RESUMO
BACKGROUND: Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells. METHODS: Here, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM. RESULTS: Comparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8+ T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors. CONCLUSIONS: These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion.
Assuntos
Neoplasias do Sistema Nervoso Central/imunologia , Peptídeos/imunologia , Tumor Rabdoide/imunologia , Adolescente , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/terapia , Criança , Pré-Escolar , Feminino , Antígenos HLA/genética , Antígenos HLA/imunologia , Antígenos HLA/metabolismo , Humanos , Imuno-Histoquímica , Imunoterapia , Masculino , Espectrometria de Massas , Oncogenes , Peptídeos/metabolismo , Peptídeos Cíclicos , Tumor Rabdoide/genética , Tumor Rabdoide/metabolismo , Tumor Rabdoide/terapiaRESUMO
Loss of nuclear SMARCB1 (INI1/hSNF5/BAF47) protein expression due to biallelic mutations of the SMARCB1 tumor suppressor gene is a hallmark of atypical teratoid/rhabdoid tumors (ATRT), but the presence of cytoplasmic SMARCB1 protein in these tumors has not yet been described. In a series of 102 primary ATRT, distinct cytoplasmic SMARCB1 staining on immunohistochemistry was encountered in 19 cases (19%) and was highly over-represented in cases showing pathogenic sequence variants leading to truncation or mutation of the C-terminal part of SMARCB1 (15/19 vs. 4/83; Chi-square: 56.04, p = 1.0E-10) and, related to this, in tumors of the molecular subgroup ATRT-TYR (16/36 vs. 3/66; Chi-square: 24.47, p = 7.6E-7). Previous reports have indicated that while SMARCB1 lacks a bona fide nuclear localization signal, it harbors a masked nuclear export signal (NES) and that truncation of the C-terminal region results in unmasking of this NES leading to cytoplasmic localization. To determine if cytoplasmic localization found in ATRT is due to unmasking of NES, we generated GFP fusions of one of the SMARCB1 truncating mutations (p.Q318X) found in the tumors along with a p.L266A mutation, which was shown to disrupt the interaction of SMARCB1-NES with exportin-1. We found that while the GFP-SMARCB1(Q318X) mutant localized to the cytoplasm, the double mutant GFP-SMARCB1(Q318X;L266A) localized to the nucleus, confirming NES requirement for cytoplasmic localization. Furthermore, cytoplasmic SMARCB1(Q318X) was unable to cause senescence as determined by morphological observations and by senescence-associated ß-galactosidase assay, while nuclear SMARCB1(Q318X;L266A) mutant regained this function. Selinexor, a selective exportin-1 inhibitor, was effective in inhibiting the nuclear export of SMARCB1(Q318X) and caused rapid cell death in rhabdoid tumor cells. In conclusion, inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1. Therapies aimed at preventing nuclear export of mutant SMARCB1 protein may represent a promising targeted therapy in ATRT harboring truncating C-terminal SMARCB1 mutations.
Assuntos
Transporte Ativo do Núcleo Celular/fisiologia , Neoplasia Residual/genética , Tumor Rabdoide/metabolismo , Proteína SMARCB1/metabolismo , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/metabolismo , Pré-Escolar , Feminino , Genes Supressores de Tumor/fisiologia , Humanos , Lactente , Masculino , Mutação/genética , Neoplasia Residual/metabolismo , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/metabolismo , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Teratoma/genéticaRESUMO
Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant brain tumor predominantly occurring in infants. Biallelic SMARCB1 mutations causing loss of nuclear SMARCB1/INI1 protein expression represent the characteristic genetic lesion. Pathogenic SMARCB1 mutations comprise single nucleotide variants, small insertions/deletions, large deletions, which may be also present in the germline (rhabdoid tumor predisposition syndrome 1), as well as somatic copy-number neutral loss of heterozygosity (LOH). In some SMARCB1-deficient AT/RT underlying biallelic mutations cannot be identified. Here we report the case of a 24-months-old girl diagnosed with a large brain tumor. The malignant rhabdoid tumor showed loss of nuclear SMARCB1/INI1 protein expression and the diagnosis of AT/RT was confirmed by DNA methylation profiling. While FISH, MLPA, Sanger sequencing and DNA methylation data-based imbalance analysis did not disclose alterations affecting SMARCB1, OncoScan array analysis revealed a 28.29 Mb sized region of copy-number neutral LOH on chromosome 22q involving the SMARCB1 locus. Targeted next-generation sequencing did also not detect a single nucleotide variant but instead revealed insertion of an AluY element into exon 2 of SMARCB1. Specific PCR-based Sanger sequencing verified the Alu insertion (SMARCB1 c.199_200 Alu ins) resulting in a frame-shift truncation not present in the patient's germline. In conclusion, transposable element insertion represents a hitherto not widely recognized mechanism of SMARCB1 disruption in AT/RT, which might not be detected by several widely applied conventional diagnostics assays. This finding has particular clinical implications, if rhabdoid predisposition syndrome 1 is suspected, but germline SMARCB1 alterations cannot be identified.
Assuntos
Neoplasias Encefálicas/genética , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Teratoma/genética , Neoplasias Encefálicas/patologia , Elementos de DNA Transponíveis , Feminino , Humanos , Lactente , Mutagênese Insercional , Tumor Rabdoide/patologia , Teratoma/patologiaRESUMO
Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system tumor predominantly occurring in infants that may also arise in older children and adults. Rare secondary AT/RT developing from other tumors such as pleomorphic xanthoastrocytoma (PXA) are on record, but AT/RT presenting with molecular features of PXA have not been described. Here, we report 3 malignant central nervous system tumors in children (10, 13, and 18 y old). All tumors were located in the temporal lobe. In 2 cases, there was no history of a low-grade precursor lesion; in 1 case anaplastic PXA had been diagnosed 3 months earlier. Histopathologically, all tumors were composed of RT cells and showed frank signs of malignancy as well as loss of nuclear SMARCB1/INI1 protein expression. Two cases displayed homozygous deletions of the SMARCB1 region while the third case showed an exon 7 mutation (c.849_850delGT; p.Met283Ilefs*77). Of note, DNA methylation profiles did not group with AT/RT or other tumor entities using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-distributed stochastic neighbor embedding analysis and hierarchical clustering analysis, however, all tumors clearly grouped with PXA. Genome-wide copy number analysis revealed homozygous CDNK2A/B deletions and gains of whole chromosome 7. BRAF V600E mutations could be demonstrated in all cases. In conclusion, the possibility of AT/RT with molecular features of PXA needs to be taken into account and warrants molecular characterization of AT/RT especially in older children. Since treatments targeting mutated BRAF are available, identification of such cases may also have therapeutic consequences.
Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Tumor Rabdoide/genética , Teratoma/genética , Adolescente , Criança , Feminino , Humanos , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteína SMARCB1/genéticaRESUMO
Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40 years (range 15-61 years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2 bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48 months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.
Assuntos
Neoplasias Encefálicas/genética , Mutação/genética , Glândula Pineal , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Proteína SMARCB1/genética , Adolescente , Adulto , Fatores Etários , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumor Rabdoide/mortalidade , Taxa de Sobrevida , Adulto JovemAssuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Renais/metabolismo , Tumor Rabdoide/metabolismo , Teratoma/metabolismo , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Evolução Fatal , Humanos , Lactente , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Mutação , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/metabolismo , Neoplasias Primárias Múltiplas/patologia , Tumor Rabdoide/diagnóstico por imagem , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Proteína SMARCB1/genética , Proteína SMARCB1/metabolismo , Teratoma/diagnóstico por imagem , Teratoma/genética , Teratoma/patologiaRESUMO
Germline variants that affect function are found in seven genes of the BAF chromatin-remodeling complex. They are linked to a broad range of diseases that, according to the gene affected, range from non-syndromic or syndromic neurodevelopmental disorders to low-grade tumors and malignancies. In the current meta-analysis, we evaluate genetic and clinical data from more than 400 families and 577 patients affected by BAF germline alterations. We focus on SMARCB1, including 43 unpublished patients from the EU-RHAB registry and our institution. For this gene, we further demonstrate whole gene as well as exon deletions and truncating variants to be associated with malignancy and early-onset disease. In contrast, non-truncating variants are associated with non-malignant disorders, such as Coffin-Siris syndrome or late-onset tumors like schwannoma or meningioma (p < 0.0001). SMARCB1 germline variants are distributed across the gene with variants in exons 1, 2, 8, and 9 being associated with low-grade entities, and single-nucleotide variants or indels outside of exon 9 that appear in patients with malignancies (p < 0.001). We attribute variants in specific BAF genes to certain disease entities. Finally, single-nucleotide variants and indels are sometimes detected in the healthy relatives of tumor patients, while Coffin-Siris syndrome and Nicolaides-Baraitser syndrome generally seem to appear de novo. Our findings add further information on the genotype-phenotype association of germline variants detected in genes of the BAF complex. Functional studies are urgently needed for a deeper understanding of BAF-related disorders and may take advantage from the comprehensive information gathered in this article.
Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Mutação em Linhagem Germinativa , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Micrognatismo/genética , Pescoço/anormalidades , Neurilemoma/genética , Proteína SMARCB1/genética , Anormalidades Múltiplas/patologia , Face/patologia , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/patologia , Neoplasias Meníngeas/patologia , Meningioma/patologia , Micrognatismo/patologia , Pescoço/patologia , Neurilemoma/patologia , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly encountered in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. A small group of ATRT stands out clinically, because these tumors are located in the sellar region of adults. To investigate if sellar region ATRT in adults represents a molecular distinct entity, we characterized molecular alterations in 7 sellar region ATRTs in adults as compared with 150 pediatric ATRTs and 47 pituitary adenomas using SMARCB1 sequencing, multiplex ligation-dependent probe amplification and fluorescence in situ hybridization as well as DNA methylation profiling. The median age of the 6 female and 1 male patients was 56 years. On histopathologic examination, all tumors were malignant rhabdoid tumors showing loss of SMARCB1/INI1 protein expression. Two cases displayed compound heterozygous SMARCB1 point mutations, 3 cases showed heterozygous SMARCB1 deletions with point mutations of the other allele and 1 case a homozygous SMARCB1 deletion; in 1 case, underlying SMARCB1 alterations could not be identified. On unsupervised hierarchical cluster analysis of DNA methylation profiles, sellar region ATRTs did not form a distinct group, but clustered with ATRT-MYC, 1 of 3 recently described molecular subgroups of ATRT. On analysis of DNA methylation array intensity data, only 1 sellar region ATRT showed characteristic features of pediatric ATRT-MYC, that is, major copy number losses affecting the SMARCB1 region. In conclusion, these results suggest that sellar region ATRTs in adults form a clinically distinct entity with a different mutational spectrum, but epigenetic similarities with pediatric ATRTs of the ATRT-MYC subgroup.
Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Epigênese Genética , Neoplasias Hipofisárias/genética , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Teratoma/genética , Adulto , Fatores Etários , Idoso , Feminino , Deleção de Genes , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Neoplasias Hipofisárias/patologia , Mutação Puntual , Tumor Rabdoide/patologia , Teratoma/patologia , Adulto JovemRESUMO
Rhabdoid phenotype and loss of SMARCB1 expression in a brain tumor are characteristic features of atypical teratoid/rhabdoid tumors (ATRT). Rare non-rhabdoid brain tumors showing cribriform growth pattern and SMARCB1 loss have been designated cribriform neuroepithelial tumor (CRINET). Small case series suggest that CRINETs may have a relatively favorable prognosis. However, the long-term outcome is unclear and it remains uncertain whether CRINET represents a distinct entity or a variant of ATRT. Therefore, 10 CRINETs were clinically and molecularly characterized and compared with 10 ATRTs of each of three recently described molecular subgroups (i.e. ATRT-TYR, ATRT-SHH and ATRT-MYC) using Illumina Infinium HumanMethylation450 arrays, FISH, MLPA, and sequencing. Furthermore, outcome was compared to a larger cohort of 27 children with ATRT-TYR. Median age of the 6 boys and 4 girls harboring a CRINET was 20 months. On histopathological examination, all CRINETs demonstrated a cribriform growth pattern and distinct tyrosinase staining. On unsupervised cluster analysis of methylation data, all CRINETs examined exclusively clustered within the ATRT-TYR molecular subgroup. As ATRT-TYR, CRINETs mainly showed large heterozygous 22q deletions (9/10) and SMARCB1 mutations of the other allele. In two patients, SMARCB1 mutations were also present in the germline. Estimated mean overall survival in patients with CRINETs was 125 months (95% confidence interval 100-151 months) as compared to only 53 (33-74) months in patients with ATRTs of the ATRT-TYR subgroup (Log-Rank P < 0.05). In conclusion, CRINET represents a SMARCB1-deficient non-rhabdoid tumor, which shares molecular similarities with the ATRT-TYR subgroup but has distinct histopathological features and favorable long-term outcome.
Assuntos
Neoplasias Encefálicas/genética , Mutação/genética , Neoplasias Neuroepiteliomatosas/genética , Tumor Rabdoide/genética , Proteína SMARCB1/deficiência , Proteína SMARCB1/genética , Criança , Pré-Escolar , Metilação de DNA/genética , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Neoplasias Neuroepiteliomatosas/patologia , Tumor Rabdoide/patologia , Estatísticas não ParamétricasRESUMO
Neurofibromas and schwannomas are benign Schwann cell-derived peripheral nerve sheath tumors arising sporadically and within neurofibromatoses. Multiple tumors are a hallmark of neurofibromatosis type 1 (NF1) and type 2 (NF2) and schwannomatosis. Neurofibromas in NF1 and schwannomas in NF2 or schwannomatosis are defined by distinctive molecular hits. Among these, multiple hybrid neurofibromas/schwannomas may also appear, not yet being defined by a molecular background. We therefore performed molecular analysis of 22 hybrid neurofibromas/schwannomas using array comparative genomic hybridization, immunohistochemistry, quantitative RT-PCR, and functional analyses of cultured Schwann cells. Furthermore, we analyzed SMARCB1 by fluorescence in situ hybridization and multiplex ligation-dependent probe. Monosomy 22 was identified in 44% of tumors of tested patients with hybrid neurofibromas/schwannomas. In addition, in a single case, we detected focal deletion of the α-T-catenin/CTNNA3 gene (10q21.3). To further characterize this candidate, transient knockdown of α-T-catenin in Schwann cells was performed. CTNNA3 depleted cells showed cytoskeletal abnormalities and reduced E-cadherin expression, indicating epithelial-mesenchymal transition-like abnormalities. To conclude, we uncovered loss of chromosome 22 in almost half of all cases with hybrid neurofibromas/schwannomas of patients with multiple peripheral nerve sheath tumors. We tagged α-T-catenin/CTNNA3 as a novel candidate gene. Our functional investigations might indicate involvement of α-T-catenin/CTNNA3 in the biology of peripheral nerve sheath tumors.
Assuntos
Neoplasias de Bainha Neural/genética , Neurilemoma/genética , Neurofibroma/genética , Neurofibromatoses/genética , Neurofibromatose 1/genética , Neoplasias Cutâneas/genética , alfa Catenina/genética , Adolescente , Adulto , Idoso , Cromossomos Humanos Par 22/genética , Hibridização Genômica Comparativa , Transição Epitelial-Mesenquimal , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Monossomia , Neoplasias de Bainha Neural/patologia , Neurilemoma/patologia , Neurofibroma/patologia , Neurofibromatoses/patologia , Neurofibromatose 1/patologia , Células de Schwann/metabolismo , Células de Schwann/patologia , Neoplasias Cutâneas/patologia , Proteínas Supressoras de Tumor/genética , Adulto JovemRESUMO
Small cell undifferentiated (SCUD) hepatoblastoma is a rare variant of hepatoblastoma with poor outcome and loss of INI1 expression, sharing this with malignant rhabdoid tumors (MRT). We studied all tumors from the files of the Kiel Pediatric Tumor Registry (KTR) with the initial diagnosis of SCUD and MRT. After re-review, we performed immunistochemistry, fluorescence in situ hybridization, and multiplex ligation dependent probe amplification for loss of expression and deletion of INI1/SMARCB1 in 23 tumors. Morphologically, 12 of the tumors had a small cell morphology, 9 showed the typical picture of MRT, and 2 were composed of both small cells and rhabdoid cells. All but 1 of the 23 tumors showed loss of INI1 protein expression by immunohistochemistry. Nineteen of the INI1 negative tumors were analyzed by FISH technique and all showed a deletion of the INI1/SMARCB1 gene (17 homozygous deletions, 2 heterozygous deletions). We investigated 14 of these cases by multiplex ligation dependent probe amplification and verified the deletions in all cases. In conclusion, we postulate that SCUD hepatoblastoma is not a hepatoblastoma but represents a malignant rhabdoid tumor of the liver. © 2016 Wiley Periodicals, Inc.
Assuntos
Biomarcadores Tumorais/genética , Deleção de Genes , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Neoplasias Pulmonares/genética , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Carcinoma de Pequenas Células do Pulmão/genética , Adolescente , Diferenciação Celular , Pré-Escolar , Feminino , Seguimentos , Hepatoblastoma/metabolismo , Hepatoblastoma/patologia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Lactente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de Neoplasias , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologiaRESUMO
Atypical teratoid rhabdoid tumors (AT/RT) are characterized by mutations and subsequent inactivation of SMARCB1 (INI1, hSNF5), a predilection for very young children and an unfavorable outcome. The European Registry for rhabdoid tumors (EU-RHAB) was established to generate a common European database and to establish a standardized treatment regimen as the basis for phase I/II trials. Thus, genetic analyses, neuropathologic and radiologic diagnoses, and a consensus treatment regimen were prospectively evaluated. From 2005 to 2009, 31 patients with AT/RT from four countries were recruited into the registry study Rhabdoid 2007 and treated with systemic and intraventricular chemotherapy. Eight patients received high-dose chemotherapy, 23 radiotherapy, and 17 maintenance therapy. Reference evaluations were performed in 64% (genetic analyses, FISH, MLPA, sequencing) up to 97% (neuropathology, INI1 stain). Germ-line mutations (GLM) were detected in 6/21 patients. Prolonged overall survival was associated with age above 3 years, radiotherapy and achievement of a complete remission. 6-year overall and event-free survival rates were 46% (±0.10) and 45% (±0.09), respectively. Serious adverse events and one treatment-related death due to insufficiency of a ventriculo peritoneal shunt (VP-shunt) and consecutive herniation were noted. Acquisition of standardized data including reference diagnosis and a standard treatment schedule improved data quality along with a survival benefit. Treatment was feasible with significant but manageable toxicity. Although our analysis is biased due to heterogeneous adherence to therapy, EU-RHAB provides the best available basis for phase I/II clinical trials.
Assuntos
Neoplasias Encefálicas/terapia , Tumor Rabdoide/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Terapia Combinada , Europa (Continente)/epidemiologia , Feminino , Mutação em Linhagem Germinativa , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Prognóstico , Radioterapia Conformacional/efeitos adversos , Radioterapia Conformacional/métodos , Sistema de Registros , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidade , Falha de Tratamento , Resultado do TratamentoRESUMO
We report the successful use of multiplex ligation-dependent probe amplification (MLPA) to detect heterozygous loss of SMARCB1/INI1/SNF5 in the germ line of an infant with a huge posterior fossa tumor. MLPA and Sanger sequencing of the SMARCB1 gene in the germ line may be useful for the initial diagnosis in a defined subgroup of infants with rhabdoid tumors, in which biopsies cannot be performed.
Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/genética , Predisposição Genética para Doença , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Neoplasias do Sistema Nervoso Central/mortalidade , Deleção de Genes , Humanos , Lactente , Reação em Cadeia da Polimerase Multiplex , Tumor Rabdoide/mortalidadeAssuntos
Cordoma/diagnóstico , Cordoma/metabolismo , Metilação de DNA , Proteína SMARCB1/deficiência , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Cordoma/genética , Cordoma/patologia , Análise por Conglomerados , Variações do Número de Cópias de DNA , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Masculino , Prognóstico , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/genética , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Proteína SMARCB1/genética , Análise de Sobrevida , Teratoma/diagnóstico , Teratoma/genética , Teratoma/metabolismo , Teratoma/patologiaRESUMO
Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed 192 ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.
Assuntos
Epigênese Genética/genética , Tumor Rabdoide/genética , Teratoma/genética , Neoplasias Encefálicas/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Humanos , Mutação/genética , Proteína SMARCB1 , Fatores de Transcrição/genéticaRESUMO
INTRODUCTION: Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive embryonal tumor of the central nervous system with a generally dismal prognosis, especially in patients younger than 12 months. DISCUSSION: We here describe the unusual case of an infant with AT/RT with long-term survival despite low-cumulative dose chemotherapy after subtotal resection. Due to a poor neurological situation and an unfavorable oncological prognosis, therapy was halted after two partial surgical resections and four of the nine chemotherapy courses recommended by the European Rhabdoid Registry, without the patient receiving either radiotherapy or high-dose chemotherapy. The patient is alive without evidence of disease 52 months after diagnosis. CONCLUSION: This case report highlights that independent prognostic factors are urgently needed for optimizing treatment stratification and preventing overtreatment.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/cirurgia , Procedimentos Neurocirúrgicos/métodos , Tumor Rabdoide , Terapia Combinada , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/mortalidade , Tumor Rabdoide/cirurgiaRESUMO
Sickle cell disease is among hereditary diseases with evidence that early diagnoses and treatment improves the clinical outcome. So far sickle cell disease has not been included in the German newborn screening program despite immigration from countries with populations at risk. To determine the birth prevalence we tested 17,018 newborns. High pressure liquid chromatography and subsequent molecular-genetic testing were used for the detection and confirmation of hemoglobin variants. The frequency of sickle cell disease-consistent genotypes was one in 2,385 newborns. Duffy-blood group typing showed evidence that affected children were likely of Sub-Saharan ancestry. An inclusion of sickle cell disease into the German newborn screening seems reasonable.
Assuntos
Anemia Falciforme/epidemiologia , Anemia Falciforme/prevenção & controle , Triagem Neonatal , Genótipo , Alemanha/epidemiologia , Humanos , Recém-Nascido , Triagem Neonatal/métodos , PrevalênciaRESUMO
We report on how MLPA and Sequencing of SMARCB1/INI1/SNF5 might be applied for initial diagnosis of rhabdoid tumor patients. These techniques were successfully used to detect loss of SMARCB1 in tumor cells of the ascites in a 3-month-old patient in which tumor biopsy could not initially be made due to life threatening intraabdominal bleedings.