PLAGL1
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AIMS: Embryonal tumours with PLAGL1 or PLAGL2 amplification (ET, PLAGL) show substantial heterogeneity regarding their clinical characteristics and have been treated inconsistently, resulting in diverse outcomes. In this study, we aimed to evaluate the clinical behaviour of ET, PLAGL and elucidate their response pattern across the different applied treatment regimens. METHODS: We conducted an in-depth retrospective analysis of clinical and serial imaging data of 18 patients with ET, PLAGL (nine each of PLAGL1 and PLAGL2 amplified). RESULTS: Patients with PLAGL1-amplified tumours (ET, PLAGL1) had fewer relapses (3/9), while PLAGL2-amplified tumours (ET, PLAGL2) were prone to early relapse or progression (8/9) and to distant, leptomeningeal and intraventricular relapses. Progression-free survival differed significantly between the subtypes (log-rank test, p = 0.0055). Postoperative treatment included chemotherapy (n = 17, various protocols), alone (n = 8) or combined with radiotherapy (n = 9). Responses to chemotherapy were observed in both subtypes, and incomplete resection was not associated with inferior survival. All three survivors with ET, PLAGL2 were treated with induction and high-dose chemotherapy with (n = 1-low-dose CSI and boost) or without (n = 2) radiotherapy, whereas five patients with less intensive chemotherapy relapsed. All six survivors with ET, PLAGL1 were treated with conventional chemotherapy regimens, with (n = 4-local radiotherapy n = 3; CSI and boost n = 1) or without (n = 2) radiotherapy. Two patients with ET, PLAGL1 relapsed after 8 years. CONCLUSIONS: Adjuvant therapy should be considered for all ET, PLAGL patients: Patients with ET, PLAGL2 might benefit from intensified chemotherapy regimens. In contrast, patients with ET, PLAGL1 showed superior outcomes without high-dose chemotherapy or craniospinal irradiation.
- MeSH
- amplifikace genu MeSH
- dítě MeSH
- DNA vazebné proteiny * genetika MeSH
- dospělí MeSH
- germinální a embryonální nádory * genetika terapie patologie diagnostické zobrazování MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nádory centrálního nervového systému * genetika terapie patologie diagnostické zobrazování MeSH
- nádory mozku * genetika terapie MeSH
- předškolní dítě MeSH
- retrospektivní studie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
BACKGROUND AND PURPOSE: CNS embryonal tumor with pleomorphic adenoma gene-like 1 (PLAGL1)/pleomorphic adenoma gene-like 2 (PLAGL2) amplification (ET, PLAGL) is a newly identified, highly malignant pediatric tumor. Systematic MRI descriptions of ET, PLAGL are currently lacking. MATERIALS AND METHODS: MRI data from 19 treatment-naïve patients with confirmed ET, PLAGL were analyzed. Evaluation focused on anatomic involvement, tumor localization, MRI signal characteristics, DWI behavior, and the presence of necrosis and hemorrhage. Descriptive statistics (median, interquartile range, percentage) were assessed. RESULTS: Ten patients had PLAGL1 and nine had PLAGL2 amplifications. The solid components of the tumors were often multinodular with heterogeneous enhancement (mild to intermediate in 47% and intermediate to strong in 47% of cases). Nonsolid components included cysts in 47% and necrosis in 84% of the cases. The tumors showed heterogeneous T2WI hyper- and isointensity (74%), relatively little diffusion restriction (ADC values less than contralateral normal-appearing WM in 36% of cases with available DWI), and tendencies toward hemorrhage/calcification (42%). No reliable distinction was found between PLAGL1- and PLAGL2-amplified tumors or compared with other embryonal CNS tumors. CONCLUSIONS: The study contributes to understanding the imaging characteristics of ET, PLAGL. It underscores the need for collaboration in studying rare pediatric tumors and advocates the use of harmonized imaging protocols for better characterization.
- MeSH
- amplifikace genu MeSH
- dítě MeSH
- DNA vazebné proteiny genetika MeSH
- germinální a embryonální nádory diagnostické zobrazování patologie MeSH
- kojenec MeSH
- lidé MeSH
- magnetická rezonanční tomografie * metody MeSH
- mladiství MeSH
- nádorové supresorové proteiny MeSH
- nádory centrálního nervového systému diagnostické zobrazování patologie MeSH
- nádory mozku diagnostické zobrazování patologie MeSH
- předškolní dítě MeSH
- proteiny buněčného cyklu MeSH
- proteiny vázající RNA MeSH
- transkripční faktory genetika MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.
- MeSH
- dítě MeSH
- DNA vazebné proteiny genetika metabolismus MeSH
- kojenec MeSH
- lidé MeSH
- metylace DNA MeSH
- nádorové supresorové proteiny genetika MeSH
- nádory centrálního nervového systému * genetika MeSH
- předškolní dítě MeSH
- primitivní neuroektodermové nádory * genetika MeSH
- proteiny buněčného cyklu genetika MeSH
- proteiny vázající RNA genetika MeSH
- signální dráha Wnt genetika MeSH
- transkripční faktory genetika metabolismus MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
- MeSH
- dítě MeSH
- ependymom genetika MeSH
- lidé MeSH
- nádorové supresorové proteiny genetika MeSH
- onkogenní fúze MeSH
- proteiny buněčného cyklu genetika MeSH
- supratentoriální nádory genetika MeSH
- transkripční faktory genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Novorozenecký diabetes je vzácné onemocnění vyskytující se s četností 1:90–160 000 dětí mladších 6 měsíců. Tranzientní hyperglykémie se mohou vyskytovat u nedonošených dětí. Pokud však trvají déle, vedou k vysokým vzestupům glykémie a dítě se narodí s intrauterinní růstovou retardací, je třeba pomýšlet na rozvoj diabetu. Novorozenecký diabetes je minimálně z 80 % způsoben mutací v některém z dosud popsaných genů. Může mít formu tranzientní, která vymizí po několika týdnech nutnosti léčby inzulinem a může recidivovat v dospívání. Permanentní novorozenecký diabetes vyžaduje léčbu trvale. Nejčastěji je příčinou mutace v genech pro kaliový kanál beta buňky (ABCC8 a KCNJ11), která může mít formu mírnější s dobrou citlivostí k léčbě deriváty sulfonylurey II. generace, nebo formu těžkou spojující diabetes s epilepsií a opožděným psychomotorickým vývojem (DEND syndrom). V etiologii se dále uplatňují geny pro inzulin, glukokinázu či abnormality imprintingu genu PLAGL1 na chromosomu 6q. Vzácně může být novorozenecký diabetes součástí dysregulace imunitního systému při syndromu IPEX apod. Včasná genetická diagnóza umožňuje cílenou léčbu těchto dětí.
The aetiology and treatment of neonatal diabetes Neonatal diabetes (ND) is a rare disease occurring at a frequency of 1: 90–160,000 in children up to 6 months of age. Transient hyperglycaemia may occur in premature babies. A combination of long lasting high hyperglycaemia in a child born with intrauterine growth retardation leads to the higher probability of developing diabetes. Neonatal diabetes is at least in 80% caused by the mutation in one of the genes described so far. Transient form that disappears after several weeks of insulin therapy may recur in adolescence. Permanent neonatal diabetes requires treatment permanently. The major causes of ND are the mutations in the genes coding the potassium channel of the beta-cell (ABCC8 and KCNJ11). This form of ND can be mild with a good sensitivity to the treatment of sulfonylurea derivatives or severe where the diabetes is associated with epilepsy and developmental delay (DEND syndrome). Aetiology also includes gene for insulin, glucokinase, or PLAGL1 gene imprinting on chromosome 6q. Rarely, neonatal diabetes can be a part of dysregulation of the immune system (IPEX syndrome, etc.). Early genetic diagnosis allows targeted treatment of these children.
