ABSTRACT
We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.
Subject(s)
Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Aged , Cluster Analysis , DNA Methylation , Humans , MicroRNAs/genetics , Middle Aged , Muscle, Smooth/pathology , RNA, Long Noncoding/genetics , Survival Analysis , Urinary Bladder/pathology , Urinary Bladder Neoplasms/epidemiology , Urinary Bladder Neoplasms/therapyABSTRACT
Ependymal tumors are the third most common brain tumor under 14 years old. Even though metastatic disease is a rare event, it affects mostly young children and carries an adverse prognosis. The factors associated with dissemination and the best treatment approach have not yet been established and there is limited published data on how to manage metastatic disease, especially in patients under 3 years of age. We provide a review of the literature on clinical characteristics and radiation-sparing treatments for metastatic ependymoma in children under 3 years of age treated. The majority (73%) of the identified cases were above 12 months old and had the PF as the primary site at diagnosis. Chemotherapy-based approaches, in different regimens, were used with radiation reserved for progression or relapse. The prognosis varied among the studies, with an average of 50%-58% overall survival. This study also describes the case of a 7-month-old boy with metastatic posterior fossa (PF) ependymoma, for whom we identified a novel SPECC1L-RAF1 gene fusion using a patient-centric comprehensive molecular profiling protocol. The patient was successfully treated with intensive induction chemotherapy followed by high-dose chemotherapy and autologous hematopoietic progenitor cell rescue (AuHSCR). Currently, the patient is in continuous remission 5 years after his diagnosis, without radiation therapy. The understanding of the available therapeutic approaches may assist physicians in their management of such patients. This report also opens the perspective of newly identified molecular alterations in metastatic ependymomas that might drive more chemo-sensitive tumors.
Subject(s)
Brain Neoplasms , Ependymoma , Hematopoietic Stem Cell Transplantation , Child , Male , Humans , Child, Preschool , Infant , Adolescent , Neoplasm Recurrence, Local , Ependymoma/drug therapy , Ependymoma/genetics , Ependymoma/radiotherapy , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/diagnosisABSTRACT
OBJECTIVE: Epilepsy-associated developmental lesions, including malformations of cortical development and low-grade developmental tumors, represent a major cause of drug-resistant seizures requiring surgical intervention in children. Brain-restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified. METHODS: We enrolled 50 children who were undergoing epilepsy surgery into a translational research study. Resected tissue was divided for clinical neuropathologic evaluation and genomic analysis. We performed exome and RNA sequencing to identify somatic variation and we confirmed our findings using high-depth targeted DNA sequencing. RESULTS: We uncovered candidate disease-causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). In agreement with previous studies, we identified somatic variation affecting solute carrier family 35 member A2 (SLC35A2) and mechanistic target of rapamycin kinase (MTOR) pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) of patients with Type I focal cortical dysplasia (FCD)s. Somatic variation in mitogen-activated protein kinase (MAPK) pathway genes (i.e., fibroblast growth factor receptor 1 [FGFR1], FGFR2, B-raf proto-oncogene, serine/threonine kinase [BRAF], and KRAS proto-oncogene, GTPase [KRAS]) was associated with low-grade epilepsy-associated developmental tumors. RNA sequencing enabled the detection of somatic structural variation that would have otherwise been missed, and which accounted for more than one-half of epilepsy-associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease-causing variants in genes not yet associated with focal cortical dysplasia. SIGNIFICANCE: These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes.
Subject(s)
Epilepsy , Malformations of Cortical Development , Brain/pathology , Child , Epilepsy/pathology , Humans , Malformations of Cortical Development/complications , Malformations of Cortical Development/genetics , Malformations of Cortical Development/metabolism , Mutation , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolismABSTRACT
Phosphatase and tensin homologue (PTEN) regulates cell growth and survival through inhibition of the mammalian target of rapamycin (MTOR) signalling pathway. Germline genetic variation of PTEN is associated with autism, macrocephaly and PTEN hamartoma tumour syndromes. The effect of developmental PTEN somatic mutations on nervous system phenotypes is not well understood, although brain somatic mosaicism of MTOR pathway genes is an emerging cause of cortical dysplasia and epilepsy in the paediatric population. Here we report two somatic variants of PTEN affecting a single patient presenting with intractable epilepsy and hemimegalencephaly that varied in clinical severity throughout the left cerebral hemisphere. High-throughput sequencing analysis of affected brain tissue identified two somatic variants in PTEN. The first variant was present in multiple cell lineages throughout the entire hemisphere and associated with mild cerebral overgrowth. The second variant was restricted to posterior brain regions and affected the opposite PTEN allele, resulting in a segmental region of more severe malformation, and the only neurons in which it was found by single-nuclei RNA-sequencing had a unique disease-related expression profile. This study reveals brain mosaicism of PTEN as a disease mechanism of hemimegalencephaly and furthermore demonstrates the varying effects of single- or bi-allelic disruption of PTEN on cortical phenotypes.
Subject(s)
Cerebral Cortex/diagnostic imaging , Genetic Variation/genetics , Hemimegalencephaly/diagnostic imaging , Hemimegalencephaly/genetics , Mutation/genetics , PTEN Phosphohydrolase/genetics , Cerebral Cortex/surgery , Hemimegalencephaly/surgery , Humans , Infant , MaleABSTRACT
Gastroblastomas are rare tumors with a biphasic epithelioid/spindle cell morphology that typically present in early adulthood and have recurrent MALAT1-GLI1 fusions. We describe an adolescent patient with Wiskott-Aldrich syndrome who presented with a large submucosal gastric tumor with biphasic morphology. Despite histologic features consistent with gastroblastoma, a MALAT1-GLI1 fusion was not found in this patient's tumor; instead, comprehensive molecular profiling identified a novel EWSR1-CTBP1 fusion and no other significant genetic alterations. The tumor also overexpressed NOTCH and FGFR by RNA profiling. The novel fusion and expression profile suggest a role for epithelial-mesenchymal transition in this tumor, with potential implications for the pathogenesis of biphasic gastric tumors such as gastroblastoma.
Subject(s)
Alcohol Oxidoreductases/genetics , Carcinoma/genetics , DNA-Binding Proteins/genetics , Oncogene Proteins, Fusion/genetics , RNA-Binding Protein EWS/genetics , Stomach Neoplasms/genetics , Adolescent , Age of Onset , Carcinoma/pathology , Humans , Male , Stomach Neoplasms/pathologyABSTRACT
BACKGROUND: Pediatric cancers typically have a distinct genomic landscape when compared to adult cancers and frequently carry somatic gene fusion events that alter gene expression and drive tumorigenesis. Sensitive and specific detection of gene fusions through the analysis of next-generation-based RNA sequencing (RNA-Seq) data is computationally challenging and may be confounded by low tumor cellularity or underlying genomic complexity. Furthermore, numerous computational tools are available to identify fusions from supporting RNA-Seq reads, yet each algorithm demonstrates unique variability in sensitivity and precision, and no clearly superior approach currently exists. To overcome these challenges, we have developed an ensemble fusion calling approach to increase the accuracy of identifying fusions. RESULTS: Our Ensemble Fusion (EnFusion) approach utilizes seven fusion calling algorithms: Arriba, CICERO, FusionMap, FusionCatcher, JAFFA, MapSplice, and STAR-Fusion, which are packaged as a fully automated pipeline using Docker and Amazon Web Services (AWS) serverless technology. This method uses paired end RNA-Seq sequence reads as input, and the output from each algorithm is examined to identify fusions detected by a consensus of at least three algorithms. These consensus fusion results are filtered by comparison to an internal database to remove likely artifactual fusions occurring at high frequencies in our internal cohort, while a "known fusion list" prevents failure to report known pathogenic events. We have employed the EnFusion pipeline on RNA-Seq data from 229 patients with pediatric cancer or blood disorders studied under an IRB-approved protocol. The samples consist of 138 central nervous system tumors, 73 solid tumors, and 18 hematologic malignancies or disorders. The combination of an ensemble fusion-calling pipeline and a knowledge-based filtering strategy identified 67 clinically relevant fusions among our cohort (diagnostic yield of 29.3%), including RBPMS-MET, BCAN-NTRK1, and TRIM22-BRAF fusions. Following clinical confirmation and reporting in the patient's medical record, both known and novel fusions provided medically meaningful information. CONCLUSIONS: The EnFusion pipeline offers a streamlined approach to discover fusions in cancer, at higher levels of sensitivity and accuracy than single algorithm methods. Furthermore, this method accurately identifies driver fusions in pediatric cancer, providing clinical impact by contributing evidence to diagnosis and, when appropriate, indicating targeted therapies.
Subject(s)
Genome , Neoplasms , Child , Genomics , Humans , Neoplasms/genetics , Sequence Analysis, DNA , Sequence Analysis, RNAABSTRACT
The AURORA US Metastasis Project was established with the goal to identify molecular features associated with metastasis. We assayed 55 females with metastatic breast cancer (51 primary cancers and 102 metastases) by RNA sequencing, tumor/germline DNA exome and low-pass whole-genome sequencing and global DNA methylation microarrays. Expression subtype changes were observed in ~30% of samples and were coincident with DNA clonality shifts, especially involving HER2. Downregulation of estrogen receptor (ER)-mediated cell-cell adhesion genes through DNA methylation mechanisms was observed in metastases. Microenvironment differences varied according to tumor subtype; the ER+/luminal subtype had lower fibroblast and endothelial content, while triple-negative breast cancer/basal metastases showed a decrease in B and T cells. In 17% of metastases, DNA hypermethylation and/or focal deletions were identified near HLA-A and were associated with reduced expression and lower immune cell infiltrates, especially in brain and liver metastases. These findings could have implications for treating individuals with metastatic breast cancer with immune- and HER2-targeting therapies.
Subject(s)
Mammary Neoplasms, Animal , Triple Negative Breast Neoplasms , Female , Animals , Humans , Multiomics , Breast , Triple Negative Breast Neoplasms/genetics , DNA Methylation/genetics , Mammary Neoplasms, Animal/genetics , Epigenesis, Genetic/genetics , Tumor Microenvironment/geneticsABSTRACT
PURPOSE: Previously, clinical trials of experimental virotherapy for recurrent glioblastoma multiforme (GBM) demonstrated that inoculation with a conditionally replication-competent Δγ134.5 oncolytic herpes simplex virus (oHSV), G207, was safe. Following the initial safety study, a phase Ib trial enrolled 6 adult patients diagnosed with GBM recurrence from which tumor tissue was banked for future studies. PATIENTS AND METHODS: Here, we analyzed tumor RNA sequencing (RNA-seq) data obtained from pre- and posttreatment (collected 2 or 5 days after G207 injection) biopsies from the phase Ib study patients. RESULTS: Using a Spearman rank-order correlation analysis, we identified approximately 500 genes whose expression pattern correlated with survival duration. Many of these genes were enriched for the intrinsic IFN-mediated antiviral and adaptive immune functional responses, including immune cell chemotaxis and antigen presentation to T-cells. Furthermore, we show that the expression of several T-cell-related genes was highest in the patient with the longest survival after G207 inoculation. CONCLUSIONS: Our data support that the oHSV-induced type I IFN production and the subsequent recruitment of an adaptive immune response differed between enrolled patients and showed association with survival duration in patients with recurrent malignant glioma after treatment with an early generation oHSV.
Subject(s)
Brain Neoplasms/genetics , Brain Neoplasms/therapy , Clinical Trials, Phase I as Topic , Gene Expression Profiling/methods , Glioblastoma/genetics , Glioblastoma/therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/therapy , Oncolytic Virotherapy/methods , Oncolytic Viruses , RNA, Neoplasm/genetics , Simplexvirus , Adult , Aged , Brain Neoplasms/immunology , Brain Neoplasms/mortality , Female , Glioblastoma/immunology , Glioblastoma/mortality , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/mortality , Survival RateABSTRACT
Primary spinal cord tumors contribute to ≤ 10% of central nervous system tumors in individuals of pediatric or adolescent age. Among intramedullary tumors, spinal ependymomas make up ~ 30% of this rare tumor population. A twelve-year-old male presented with an intradural, extramedullary mass occupying the dorsal spinal canal from C6 through T2. Gross total resection and histopathology revealed a World Health Organization (WHO) grade 2 ependymoma. He recurred eleven months later with extension from C2 through T1-T2. Subtotal resection was achieved followed by focal proton beam irradiation and chemotherapy. Histopathology was consistent with WHO grade 3 ependymoma. Molecular profiling of the primary and recurrent tumors revealed a novel amplification of the MYC (8q24) gene, which was confirmed by fluorescence in situ hybridization studies. Although MYC amplification in spinal ependymoma is exceedingly rare, a newly described classification of spinal ependymoma harboring MYCN (2p24) amplification (SP-MYCN) has been defined by DNA methylation-array based profiling. These individuals typically present with a malignant progression and dismal outcomes, contrary to the universally excellent survival outcomes seen in other spinal ependymomas. DNA methylation array-based classification confidently classified this tumor as SP-MYCN ependymoma. Notably, among the cohort of 52 tumors comprising the SP-MYCN methylation class, none harbor MYC amplification, highlighting the rarity of this genomic amplification in spinal ependymoma. A literature review comparing our individual to reported SP-MYCN tumors (n = 26) revealed similarities in clinical, histopathologic, and molecular features. Thus, we provide evidence from a single case to support the inclusion of MYC amplified spinal ependymoma within the molecular subgroup of SP-MYCN.
Subject(s)
Ependymoma/diagnosis , N-Myc Proto-Oncogene Protein , Spinal Cord Neoplasms/diagnosis , Spinal Neoplasms/diagnosis , Child , Ependymoma/genetics , Ependymoma/pathology , Humans , Male , Spinal Cord Neoplasms/genetics , Spinal Cord Neoplasms/pathology , Spinal Neoplasms/genetics , Spinal Neoplasms/pathologyABSTRACT
Meningiomas are a central nervous system tumor primarily afflicting adults, with <1% of cases diagnosed during childhood or adolescence. Somatic variation in NF2 may be found in â¼50% of meningiomas, with other genetic drivers (eg, SMO, AKT1, TRAF7) contributing to NF2 wild-type tumors. NF2 is an upstream negative regulator of YAP signaling and loss of the NF2 protein product, Merlin, results in YAP overexpression and target gene transcription. This mechanism of dysregulation is described in NF2-driven meningiomas, but further work is necessary to understand the NF2-independent mechanism of tumorigenesis. Amid our institutional patient-centric comprehensive molecular profiling study, we identified an individual with meningioma harboring a YAP1-FAM118B fusion, previously reported only in supratentorial ependymoma. The tumor histopathology was remarkable, characterized by prominent islands of calcifying fibrous nodules within an overall collagen-rich matrix. To gain insight into this finding, we subsequently evaluated the genetic landscape of 11 additional pediatric and adolescent/young adulthood meningioma patients within the Children's Brain Tumor Tissue Consortium. A second individual harboring a YAP1-FAM118B gene fusion was identified within this database. Transcriptomic profiling suggested that YAP1-fusion meningiomas are biologically distinct from NF2-driven meningiomas. Similar to other meningiomas, however, YAP1-fusion meningiomas demonstrated overexpression of EGFR and MET. DNA methylation profiling further distinguished YAP1-fusion meningiomas from those observed in ependymomas. In summary, we expand the genetic spectrum of somatic alteration associated with NF2 wild-type meningioma to include the YAP1-FAM118B fusion and provide support for aberrant signaling pathways potentially targetable by therapeutic intervention.
Subject(s)
Biomarkers, Tumor/genetics , Gene Fusion , Meningeal Neoplasms/genetics , Meningioma/genetics , Adolescent , Adult , Age of Onset , Child , DNA Methylation , Databases, Genetic , Female , Genetic Predisposition to Disease , Humans , Infant , Male , Meningeal Neoplasms/pathology , Meningeal Neoplasms/surgery , Meningioma/pathology , Meningioma/surgery , Phenotype , Transcriptome , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses. METHODS: Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median). Cases proposed by patients' clinicians were reviewed by clinical and translational experts. Tumor and normal tissue (if possible) were profiled with whole exome sequencing and, if possible, targeted deep sequencing, RNA sequencing, methylation arrays, and immunohistochemistry. Potential germline mutations were tracked for relevance to disease. RESULTS: Cases reflected a variety of tumors and standard and investigational treatments. Of 520 cases, 476 (91.5%) were accepted for further review, and 222 of 476 (46.6%) proposed cases met requirements as exceptional responders. Clinical data were obtained from 168 of 222 cases (75.7%). Tumor was provided from 130 of 168 cases (77.4%). Of 117 of the 130 (90.0%) cases with sufficient nucleic acids, 109 (93.2%) were successfully analyzed; 6 patients had potentially actionable germline mutations. CONCLUSION: Exceptional responses occur with standard and investigational treatment. Retrospective identification of exceptional responders, accessioning, and sequencing of pretreatment archived tissue is feasible. Data from molecular analyses of tumors, particularly when combining results from patients who received similar treatments, may elucidate molecular bases for exceptional responses.
Subject(s)
Neoplasms/drug therapy , Neoplasms/genetics , Transcriptome/genetics , Adult , Aged , Aged, 80 and over , Feasibility Studies , Female , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Mutation/genetics , National Cancer Institute (U.S.) , Neoplasms/epidemiology , Neoplasms/pathology , Pilot Projects , Precision Medicine , Retrospective Studies , Sequence Analysis, RNA , United States/epidemiology , Exome SequencingABSTRACT
A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories-DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis-with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy.
Subject(s)
Antineoplastic Agents/therapeutic use , Gene Regulatory Networks , Genetic Variation , Genomics/methods , Neoplasms/drug therapy , Biopsy , Epigenesis, Genetic , Female , Humans , Male , Neoplasms/genetics , Neoplasms/pathology , Prognosis , Survival Analysis , Treatment Outcome , Tumor MicroenvironmentABSTRACT
Infantile fibrosarcoma (IFS) is nearly universally driven by gene fusions involving the NTRK family. ETV6-NTRK3 fusions account for â¼85% of alterations; the remainder are attributed to NTRK-variant fusions. Rarely, other genomic aberrations have been described in association with tumors identified as IFS or IFS-like. We describe the utility of genomic characterization of an IFS-like tumor. We also describe the successful treatment combination of VAC (vincristine, actinomycin, cyclophosphamide) with tyrosine kinase inhibitor (TKI) maintenance in this entity. This patient presented at birth with a right facial mass, enlarging at 1 mo to 4.9 × 4.5 × 6.3 cm. Biopsy demonstrated hypercellular fascicles of spindle cells with patchy positivity for smooth muscle actin (SMA) and negativity for S100, desmin, myogenin, and MyoD1. Targeted RNA sequencing identified a novel RBPMS-MET fusion with confirmed absence of ETV6-NTRK3, and the patient was diagnosed with an IFS-like tumor. A positron emission tomography (PET) scan was negative for metastatic disease. VAC was given for a duration of 10 mo. Resection at 13 mo of age demonstrated positive margins. Cabozantinib, a MET-targeting TKI, was initiated. The patient tolerated cabozantinib well and has no evidence of disease at 24 mo of age. We describe a novel RBPMS-MET driver fusion in association with a locally aggressive IFS-like tumor. MET functions as an oncogene and, when associated with the RNA binding protein RBPMS, forms an in-frame fusion product that retains the MET kinase domain. This fusion is associated with aberrant cell signaling pathway expression and subsequent malignancy. We describe treatment with cabozantinib in a patient with an IFS-like neoplasm.
Subject(s)
Anilides/therapeutic use , Fibrosarcoma/drug therapy , Proto-Oncogene Proteins c-met/genetics , Pyridines/therapeutic use , RNA-Binding Proteins/genetics , Anilides/metabolism , Biomarkers, Tumor/genetics , Fibrosarcoma/genetics , Fibrosarcoma/metabolism , Gene Fusion/genetics , Humans , Infant , Oncogene Proteins, Fusion/genetics , Oncogenes/genetics , Protein Kinase Inhibitors , Proto-Oncogene Proteins c-ets/genetics , Proto-Oncogene Proteins c-met/metabolism , Pyridines/metabolism , Repressor Proteins/geneticsABSTRACT
Modeling of genomic profiles from the Cancer Genome Atlas (TCGA) by using recently developed mathematical frameworks has associated a genome-wide pattern of DNA copy-number alterations with a shorter, roughly one-year, median survival time in glioblastoma (GBM) patients. Here, to experimentally test this relationship, we whole-genome sequenced DNA from tumor samples of patients. We show that the patients represent the U.S. adult GBM population in terms of most normal and disease phenotypes. Intratumor heterogeneity affects ≈ 11 % and profiling technology and reference human genome specifics affect <1% of the classifications of the tumors by the pattern, where experimental batch effects normally reduce the reproducibility, i.e., precision, of classifications based upon between one to a few hundred genomic loci by >30%. With a 2.25-year Kaplan-Meier median survival difference, a 3.5 univariate Cox hazard ratio, and a 0.78 concordance index, i.e., accuracy, the pattern predicts survival better than and independent of age at diagnosis, which has been the best indicator since 1950. The prognostic classification by the pattern may, therefore, help to manage GBM pseudoprogression. The diagnostic classification may help drugs progress to regulatory approval. The therapeutic predictions, of previously unrecognized targets that are correlated with survival, may lead to new drugs. Other methods missed this relationship in the roughly 3B-nucleotide genomes of the small, order of magnitude of 100, patient cohorts, e.g., from TCGA. Previous attempts to associate GBM genotypes with patient phenotypes were unsuccessful. This is a proof of principle that the frameworks are uniquely suitable for discovering clinically actionable genotype-phenotype relationships.
ABSTRACT
OBJECTIVE: Many genetic studies of intractable epilepsy in pediatric patients primarily focus on inherited, constitutional genetic deficiencies identified in patient blood. Recently, studies have revealed somatic mosaicism associated with epilepsy in which genetic variants are present only in a subset of brain cells. We hypothesize that tissue-specific, somatic mosaicism represents an important genetic etiology in epilepsy and aim to discover somatic alterations in epilepsy-affected brain tissue. METHODS: We have pursued a research study to identify brain somatic mosaicism, using next-generation sequencing (NGS) technologies, in patients with treatment refractory epilepsy who have undergone surgical resection of affected brain tissue. RESULTS: We used an integrated combination of NGS techniques and conventional approaches (radiology, histopathology, and electrophysiology) to comprehensively characterize multiple brain regions from a single patient with intractable epilepsy. We present a 3-year-old male patient with West syndrome and intractable tonic seizures in whom we identified a pathogenic frameshift somatic variant in SLC35A2, present at a range of variant allele fractions (4.2%-19.5%) in 12 different brain tissues detected by targeted sequencing. The proportion of the SLC35A2 variant correlated with severity and location of neurophysiology and neuroimaging abnormalities for each tissue. CONCLUSIONS: Our findings support the importance of tissue-based sequencing and highlight a correlation in our patient between SLC35A2 variant allele fractions and the severity of epileptogenic phenotypes in different brain tissues obtained from a grid-based resection of clinically defined epileptogenic regions.
ABSTRACT
There has been a wealth of research providing evidence for the relationship between stress and cigarette smoking during adolescence. Despite this knowledge, little is known about possible behavioral mechanisms by which stress exerts its influence on the decision to smoke. This study sought to examine one such behavioral characteristic, delay discounting, that may mediate the relationship between stress and cigarette smoking. Delay discounting generally refers to the discounting of value for outcomes because they are delayed; and high rates of delay discounting have been linked to impulsive behavior. For the current research, adolescent smokers (n = 50) and nonsmokers (n = 50) were compared using a self-report measure of perceived stress and a laboratory assessment of delay discounting. Smokers tended to report higher levels of stress and to discount more by delay, and there was a significant association between reported stress and delay discounting. In addition, delay discounting mediated the relationship between stress and cigarette smoking status. These results suggest that discounting by delay may be a behavior through which stress exerts influence on an adolescent's decision to smoke.
Subject(s)
Extinction, Psychological/physiology , Smoking/psychology , Stress, Psychological/psychology , Adolescent , Area Under Curve , Choice Behavior/physiology , Female , Humans , Intelligence/physiology , Logistic Models , Male , Self Concept , Surveys and Questionnaires , Time FactorsABSTRACT
This research compared impulsive behavior in adolescent nonsmokers with low ratings of psychopathy (n = 25) and daily smokers with low (n = 25) and high (n = 25) ratings of psychopathy. Assessments of impulsive behavior included question-based and real-time measures of delay discounting and a self report assessment of impulsivity (Barratt Impulsiveness Scale-Adolescent). Smokers with low psychopathy ratings discounted more by delay (i.e., more impulsively) than nonsmokers on both assessments of discounting; however, smokers with high psychopathy ratings did not differ from nonsmokers on either measure. Inversely, from the self report assessment of impulsivity, smokers with low psychopathy ratings did not differ from nonsmokers, but smokers with high psychopathy ratings were more impulsive than nonsmokers. These findings indicate that delay discounting and self reported impulsivity relate differently to characteristics of psychopathy in adolescent nonsmokers and smokers. Also, these findings demonstrate that there are definable subgroups of smokers for whom the frequently observed relationship between cigarette smoking and delay discounting does not apply.
Subject(s)
Antisocial Personality Disorder/psychology , Impulsive Behavior/psychology , Smoking/psychology , Adolescent , Adolescent Behavior/psychology , Female , Humans , MaleABSTRACT
Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.
Subject(s)
Central Nervous System Neoplasms/genetics , Neurofibromin 1/antagonists & inhibitors , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Tumor Suppressor Protein p53/antagonists & inhibitors , Xenograft Model Antitumor Assays , Animals , Cell Line, Tumor , Central Nervous System Neoplasms/metabolism , Child , Clinical Trials as Topic , Disease Models, Animal , Genomics , Humans , Mice , Mutation , Neuroblastoma/genetics , Neuroblastoma/metabolism , Neurofibromin 1/genetics , Neurofibromin 1/metabolism , Osteosarcoma/genetics , Osteosarcoma/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Recurrence , Rhabdomyosarcoma/genetics , Rhabdomyosarcoma/metabolism , Sarcoma, Ewing/genetics , Sarcoma, Ewing/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Exome Sequencing , Wilms Tumor/genetics , Wilms Tumor/metabolismABSTRACT
The present study evaluated a new 30-day Web-based contingency management program for smoking abstinence with 4 daily-smoking adolescents. Participants made 3 daily video recordings of themselves giving breath carbon monoxide (CO) samples at home that were sent electronically to study personnel. Using a reversal design, participants could earn money for continued abstinence during the treatment phases (CO < or =5 ppm). All participants were compliant with the treatment (submitting 97.2% of samples), and all achieved prolonged abstinence from smoking.