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A large-scale genomic analysis of patients with ASXL1-mutated myeloid disease has not been performed to date. We reviewed comprehensive genomic profiling results from 6043 adults to characterize clinicopathologic features and co-mutation patterns by ASXL1 mutation status. ASXL1 mutations occurred in 1414 patients (23%). Mutation co-occurrence testing revealed strong co-occurrence (p < 0.01) between mutations in ASXL1 and nine genes (SRSF2, U2AF1, RUNX1, SETBP1, EZH2, STAG2, CUX1, CSF3R, CBL). Further analysis of patients with these co-mutations yielded several novel findings. Co-mutation patterns supported that ASXL1/SF3B1 co-mutation may be biologically distinct from ASXL1/non-SF3B1 spliceosome co-mutation. In AML, ASXL1/SRSF2 co-mutated patients frequently harbored STAG2 mutations (42%), which were dependent on the presence of both ASXL1 and SRSF2 mutation (p < 0.05). STAG2 and SETBP1 mutations were also exclusive in ASXL1/SRSF2 co-mutated patients and associated with divergent chronic myeloid phenotypes. Our findings support that certain multi-mutant genotypes may be biologically relevant in ASXL1-mutated myeloid disease.
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Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Neoplasias , Adulto , Humanos , Transtornos Mieloproliferativos/genética , Spliceossomos/genética , Spliceossomos/patologia , Fatores de Transcrição/genética , Genômica , Mutação , Leucemia Mieloide Aguda/genética , Prognóstico , Proteínas Repressoras/genéticaRESUMO
The authors present a cohort of 661 young adult glioblastomas diagnosed using 2016 WHO World Health Organization Classification of Tumors of the Central Nervous System, utilizing comprehensive genomic profiling (CGP) to explore their genomic landscape and assess their relationship to currently defined disease entities. This analysis explored variants with evidence of pathogenic function, common copy number variants (CNVs), and several novel fusion events not described in literature. Tumor mutational burden (TMB) mutational signatures, anatomic location, and tumor recurrence are further explored. Using data collected from CGP, unsupervised machine-learning techniques were leveraged to identify 10 genomic classes in previously assigned young adult glioblastomas. The authors relate these molecular classes to current World Health Organization guidelines and reference current literature to give therapeutic and prognostic descriptions where possible.
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Neoplasias do Sistema Nervoso Central , Glioblastoma , Humanos , Adulto Jovem , Glioblastoma/diagnóstico , Glioblastoma/genética , Estudos Retrospectivos , Mutação , Recidiva Local de Neoplasia , Genômica/métodosRESUMO
PURPOSE: Anaplastic lymphoma kinase (ALK) aberrations have been identified in pediatric-type infant gliomas, but their occurrence across age groups, functional effects, and treatment response has not been broadly established. EXPERIMENTAL DESIGN: We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric, and 10 congenital) with in vitro and in vivo validation of aberrations. RESULTS: ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years). Recurrent as well as novel ALK fusions (LRRFIP1-ALK, DCTN1-ALK, PRKD3-ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo. ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to the treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages, and no gross effects on perinatal brain development were seen in pregnant mice treated with the ALK inhibitor ceritinib. CONCLUSIONS: These findings support use of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs. See related commentary by Mack and Bertrand, p. 2567.
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Glioblastoma , Glioma , Camundongos , Animais , Quinase do Linfoma Anaplásico/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Estudos Retrospectivos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Glioma/tratamento farmacológicoRESUMO
In the last decade, next-generation sequencing (NGS) has rapidly progressed from a research method to a core component of standard-of-care clinical testing. In oncology, tumor sequencing provides a critical tool to detect somatic driver mutations that not only characterize disease but also impact therapeutic decision-making. Here, we review the important role of NGS in the evaluation of hematopoietic neoplasms. We discusstechnical and practical considerations relevant in somatic mutation testing, emphasizing issues unique to blood cancers. Then, we describe how NGS data is being used to facilitate diagnosis, inform prognosis, guide therapy selection, and even monitor disease. This broad overview highlights the transformative impacts NGS data provides throughout the clinical course of patients with hematologic malignancies.
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Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Neoplasias Hematológicas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Mutação , Medicina de Precisão/métodos , Prognóstico , Medição de Risco/métodosRESUMO
Despite advances in systemic therapies for solid tumors, the development of brain metastases remains a significant contributor to overall cancer mortality and requires improved methods for diagnosing and treating these lesions. Similarly, the prognosis for malignant primary brain tumors remains poor with little improvement in overall survival over the last several decades. In both primary and metastatic central nervous system (CNS) tumors, the challenge from a clinical perspective centers on detecting CNS dissemination early and understanding how CNS lesions differ from the primary tumor, in order to determine potential treatment strategies. Acquiring tissue from CNS tumors has historically been accomplished through invasive neurosurgical procedures, which restricts the number of patients to those who can safely undergo a surgical procedure, and for which such interventions will add meaningful value to the care of the patient. In this review we discuss the potential of analyzing cell free DNA shed from tumor cells that is contained within the cerebrospinal fluid (CSF) as a sensitive and minimally invasive method to detect and characterize primary and metastatic tumors in the CNS.
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Newborn screening (NBS) was established as a public health program in the 1960s and is crucial for facilitating detection of certain medical conditions in which early intervention can prevent serious, life-threatening health problems. Genomic sequencing can potentially expand the screening for rare hereditary disorders, but many questions surround its possible use for this purpose. We examined the use of exome sequencing (ES) for NBS in the North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project, comparing the yield from ES used in a screening versus a diagnostic context. We enrolled healthy newborns and children with metabolic diseases or hearing loss (106 participants total). ES confirmed the participant's underlying diagnosis in 15 out of 17 (88%) children with metabolic disorders and in 5 out of 28 (â¼18%) children with hearing loss. We discovered actionable findings in four participants that would not have been detected by standard NBS. A subset of parents was eligible to receive additional information for their child about childhood-onset conditions with low or no clinical actionability, clinically actionable adult-onset conditions, and carrier status for autosomal-recessive conditions. We found pathogenic variants associated with hereditary breast and/or ovarian cancer in two children, a likely pathogenic variant in the gene associated with Lowe syndrome in one child, and an average of 1.8 reportable variants per child for carrier results. These results highlight the benefits and limitations of using genomic sequencing for NBS and the challenges of using such technology in future precision medicine approaches.
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Neoplasias da Mama/diagnóstico , Testes Genéticos/estatística & dados numéricos , Perda Auditiva/diagnóstico , Doenças Metabólicas/diagnóstico , Síndrome Oculocerebrorrenal/diagnóstico , Neoplasias Ovarianas/diagnóstico , Neoplasias da Mama/genética , Pré-Escolar , Feminino , Genoma Humano , Perda Auditiva/genética , Heterozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Metabólicas/genética , Triagem Neonatal , North Carolina , Síndrome Oculocerebrorrenal/genética , Neoplasias Ovarianas/genética , Saúde Pública/métodos , Sequenciamento do ExomaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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PURPOSE: We investigated the diagnostic and clinical performance of trio exome sequencing (ES) in parent-fetus trios where the fetus had sonographic abnormalities but normal karyotype, microarray and, in some cases, normal gene-specific sequencing. METHODS: ES was performed from DNA of 102 anomalous fetuses and from peripheral blood from their parents. Parents provided consent for the return of diagnostic results in the fetus, medically actionable findings in the parents, and identification as carrier couple for significant autosomal recessive conditions. RESULTS: In 21/102 (20.6%) fetuses, ES provided a positive-definitive or positive-probable diagnosis. In 10/102 (9.8%), ES provided an inconclusive-possible result. At least 2/102 (2.0%) had a repeat pregnancy during the study period and used the information from the study for prenatal diagnosis in the next pregnancy. Six of 204 (2.9%) parents received medically actionable results that affected their own health and 3/102 (2.9%) of couples received results that they were carriers for the same autosomal recessive condition. CONCLUSION: ES has diagnostic utility in a select population of fetuses where a genetic diagnosis was highly suspected. Challenges related to genetics literacy, variant interpretation, and various types of diagnostic results affecting both fetal and parental health must be addressed by highly tailored pre- and post-test genetic counseling.
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Exoma , Ultrassonografia Pré-Natal , Exoma/genética , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Diagnóstico Pré-Natal , Sequenciamento do ExomaRESUMO
Pediatric Low Grade Gliomas (PLGGs) display heterogeneity regarding morphology, genomic drivers and clinical outcomes. The treatment modality dictates the outcome and optimizing patient management can be challenging. In this study, we profiled a targeted panel of cancer-related genes in 37 Saudi Arabian patients with pLGGs to identify genetic abnormalities that can inform prognostic and therapeutic decision-making. We detected genetic alterations (GAs) in 97% (36/37) of cases, averaging 2.51 single nucleotide variations (SNVs) and 0.91 gene fusions per patient. The KIAA1549-BRAF fusion was the most common alteration (21/37 patients) followed by AFAP1-NTRK2 (2/37) and TBLXR-PI3KCA (2/37) fusions that were observed at much lower frequencies. The most frequently mutated) genes were NOTCH1-3 (7/37), ATM (4/37), RAD51C (3/37), RNF43 (3/37), SLX4 (3/37) and NF1 (3/37). Interestingly, we identified a GOPC-ROS1 fusion in an 8-year-old patient whose tumor lacked BRAF alterations and histologically classified as low grade glioma. The patient underwent gross total resection (GTR). The patient is currently disease free. To our knowledge this is the first report of GOPC-ROS1 fusion in PLGG. Taken together, we reveal the genetic characteristics of pLGG patients can enhance diagnostics and therapeutic decisions. In addition, we identified a GOPC-ROS1 fusion that may be a biomarker for pLGG.
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Neoplasias Encefálicas/genética , Fusão Gênica , Genômica/métodos , Glioma/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Encefálicas/cirurgia , Criança , Pré-Escolar , Tomada de Decisão Clínica , Feminino , Glioma/cirurgia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Arábia Saudita , Resultado do TratamentoRESUMO
PIK3CA is the most frequently mutated gene in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Prognostic implications of such mutations remain unknown. We sought to elucidate the clinical significance of PIK3CA mutations in HPV-associated OPSCC patients treated with definitive chemoradiation (CRT). Seventy-seven patients with HPV-associated OPSCC were enrolled on two phase II clinical trials of deintensified CRT (60 Gy intensity-modulated radiotherapy with concurrent weekly cisplatin). Targeted next-generation sequencing was performed. Of the 77 patients, nine had disease recurrence (two regional, four distant, three regional and distant). Thirty-four patients had mutation(s) identified; 16 had PIK3CA mutations. Patients with wild-type-PIK3CA had statistically significantly higher 3-year disease-free survival than PIK3CA-mutant patients (93.4%, 95% confidence interval [CI] = 85.0% to 99.9% vs 68.8%, 95% CI = 26.7% to 89.8%; P = .004). On multivariate analysis, PIK3CA mutation was the only variable statistically significantly associated with disease recurrence (hazard ratio = 5.71, 95% CI = 1.53 to 21.3; P = .01). PIK3CA mutation is associated with worse disease-free survival in a prospective cohort of newly diagnosed HPV-associated OPSCC patients treated with deintensified CRT.
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Alphapapillomavirus/fisiologia , Carcinoma de Células Escamosas , Quimiorradioterapia/métodos , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Orofaríngeas , Adulto , Idoso , Idoso de 80 Anos ou mais , Alphapapillomavirus/patogenicidade , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/virologia , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Estudos de Coortes , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/virologia , Prognóstico , Estudos Prospectivos , Dosagem Radioterapêutica , Resultado do TratamentoRESUMO
OPINION STATEMENT: In recent years, large-scale genomic studies have expanded our knowledge regarding genomic drivers in tumors of the central nervous system. While histopathologic analysis of brain tumors remains the primary method for tumor classification, the clinical utility of molecular and genomic testing to support and/or complement tumor classification continues to expand. This approach enhances diagnostic accuracy and provides clinicians with objective data to facilitate discussions regarding prognosis and treatment decisions, including selection of clinical trials. Ensuring accurate diagnoses is fundamental to the management of brain tumor patients. However, given the morphologic overlap among primary brain tumors, genomic data can be used to help distinguish tumor lineage. In its clearest form, we have embraced the concept of an integrated diagnosis, which combines traditional histopathology findings with molecular and genomic data. Patient prognosis varies significantly based on a tumor's genomic profile. For neuro-oncology patients, outcome studies linking diagnoses with genomic profiles show significant differences based on tumor biomarkers such as IDH1/2, H3F3A, BRAF, and CDKN2A and TERT status. Therefore, easy access to reliable genomic data is important in understanding a patient's disease and developing a clinical strategy wherein targeted molecular or immune therapies can be incorporated into the discussion.
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Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Glioma/diagnóstico , Glioma/terapia , Medicina de Precisão , Fatores Etários , Biomarcadores Tumorais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Ensaios Clínicos como Assunto , Terapia Combinada , Gerenciamento Clínico , Predisposição Genética para Doença , Testes Genéticos , Genômica/métodos , Glioma/genética , Glioma/mortalidade , Humanos , Imunoterapia , Terapia de Alvo Molecular , Gradação de Tumores , Estadiamento de Neoplasias , Medicina de Precisão/métodos , Prognóstico , Resultado do TratamentoRESUMO
Purpose: Isocitrate dehydrogenase (IDH) mutations in glioma patients confer longer survival and may guide treatment decision making. We aimed to predict the IDH status of gliomas from MR imaging by applying a residual convolutional neural network to preoperative radiographic data.Experimental Design: Preoperative imaging was acquired for 201 patients from the Hospital of University of Pennsylvania (HUP), 157 patients from Brigham and Women's Hospital (BWH), and 138 patients from The Cancer Imaging Archive (TCIA) and divided into training, validation, and testing sets. We trained a residual convolutional neural network for each MR sequence (FLAIR, T2, T1 precontrast, and T1 postcontrast) and built a predictive model from the outputs. To increase the size of the training set and prevent overfitting, we augmented the training set images by introducing random rotations, translations, flips, shearing, and zooming.Results: With our neural network model, we achieved IDH prediction accuracies of 82.8% (AUC = 0.90), 83.0% (AUC = 0.93), and 85.7% (AUC = 0.94) within training, validation, and testing sets, respectively. When age at diagnosis was incorporated into the model, the training, validation, and testing accuracies increased to 87.3% (AUC = 0.93), 87.6% (AUC = 0.95), and 89.1% (AUC = 0.95), respectively.Conclusions: We developed a deep learning technique to noninvasively predict IDH genotype in grade II-IV glioma using conventional MR imaging using a multi-institutional data set. Clin Cancer Res; 24(5); 1073-81. ©2017 AACR.
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Neoplasias Encefálicas/diagnóstico por imagem , Glioma/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Isocitrato Desidrogenase/genética , Redes Neurais de Computação , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/cirurgia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/cirurgia , Conjuntos de Dados como Assunto , Feminino , Glioma/genética , Glioma/mortalidade , Glioma/cirurgia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Valor Preditivo dos Testes , Período Pré-Operatório , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Clinical genomics platforms are needed to identify targetable alterations, but implementation of these technologies and best practices in routine clinical pediatric oncology practice are not yet well established. METHODS: Profile is an institution-wide prospective clinical research initiative that uses targeted sequencing to identify targetable alterations in tumors. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer-causing genes, was used to assess single nucleotide variants and rearrangements/indels. Alterations were annotated (Tiers 1-4) based on clinical significance, with Tier 1 alterations having well-established clinical utility. OncoCopy, a clinical genome-wide array comparative genomic hybridization (aCGH) assay, was also performed to evaluate copy number alterations and better define rearrangement breakpoints. RESULTS: Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes, including 117 samples analyzed by OncoPanel, 146 by OncoCopy, and 60 tumors subjected to both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. Rearrangements in MYB-QKI, MYBL1, BRAF, and FGFR1 were also detected. Furthermore, while copy number profiles differed across histologies, the combined use of OncoPanel and OncoCopy identified subgroup-specific alterations in 89% (17/19) of medulloblastomas. CONCLUSION: The combination of OncoPanel and OncoCopy multiplex genomic assays can identify critical diagnostic, prognostic, and treatment-relevant alterations and represents an effective precision medicine approach for clinical evaluation of pediatric brain tumors.
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Neoplasias Encefálicas/genética , Variações do Número de Cópias de DNA , Exoma , Genômica/métodos , Medicina de Precisão/métodos , Neoplasias Encefálicas/diagnóstico , Criança , Hibridização Genômica Comparativa , Dosagem de Genes , Humanos , Mutação , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
Background: Activating mutations or structural rearrangements in BRAF are identified in roughly 75% of all pediatric low-grade astrocytomas (PLGAs). However, first-generation RAF inhibitors approved for adult melanoma have poor blood-brain penetrance and are only effective on tumors that express the canonical BRAFV600E oncoprotein, which functions as a monomer. These drugs (type I antagonists that target the "DFG-in" conformation of the kinase) fail to block signaling via KIAA1549:BRAF, a truncation/fusion BRAF oncoprotein which functions as a dimer and is found in the most common form of PLGA. Methods: A panel of small molecule RAF inhibitors (including type II inhibitors, targeting the "DFG-out" conformation of the kinase) was screened for drugs showing efficacy on murine models of PLGA and on authentic human PLGA cells expressing KIAA1549:BRAF. Results: We identify a type II RAF inhibitor that serves as an equipotent antagonist of BRAFV600E, KIAA1549:BRAF, and other noncanonical BRAF oncoproteins that function as dimers. This drug (MLN2480, also known as TAK-580) has good brain penetrance and is active on authentic human PLGA cells in brain organotypic cultures. Conclusion: MLN2480 may be an effective therapeutic for BRAF mutant pediatric astrocytomas.
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Astrocitoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacologia , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Multimerização Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Quinases raf/antagonistas & inibidores , Animais , Astrocitoma/metabolismo , Astrocitoma/patologia , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Compostos Heterocíclicos com 3 Anéis/química , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases raf/genética , Quinases raf/metabolismoRESUMO
Although p53 protein aggregates have been observed in cancer cell lines and tumour tissue, their impact in cancer remains largely unknown. Here, we extensively screened for p53 aggregation phenotypes in tumour biopsies, and identified nuclear inclusion bodies (nIBs) of transcriptionally inactive mutant or wild-type p53 as the most frequent aggregation-like phenotype across six different cancer types. p53-positive nIBs co-stained with nuclear aggregation markers, and shared molecular hallmarks of nIBs commonly found in neurodegenerative disorders. In cell culture, tumour-associated stress was a strong inducer of p53 aggregation and nIB formation. This was most prominent for mutant p53, but could also be observed in wild-type p53 cell lines, for which nIB formation correlated with the loss of p53's transcriptional activity. Importantly, protein aggregation also fuelled the dysregulation of the proteostasis network in the tumour cell by inducing a hyperactivated, oncogenic heat-shock response, to which tumours are commonly addicted, and by overloading the proteasomal degradation system, an observation that was most pronounced for structurally destabilized mutant p53. Patients showing tumours with p53-positive nIBs suffered from a poor clinical outcome, similar to those with loss of p53 expression, and tumour biopsies showed a differential proteostatic expression profile associated with p53-positive nIBs. p53-positive nIBs therefore highlight a malignant state of the tumour that results from the interplay between (1) the functional inactivation of p53 through mutation and/or aggregation, and (2) microenvironmental stress, a combination that catalyses proteostatic dysregulation. This study highlights several unexpected clinical, biological and therapeutically unexplored parallels between cancer and neurodegeneration. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Neoplasias do Colo/genética , Glioblastoma/genética , Corpos de Inclusão Intranuclear/metabolismo , Agregação Patológica de Proteínas/genética , Deficiências na Proteostase/genética , Proteína Supressora de Tumor p53/genética , Biópsia , Linhagem Celular Tumoral , Neoplasias do Colo/complicações , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Citoplasma/metabolismo , Glioblastoma/complicações , Glioblastoma/metabolismo , Glioblastoma/patologia , Resposta ao Choque Térmico/genética , Resposta ao Choque Térmico/fisiologia , Humanos , Estimativa de Kaplan-Meier , Mutação , Agregação Patológica de Proteínas/etiologia , Agregação Patológica de Proteínas/metabolismo , Deficiências na Proteostase/etiologia , Deficiências na Proteostase/metabolismo , Receptores sigma/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.
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Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Everolimo/farmacologia , Morfolinas/farmacologia , Complexos Multiproteicos/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Proteínas de Ciclo Celular , Reparo do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Quimioterapia Combinada , Fatores de Iniciação em Eucariotos , Feminino , Perfilação da Expressão Gênica , Instabilidade Genômica , Humanos , Imuno-Histoquímica , Antígeno Ki-67/efeitos dos fármacos , Antígeno Ki-67/metabolismo , Imageamento por Ressonância Magnética , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos SCID , Terapia de Alvo Molecular , Transplante de Neoplasias , Fosfoproteínas/efeitos dos fármacos , Fosfoproteínas/metabolismo , Fosforilação , Receptor ErbB-2/metabolismo , Indução de Remissão , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Pituitary spindle cell oncocytoma (SCO) is an uncommon primary pituitary neoplasm that presents with mass effect on adjacent neurovascular structures, similar to non-hormone-producing pituitary adenomas. To determine the molecular etiology of SCO, we performed exome sequencing on four SCO cases, with matched normal controls, to assess somatic mutations and copy number alterations. Our analysis revealed a low mutation rate and a copy-neutral profile, consistent with the low-grade nature of this tumor. However, we identified a co-occurring somatic HRAS (p.Q61R) activating point mutation and MEN1 frameshift mutation (p.L117fs) present in a primary and recurrent tumor from one patient. Other SCOs demonstrated mutations in SND1 and FAT1, which are associated with MAPK pathway activation. Immunohistochemistry across the SCO cohort demonstrated robust MAPK activity in all cases (n=4), as evidenced by strong phospho-ERK staining, while phospho-AKT levels suggested only basal levels of PI3K pathway activation. Taken together, this identifies the MAPK signaling pathway as a novel therapeutic target for spindle cell oncocytoma, which may offer a powerful adjunct for aggressive tumors refractory to surgical resection.
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Adenoma Oxífilo/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Neoplasias Hipofisárias/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenoma Oxífilo/metabolismo , Idoso , Análise Mutacional de DNA , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Hipofisárias/metabolismoRESUMO
Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.