Sinonasal undifferentiated carcinoma with intracranial extension.
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ABSTRACT:
SUBMITTER: Donald PJ
PROVIDER: S-EPMC3324213 | biostudies-other | 2006 May
REPOSITORIES: biostudies-other
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Project description:Sinonasal undifferentiated carcinoma (SNUC) is an aggressive malignancy harboring IDH2 R172 mutations in >80% cases. We explored the potential of genome-wide DNA methylation profiling to elucidate tumor biology and improve the diagnosis of sinonasal undifferentiated carcinoma and its histologic mimics. Forty-two cases, including sinonasal undifferentiated, large cell neuroendocrine, small cell neuroendocrine, and SMARCB1-deficient carcinomas and olfactory neuroblastoma, were profiled by Illumina Infinium Methylation EPIC array interrogating >850,000 CpG sites. The data were analyzed using a custom bioinformatics pipeline. IDH2 mutation status was determined by the targeted exome sequencing (MSK-IMPACTTM) in most cases. H3K27 methylation level was assessed by the immunohistochemistry-based H-score. DNA methylation-based semi-supervised hierarchical clustering analysis segregated IDH2 mutants, mostly sinonasal undifferentiated (n = 10) and large cell neuroendocrine carcinomas (n = 4), from other sinonasal tumors, and formed a single cluster irrespective of the histologic type. t-distributed stochastic neighbor embedding dimensionality reduction analysis showed no overlap between IDH2 mutants, SMARCB1-deficient carcinoma and olfactory neuroblastoma. IDH2 mutants demonstrated a global methylation phenotype and an increase in repressive trimethylation of H3K27 in comparison to IDH2 wild-type tumors (p < 0.001). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed no difference in pathway activation between IDH2-mutated sinonasal undifferentiated and large cell neuroendocrine carcinomas. In comparison to SMARCB1-deficient, IDH2-mutated carcinomas were associated with better disease-free survival (p = 0.034) and lower propensity for lung metastasis (p = 0.002). ARID1A mutations were common in small cell neuroendocrine carcinoma but not among IDH2 mutants (3/3 versus 0/18 and p < 0.001). IDH2 mutations in sinonasal carcinomas induce a hypermethylator phenotype and define a molecular subgroup of tumors arising in this location. IDH2-mutated sinonasal undifferentiated carcinoma and large cell neuroendocrine carcinoma likely represent a phenotypic spectrum of the same entity, which is distinct from small cell neuroendocrine and SMARCB1-deficient sinonasal carcinomas. DNA methylation-based analysis of the sinonasal tumors has potential to improve the diagnostic accuracy and classification of tumors arising in this location.
| S-EPMC7391258 | biostudies-literature
Project description:Introduction Malignant sinonasal tumors comprise less than 1% of all neoplasms. A wide variety of tumors occurring primarily in this site can present with an undifferentiated or poorly differentiated morphology. Among them are esthesioneuroblastomas, sinonasal undifferentiated carcinomas, and neuroendocrine carcinomas. Objectives We will discuss diagnostic strategies, recent advances in immunohistochemistry and molecular diagnosis, and treatment strategies. Data Synthesis These lesions are diagnostically challenging, and up to 30% of sinonasal malignancies referred to the University of Texas MD Anderson Cancer Center are given a different diagnosis on review of pathology. Correct classification is vital, as these tumors are significantly different in biological behavior and response to treatment. The past decade has witnessed advances in diagnosis and therapeutic modalities leading to improvements in survival. However, the optimal treatment for esthesioneuroblastoma, sinonasal undifferentiated carcinoma, and neuroendocrine carcinoma remain debated. We discuss advances in immunohistochemistry and molecular diagnosis, diagnostic strategies, and treatment selection. Conclusions There are significant differences in prognosis and treatment for esthesioneuroblastoma, neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma. Recent advances have the potential to improve oncologic outcomes but further investigation in needed.
| S-EPMC4399581 | biostudies-other
Project description:Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive cancer. Despite the use of multimodality treatment, the overall prognosis remains poor. To better understand the biologic features of SNUC and help develop new therapies for the disease, we established SNUC cell lines and characterized their biologic behaviors.Cell lines were established from a patient with a T4N0M0 SNUC of the right maxillary sinus who was treated with surgical resection at our center. Tumor colonies were harvested and were sequentially replated onto larger plates. Two populations were developed and labeled MDA8788-6 and MDA8788-7. These cell lines were characterized with molecular, biomarker, functional, and histologic analyses.Short tandem repeat genotyping revealed that the cell line is isogenic to the parental tumor, and cytogenetic analysis identified 12 chromosomal translocations. The SNUC cell lines do not form colonies in soft agar but are tumorigenic and nonmetastatic in an orthotopic mouse model of sinonasal cancer. Western blot analysis revealed that both MDA8788 cell lines express epithelial markers but do not express mesenchymal markers or the endocrine marker synaptophysin.This is the first report of the establishment of stable human-derived SNUC cell lines. The lines were highly tumorigenic and maintain the histologic and molecular features of the original tumor. These cell lines should serve as useful tools for the future study of SNUC biology and the development and testing of novel therapies for this deadly disease.
| S-EPMC3513379 | biostudies-literature
Project description:Objective To determine trends in sinonasal undifferentiated carcinoma (SNUC) survival patterns in the United States. Design Retrospective review of national database. Participants All cases of SNUC in the National Cancer Institute's Surveillance Epidemiology and End Results program from 1973 to 2010 were examined. Main Outcome Measures Age-adjusted incidence and survival rates were calculated and stratified by demographic information and treatment modality. Cohort analysis was performed to analyze survival patterns over time. Results A total of 318 SNUC cases were identified. Age-adjusted incidence rate (IR) was 0.02 per 100,000. Incidence was greater in males (IR: 0.03) than females (IR: 0.01; p = 0.03). Overall 5- and 10-year relative survival rate was 34.9% and 31.3%, respectively. Overall median survival was 22.1 months. Median survival following surgery combined with radiation was 41.9 months. Five-year relative survival rate following surgery, radiation, or surgery combined with radiation was 38.7%, 36.0%, and 39.1%, respectively. Median survival from 1973-1986 and 1987-2010 was 14.5 and 23.5 months, respectively. Conclusions This study provides new data regarding survival patterns of SNUC in the United States, confirming survival benefit with surgery and radiation as well as identifying a trend toward improved survival in recent decades.
| S-EPMC4375051 | biostudies-other
Project description:Sinonasal tumors consist of a group of rare heterogeneous malignancies, accounting for 3%-5% of all head and neck cancers. Although squamous cell carcinomas make up a significant portion of cancers arising in the sinonasal tract, there are a variety of aggressive tumor types that can present with a poorly differentiated morphology and continue to pose diagnostic challenges. Accurate classification of these unique malignancies has treatment implications for patients. Recent discoveries have allowed more detailed molecular characterization of subsets of these tumor types, and may lead to individualized treatments. INI-1 (SMARCB1)-deficient sinonasal carcinoma is a recently identified subtype of sinonasal malignancy, which is characterized by deletion of the INI-1 tumor suppressor gene. Loss of INI-1 expression has emerged as an important diagnostic feature in several human malignancies including a subset of sinonasal carcinomas. In this article, we present a case of INI-1 (SMARCB1)-deficient sinonasal carcinoma, provide an overview of recent advances in histological and molecular classification of sinonasal malignancies, and discuss challenges of caring for patients with these rare malignancies, as well as potential treatment implications. KEY POINTS: Clinicians and pathologists should recognize that a variety of sinonasal tumors can present with a poorly differentiated morphology that warrants further workup and molecular classification. Routine workup of poorly or undifferentiated sinonasal tumors should include testing for INI-1/SMARCB1, SMARCA4, and NUT. Patients with these molecularly defined subsets of tumors may benefit from clinical trials that seek to exploit these molecular alterations. The EZH2 inhibitor, tazemetostat, has demonstrated some antitumor activity in INI-1-deficient tumors, and is currently under investigation.
| S-EPMC7485347 | biostudies-literature
Project description:BackgroundSinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive cancer. Despite multimodal therapy, the prognosis in SNUC remains poor, and new therapies are needed. Thus, the purpose of this study was to explore potential therapeutic targets in SNUC.MethodsUsing the human-derived SNUC MDA8788-6 cell line, we performed whole genome single nucleotide polymorphism (SNP) analysis to identify copy number changes in this line. Protein expression levels were evaluated by Western blotting. Cell growth inhibition was assessed by methylthiazol tetrazolium (MTT) and clonogenic assays. The mouse flank model was used to examine the effect of growth inhibition in vivo.ResultsThe ERBB2 gene was highly amplified and cell extracts showed human epidermal growth factor receptor 2 (HER2) was overexpressed and phosphorylated in MDA8788-6. Lapatinib effectively inhibited the HER2 signaling pathway in our SNUC cell line. HER2 inhibition successfully suppressed the cell growth of MDA8788-6 cells both in vitro and in vivo.ConclusionTargeting HER2 may be a promising avenue for the development of novel therapies for SNUC. © 2016 Wiley Periodicals, Inc. Head Neck 38: E1926-E1934, 2016.
| S-EPMC6453572 | biostudies-literature
Project description:BackgroundSinonasal Undifferentiated Carcinoma (SNUC) is a rare and aggressive skull base tumor with poor survival and limited treatment options. To date, targeted sequencing studies have identified IDH2 and SMARCB1 as potential driver alterations, but the molecular alterations found in SMARCB1 wild type tumors are unknown.MethodsWe evaluated survival outcomes in a cohort of 46 SNUC patients treated at an NCI designated cancer center and identify clinical and disease variables associated with survival on Kaplan-Meier and Cox multivariate survival analysis. We performed exome sequencing to characterize a series of SNUC tumors (n = 5) and cell line (MDA8788-6) to identify high confidence mutations, copy number alterations, microsatellite instability, and fusions. Knockdown studies using siRNA were utilized for validation of a novel PGAP3-SRPK1 gene fusion.ResultsOverall survival analysis revealed no significant difference in outcomes between patients treated with surgery +/- CRT and CRT alone. Tobacco use was the only significant predictor of survival. We also confirmed previously published findings on IDH and SMARC family mutations and identified novel recurrent aberrations in the JAK/STAT and PI3K pathways. We also validated a novel PGAP3-SRPK1 gene fusion in the SNUC cell line, and show that knockdown of the fusion is negatively associated with EGFR, E2F and MYC signaling.ConclusionCollectively, these data demonstrate recurrent alterations in the SWI/SNF family as well as IDH, JAK/STAT, and PI3K pathways and discover a novel fusion gene (PGAP3-SRPK1). These data aim to improve understanding of possible driver mutations and guide future therapeutic strategies for this disease.
| S-EPMC8164750 | biostudies-literature
Project description:Sinonasal undifferentiated carcinoma (SNUC) is a high-grade malignancy with limited treatment options and poor outcome. A morphological spectrum of 47 sinonasal tumours including 17 (36.2%) SNUCs was analysed at genomic level. Thirty carcinomas (cohort 1) were subjected to a hybridization exon-capture next-generation sequencing assay (MSK-IMPACTTM ) to interrogate somatic variants in 279 or 410 cancer-related genes. Seventeen sinonasal tumours (cohort 2) were examined only for the presence of IDH1/2 exon 4 mutations by Sanger sequencing. IDH2 R172 single nucleotide variants were overall detected in 14 (82.4%) SNUCs, in two (20%) poorly-differentiated carcinomas with glandular/acinar differentiation, and in one of two high-grade neuroendocrine carcinomas, large cell type (HGNECs). No IDH2 mutation was detected in any of five olfactory neuroblastomas or in any of five SMARCB1-deficient carcinomas. Among 12 IDH2-mutated cases in cohort 1, five (41.7%) harboured co-existing TP53 mutations, four (33.3%) CDKN2A/2B loss-of-function alterations, four (33.3%) MYC amplification, and three (25%) had concurrent SETD2 mutations. AKT1 E17K and KIT D816V hotspot variants were each detected in one IDH2-mutated SNUC. The vast majority of SNUCs and variable proportions of other poorly-differentiated sinonasal carcinomas may be amenable to IDH2-targeted therapy. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
| S-EPMC5639875 | biostudies-literature
Project description:NUT midline carcinoma (NMC) is a fatal cancer that arises in various tissues along the upper midline of the body. The defining molecular feature of NMC is a chromosomal translocation that joins (in the majority of cases) the nuclear testis gene NUT (NUTM1) to the bromodomain protein family member 4 (BRD4) and thereby creating a fusion oncogene that disrupts cellular differentiation and drives the disease. In this study, we report the case of an adolescent NMC patient presenting with severe facial pain, proptosis and visual impairment due to a mass arising from the ethmoid sinus that invaded the right orbit and frontal lobe. Treatment involved radical resection, including exenteration of the affected eye with the view to consolidate treatment with radiation therapy; however, the patient experienced rapid tumor progression and passed away 79 days post resection. Molecular analysis of the tumor tissue identified a novel in-frame BRD4-NUT transcript, with BRD4 exon 15 fused to the last 124 nucleotides of NUT exon 2 (BRD4-NUT ex15:ex2Δnt1-585). The partial deletion of NUT exon 2 was attributed to a mid-exonic genomic breakpoint and the subsequent activation of a cryptic splice site further downstream within the exon. Inhibition of the canonical 3' acceptor splice site of NUT intron 1 in cell lines expressing the most common NMC fusion transcripts (PER-403, BRD4-NUT ex11:ex2; PER-624, BRD4-NUT ex15:ex2) induced alternative splicing from the same cryptic splice site as identified in the patient. Detection of low levels of an in-frame BRD4-NUT ex11:ex2Δnt1-585 transcript in PER-403 confirmed endogenous splicing from this alternative exon 2 splice site. Although further studies are necessary to assess the clinical relevance of the increasing number of variant fusions described in NMC, the findings presented in this case identify alternative splicing as a mechanism that contributes to this pathogenic complexity.
| S-EPMC4670959 | biostudies-literature
Project description:SMARCB1 (INI1)-deficient sinonasal carcinomas were first described in 2014, and this series of 17 cases represents the first imaging description. This tumor is part of a larger group of SMARCB1-deficient neoplasms, characterized by aggressive behavior and a rhabdoid cytopathologic appearance, that affect multiple anatomic sites. Clinical and imaging features overlap considerably with other aggressive sinonasal malignancies such as sinonasal undifferentiated carcinoma, which represents a common initial pathologic diagnosis in this entity. SMARCB1 (INI1)-deficient sinonasal tumors occurred most frequently in the nasoethmoidal region with invasion of the adjacent orbit and anterior cranial fossa. Avid contrast enhancement, intermediate to low T2 signal, and FDG avidity were frequent imaging features. Approximately half of the lesions demonstrated calcification, some with an unusual "hair on end" appearance, suggesting aggressive periosteal reaction.
| S-EPMC7960454 | biostudies-literature