, the International NUT Midline Carcinoma Registry had 48 patients treated for NMC. Laryngeal NMC are exceedingly rare, and we report a case series of seven cases. Methods and results We searched for cases in files of different hospitals as well as a thorough search of the English language literature. The diagnosis of NMC is made by demonstration of NUT rearrangement either by immunohistochemistry, fluorescence in-situ hybridization (FISH) or reverse transcription–polymerase chain reaction (RT–PCR). We found three previously published cases, and in this series add four cases of our own. Conclusions NMC consists of monomorphic, often discohesive, cells with an epithelioid appearance and distinct nucleoli. The tumours typically show abrupt squamous differentiation. The mean age of the patients was 34 years, hence significantly lower than that for conventional laryngeal Carcinoma. All tumours were located in the supraglottis and five patients died of the disease after 3, 7, 8, 9 and 11 months. Laryngeal NMC may be underdiagnosed, and an increased awareness among pathologists is warranted. NMC has characteristic morphological features, and positive immunostaining with the NUT antibody is diagnostic. Its aggressive behaviour demands a very intense treatment strategy and the need for its recognition is emphasized further by new promising treatment strategies.
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NUT Midline Carcinoma: Case Report and Review of the Literature
2016Co-Authors: Min-shu Hsieh, Christopher A. French, Cher-wei Liang, Cheng-hsiang HsiaoAbstract:NUT Midline Carcinoma (NMC) is a recently described, undifferentiated Carcinoma with specific NUT gene rearrangement, which often involves Midline organs such as the nasal cavity, paranasal sinuses, mediastinum, or intrathoracic organs. It was previously considered a disease of children or young adults, but middle-aged or elderly patients have subsequently been seen. Here, the authors report the case of a 54-year-old woman who presented with a left-nasal-cavity mass and diplopia. The tumor enlarged rapidly and extended to the left orbital cavity and brain base despite chemotherapy and radiotherapy. Pathological examination of the resected tumor showed an undifferentiated Carcinoma with occasional abrupt keratinizing squamous differentiation. Immunohistochemical analysis with an antibody to NUT revealed that most of the tumor cells were positive. BRD4-NUT gene fusion was demonstrated by fluorescence in situ hybridization, confirming the diagnosis of NMC. This case emphasizes the importance of considering NMC in the differential diagnosis in older adults
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the oncoprotein brd4 NUT generates aberrant histone modification patterns
PLOS ONE, 2016Co-Authors: Christopher A. French, Artyom A Alekseyenko, Barry M Zee, Amy Dibona, Mitzi I KurodaAbstract:Defects in chromatin proteins frequently manifest in diseases. A striking case of a chromatin-centric disease is NUT-Midline Carcinoma (NMC), which is characterized by expression of NUT as a fusion partner most frequently with BRD4. ChIP-sequencing studies from NMC patients revealed that BRD4-NUT (B4N) covers large genomic regions and elevates transcription within these domains. To investigate how B4N modulates chromatin, we performed affinity purification of B4N when ectopically expressed in 293-TREx cells and quantified the associated histone posttranslational modifications (PTM) using proteomics. We observed significant enrichment of acetylation particularly on H3 K18 and of combinatorial patterns such as H3 K27 acetylation paired with K36 methylation. We postulate that B4N complexes override the preexisting histone code with new PTM patterns that reflect aberrant transcription and that epigenetically modulate the nucleosome environment toward the NMC state.
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NSD3–NUT Fusion Oncoprotein in NUT Midline Carcinoma: Implications for a Novel Oncogenic Mechanism
2016Co-Authors: Christopher A. French, Shaila Rahman, Erica M Walsh, Simone Kuhnle, Adlai R Grayson, Madeleine E Lemieux, Noam Grunfeld, Brian P Rubin, Cristina R Antonescu, Songlin ZhangAbstract:ABSTRACT NUT Midline Carcinoma (NMC) is an aggressive subtype of squamous cell Carcinoma that typically harbors BRD4/3–NUT fusion oncoproteins that block differentia-tion and maintain tumor growth. In 20 % of cases, NUT is fused to uncharacterized non- BRD gene(s). We established a new patient-derived NMC cell line (1221) and demonstrated that it harbors a novel NSD3–NUT fusion oncogene. We fi nd that NSD3–NUT is both necessary and suffi cient for the blockade of differentiation and maintenance of proliferation in NMC cells. NSD3–NUT binds to BRD4, and BRD bromodomain inhibitors induce differentiation and arrest proliferation of 1221 cells. We fi nd further that NSD3 is required for the blockade of differentiation in BRD4–NUT-expressing NMCs. These fi nd-ings identify NSD3 as a novel critical oncogenic component and potential therapeutic target in NMC. SIGNIFICANCE: The existence of a family of fusion oncogenes in squamous cell Carcinoma is unprec-edented, and should lead to key insights into aberrant differentiation in NMC and possibly other squa-mous cell Carcinomas. The involvement of the NSD3 methyltransferase as a component of the NUT fusion protein oncogenic complex identifi es a new potential therapeutic target. Cancer Discov; 4(8)
Tim Van Acker - One of the best experts on this subject based on the ideXlab platform.
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bromodomain protein brd4 is a transcriptional repressor of autophagy and lysosomal function
Molecular Cell, 2017Co-Authors: Junichi Sakamaki, Marcel Hahn, Nilgun Tasdemir, William Clark, Ann Hedley, Colin Nixon, Jaclyn S Long, Simon Wilkinson, Jim Oprey, Tim Van AckerAbstract:Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations. In the case of starvation, a signaling cascade involving AMPK and histone deacetylase SIRT1 displaces chromatin-bound BRD4, instigating autophagy gene activation and cell survival. Importantly, this program is directed independently and also reciprocally to the growth-promoting properties of BRD4 and is potently repressed by BRD4-NUT, a driver of NUT Midline Carcinoma. These findings therefore identify a distinct and selective mechanism of autophagy regulation.
Geoffrey I Shapiro - One of the best experts on this subject based on the ideXlab platform.
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an anatomical site and genetic based prognostic model for patients with nuclear protein in testis NUT Midline Carcinoma analysis of 124 patients
JNCI Cancer Spectrum, 2020Co-Authors: Nicole G Chau, Kristina Danga, Hasan Alsayegh, Valentina Nardi, Ryan Barrette, Christopher S Lathan, Steven G Dubois, Robert I Haddad, Geoffrey I ShapiroAbstract:Background NUT Midline Carcinoma, renamed NUT Carcinoma (NC), is an aggressive squamous cancer defined by rearrangement of the NUTM1 gene. Although a subset of patients can be cured, for the majority of patients the prognosis is grim. We sought to classify patients into risk groups based on molecular and clinicopathologic factors at the time of diagnosis. Methods Clinicopathologic variables and survival outcomes were extracted for a total of 141 NC patients from the NUT Midline Carcinoma Registry using questionnaires and medical records. Translocation type was identified by molecular analyses. Survival tree regression analysis was performed to determine risk factors associated with overall survival (OS). Results For 141 patients, the median age at diagnosis was 23.6 years. Fifty-one percent had thoracic origin compared with 49% nonthoracic sites (41% head and neck, 6% bone or soft tissue, 1% other). The median OS was 6.5 months (95% confidence interval [CI] = 5.8 to 9.1 months). Most patients had the BRD4-NUTM1 fusion (78%), followed by BRD3-NUTM1 (15%) and NSD3-NUTM1 (6%). Survival tree regression identified three statistically distinct risk groups among 124 patients classified by anatomical site and genetics: group A is nonthoracic primary, BRD3-, or NSD3-NUT (n = 12, median OS = 36.5 months, 95% CI = 12.5 to not reported months); group B is nonthoracic primary, BRD4-NUT (n = 45, median OS = 10 months, 95% CI = 7 to 14.6 months); and group C is thoracic primary (n = 67, median OS = 4.4 months, 95% CI = 3.5 to 5.6 months). Only groups A and B had long-term (≥3 years, n = 12) survivors. Conclusions We identify three risk groups defined by anatomic site and NUT fusion type. Nonthoracic primary with non-BRD4-NUT fusion confers the best prognosis, followed by nonthoracic primary with BRD4-NUT. Thoracic NC patients, regardless of the NUT fusion, have the worst survival.
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abstract a49 clinically efficacy of the bet bromodomain inhibitor ten 010 in an open label substudy with patients with documented NUT Midline Carcinoma nmc
Molecular Cancer Therapeutics, 2015Co-Authors: Geoffrey I Shapiro, James E. Bradner, Afshin Dowlati, Patricia Lorusso, Joseph Paul Eder, Adrienne Anderson, Michael Kagey, Cynthia A Sirard, Steven B LandauAbstract:Introduction: The chemical probe JQ-1 is a thienodiazepine BET-bromodomain inhibitor targeting BRD4 with previously reported efficacy in a patient-derived xenograft mouse model of NMC. TEN-010 is structurally related to JQ1 with superior chemical and biological properties currently under clinical study study solid tumors, including NMC, and hematologic malignancies. NMC is a squamous cell Carcinoma commonly observed in Midline structures in the lung and mediastinum, and commonly involves a t(15:19) chromosomal translocation encoding a chimeric BRD4-NUT fusion protein. This rare, with estimates of less than 100 people in the United States, disease is typically unresectable, poorly responsive to chemotherapies and clinically aggressive with median survival of ∼ 6 months establishing an unmet need for targeted therapy. Design: A Phase 1 dose escalation “3+3” multi-center study is being conducted in adults with advanced solid tumors. A separate sub-study enrolls patients with NMC at the highest tolerated dose level at the time of patient screening. The NMC patients received subcutaneous daily dosing of TEN-010 for three weeks in a four-week cycle. Patients must have documented NMC by FISH or IHC and cannot not be on chemotherapy at time of treatment. Patients are monitored for safety, pharmacokinetics and pharmacodynamics measured at initial dose and at steady-state, and assessment of anti-tumor activity assessed by RECIST 1.1. (CT) or PET/CT. Pharmacodynamics use a peripheral blood bioassay serially examining systemic integrin expression with TEN-010 dosing. Results: Data are available for the three NMC patients; 1 patient received TEN-010 at 0.1 mg/kg and 2 received 0.45 mg/kg. The 0.1 mg/kg patient had disease progression after 2 weeks. Both patients at the 0.45 mg/kg dose had clinical responses. One patient exhibited a 30% and 50% NMC tumor regression after cycles 1 and 2, respectively. This patient demonstrated rapid symptomatic improvement within two weeks, and remains on therapy into Cycle 3. The other patient exhibited a reduction of ∼50% summed SUV(max) by PET/CT with symptomatic improvement evident after three weeks of therapy during Cycle 1. This patient received two cycles of therapy before having disease progression. Plasma LDH in the 0.45 mg/kg patients, but not the 0.1 mg/kg patient, decreased after one week on treatment; the first 0.45 mg/kg pt had normal LDH through Cycle 2 with continued values in the normal range. On-target pharmacodynamic activity corroborated LDH response. This regimen has been tolerated with grade 1 irritation of the injection site and mild/moderate increases in indirect bilirubin and anorexia. All adverse events have been reversible. Discussion: This is the first documented partial response in NMC using a BET inhibitor. Reduced metabolic activity and clinical responses also are observed Overall the results serve as proof of concept and validate pre-clinical xenograft studies. Further testing and exploration of the optimal dosing regimen are on-going. The results support the promise for TEN-010 as an important new needed treatment for NMC. Citation Format: Geoffrey I. Shapiro, Afshin Dowlati, Patricia M. LoRusso, Joseph P. Eder, Adrienne Anderson, Khanh T. Do, Michael H. Kagey, Cynthia Sirard, James E. Bradner, Steven B. Landau. Clinically efficacy of the BET bromodomain inhibitor TEN-010 in an open-label substudy with patients with documented NUT-Midline Carcinoma (NMC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A49.
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NUT Midline Carcinoma an aggressive intrathoracic neoplasm
Journal of Thoracic Oncology, 2013Co-Authors: Sameer A Parikh, Christopher A. French, Brian A Costello, Randolph S Marks, Roxana S Dronca, Craig L Nerby, Anja C Roden, Vijay Gopal Reddy Peddareddigari, John Hilton, Geoffrey I ShapiroAbstract:Nuclear protein in testis (NUT) Midline Carcinoma (NMC) is a poorly differentiated squamous cell Carcinoma that is characterized by a balanced translocation between chromosomes 15 and 19 [t(15;19)(q14;p13.1)]. This genetic aberration results in the fusion of the NUT gene on chromosome 15 to the bromodomain containing 4 (BRD4) gene on chromosome 19. The resultant BRD4-NUT fusion oncogene leads to global hypoacetylation and transcriptional repression of genes required for differentiation." Although it was first reported in 1991 by Kubonishi et al., awareness of this condition remains low and the diagnosis is overlooked initially in a number of patients. A 36-year-old man complained of cough and right-sided chest pain for 3 weeks before presentation. Imaging studies revealed a right hilar mass, and a bronchoscopic biopsy was consistent with an aggressive poorly differentiated neoplasm. A combination of cisplatin, ifosfamide, and etoposide was administered for two cycles without any improvement. A repeat core biopsy showed focal squamous differentiation; and given the clinical presentation along with the histologic features, NMC was considered in the differential diagnosis. Immunohistochemical staining for NUT was positive, and dual-color break-apart fluorescence in situ hybridization demonstrated BRD4-NUT rearrangement, thereby confirming a diagnosis of NMC. Our patient was subsequently enrolled on a phase 1 clinical trial of a novel, orally bioavailable bromodomain and extra terminal inhibitor, GSK525762 (NCT01587703). This report illustrates the challenges in diagnosing this rare malignancy, and highlights new treatment options for these patients.
Ilan Weinreb - One of the best experts on this subject based on the ideXlab platform.
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ini1 smarcb1 deficient sinonasal Carcinoma a clinicopathologic report of 2 cases
Head and Neck Pathology, 2017Co-Authors: Jason K Wasserman, Brendan C Dickson, Bayardo Perezordonez, John R De Almeida, Jonathan C Irish, Ilan WeinrebAbstract:Poorly differentiated sinonasal malignancies are amongst the hardest differential diagnoses in pathology, owing to the large number of rare entities that arise there. Complicating the matter is that most pathologists, including those with experience in head and neck pathology, have little experience in any one of these rare entities. Most patients with sinonasal Carcinoma present with locally advanced disease and in the past a combination of chemotherapy, radiotherapy, and surgery would usually be recommended without the specific disease subtype playing a large part of the decision making. However, in the era of “precision medicine” and targeted therapies, the specific tumour subtype and an accurate diagnosis will become increasingly important even for the so-called “undifferentiated Carcinoma”. Specific entities that tend to enter into the differential diagnosis include olfactory neuroblastoma, sinonasal undifferentiated Carcinoma (SNUC), and non-keratinizing squamous cell Carcinoma (viral and non-viral). However, recent new entities, such as NUT-Midline Carcinoma also have to be considered. Recently it was found that a subset of tumours originally diagnosed as one of the aforementioned entities all demonstrated loss of the ubiquitously expressed protein Integrase Interactor 1 (INI1; SMARCB1). These tumours were often basaloid with at least partial rhabdoid differentiation and most were considered a part of the SNUC spectrum. In this report, we describe two additional cases of INI1-deficient sinonasal Carcinoma prospectively identified, both of which appeared to have a marked response to neo-adjuvant chemoradiation, a finding not previously described.
Abbas Agaimy - One of the best experts on this subject based on the ideXlab platform.
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YAP1-NUTM1 Gene Fusion in PoroCarcinoma of the External Auditory Canal
Head and Neck Pathology, 2020Co-Authors: Abbas Agaimy, Lars Tögel, Florian Haller, Johannes Zenk, Joachim Hornung, Bruno MärklAbstract:Gene fusions involving the NUTM1 gene ( NUT ) represent defining genetic markers of a highly aggressive Carcinoma type with predilection for the Midline structures of children and young adults, hence the original description as NUT Midline Carcinoma. Recent studies have increasingly documented involvement of the NUTM1 gene in the pathogenesis of other entities as well. We herein describe two cases of auditory canal Carcinomas with features of poroCarcinoma, both harboring a newly described YAP1-NUTM1 gene fusion. Patients were males aged 28 and 82 years who presented with slowly growing lesions in the external auditory canal. Histologic examination showed monomorphic basaloid and squamoid cells arranged into organoid solid aggregates, nests, ducts, small cysts, and focal pseudocribriform pattern with variable mitotic activity, infiltrative growth, and focal squamous differentiation, particularly in the most superficial part of the tumor. Immunohistochemistry revealed consistent reactivity for CK5, p63 and SOX10 and diffuse aberrant expression of TP53. CK7 expression was limited to a few luminal ductal cells. The androgen receptor and S100 were negative. Next generation sequencing (TruSight RNA fusion panel, Illumina) revealed the same YAP1-NUTM1 gene fusion in both tumors, which was subsequently confirmed by NUT-FISH and the monoclonal anti-NUT antibody. These cases represent a novel contribution to the spectrum of NUT-rearranged head and neck malignancies. This adnexal Carcinoma variant should not be confused with the highly lethal NUT Carcinoma based on NUT immunoreactivity alone.
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smarca4 deficient sinonasal Carcinoma
Head and Neck Pathology, 2017Co-Authors: Abbas Agaimy, Wilko WeichertAbstract:The term “sinonasal undifferentiated Carcinoma (SNUC)” has been coined in 1986 for a highly aggressive sinonasal tract epithelial neoplasm showing distinctive morphology, but lacking any specific line of differentiation. Recent developments resulted in a dynamic splitting of new entities traditionally included in the spectrum of SNUC. Sinonasal NUT-Midline Carcinoma, adamantinoma-like Ewing family tumors and most recently, SMARCB1(INI1)-deficient sinonasal Carcinoma are the main entities defined by specific genetic aberrations. To our knowledge, involvement of subunits of the SWItch/Sucrose Non-fermentable (SWI/SNF) chromatin remodeling complex other than SMARCB1 has not been implicated in the pathogenesis of SNUC-like neoplasms. We herein describe a 40-year-old woman who presented with a large infiltrative mass involving the right nasal cavity and the sinuses with extension into the skull base and periorbital tissue (cT4N2M0). Biopsies were interpreted initially as poorly differentiated neuroendocrine Carcinoma followed by surgical resection and radiochemotherapy. No other extra-nasal tumor was detected on imaging. The patient was alive with disease at last follow-up (9 months from initial diagnosis). Histological evaluation showed poorly differentiated small round blue cell neoplasm with diffuse expression of pancytokeratin but not high molecular weight cytokeratin subsets, CK7, p63, S100, desmin or NUT. Neuroendocrine markers showed limited focal weak reactivity. SMARCB1, SMARCA2 and ARID1A were intact in the tumor cells but SMARCA4 was completely lost. This case highlights the rare occurrence of SMARCA4-deficiency in poorly differentiated sinonasal Carcinomas and points to the importance of including other SWI/SNF complex subunits in the evaluation of SMARCB1-intact sinonasal malignancies.
