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1.
Pediatr Surg Int ; 40(1): 248, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-39237666

RESUMEN

PURPOSE: To study the biological relationship between congenital lung malformations (CLMs) and malignancy. METHODS: Biopsies of 12 CPAMs, 6 intralobar sequestrations and 2 extralobar sequestrations were analyzed through whole-genome sequencing. Blood samples from 10 patients were used to confirm or exclude somatic mosaicism. Putative somatic Single Nucleotide Variants (SNVs) were called for each malformed sample with a Panel of Normals built with control DNA samples extracted from blood. The variants were subsequently confirmed by Sanger sequencing and searched, whenever possible, in the blood samples of patients. RESULTS: All CLMs but one presented a signature of genomic instability by means of multiple clusters of cells with gene mutations. Seven tumor transformation-related SNVs were detected in 6/20 congenital lung malformations. Four very rare in the general population SNVs were found in a region previously linked to lung cancer in 5p15.33, upstream of TERT oncogene. Furthermore, we identified missense genetic variants, whose tumorigenic role is well known, in the RET, FANCA and MET genes. CONCLUSIONS: Genomic instability in 95% of CLMs and genetic variants linked to tumor development in 30% of them, regardless of histopathology, are predisposing factors to malignancy, that combined with exposure to carcinogens, might trigger the development of malignancy and explain the association between CLMs and lung cancer.


Asunto(s)
Inestabilidad Genómica , Humanos , Inestabilidad Genómica/genética , Masculino , Femenino , Niño , Lactante , Preescolar , Pulmón/anomalías , Pulmón/patología , Neoplasias Pulmonares/genética , Adolescente , Malformación Adenomatoide Quística Congénita del Pulmón/genética , Polimorfismo de Nucleótido Simple , Mutación , Recién Nacido , Secuenciación Completa del Genoma/métodos
3.
Mod Pathol ; 37(9): 100539, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38880352

RESUMEN

EGFR aberrations are reported in a subset of myofibroblastic lesions with kinase domain duplication (EGFR-KDD) and exon 20 mutations being assigned to infantile fibrosarcomas (IFS), mesoblastic nephroma, and fibrous hamartoma of infancy (FHI), respectively. In this retrospective study, we correlated molecular findings with the histomorphology of 14 myofibroblastic lesions harboring such genetic changes identified by NGS. We additionally performed DNA methylation profiling (DNAmp) and immunohistochemistry. Lesions were from 10 males and 4 females with a mean age of 3 years (range, 0.3-14) and occurred subcutaneously in the upper limbs (n = 5), lower limbs (n = 3), back/thorax (n = 5), and the nasal cavity (n = 1). Eleven were cured by surgery, including 1 relapsed case. Two patients were lost to follow-up. One case was very recent, and the patient was biopsied. Histologically, the lesions showed a wide spectrum varying from classic FHI (n = 9) to IFS (n = 1) or lipofibromatosis-like tumors (LFT-like) (n = 2) or dermatofibrosarcoma protuberans-like (DFSP-like) (n = 1) to a predominantly myxoid spindle cell lesion (n = 1). Immunohistochemically, all neoplasms stained with CD34, whereas S100 was positive in 2/14. EGFR expression was observed in 9/10 cases. Molecularly, the IFS and 1 LFT-like harbored EGFR-KDD, whereas an exon 20 mutation was identified in all FHI, 1 LFT-like, the DFSP-like, and in predominant myxoid spindle cell lesion. By DNAmp, all but 2 cases formed a well-defined cluster, demonstrating that these lesions are also epigenetically related. In conclusion, EGFR kinase domain aberrations found in FHI, IFS, LFT-like, DFSP-like, and a spindle cell lesion with a predominant myxoid stroma of children and adolescents showed that these neoplasms with a broad morphologic spectrum belong to the group of protein kinase-related lesions with a distinct epigenetic signature. Molecular analyses, including DNAmp, help to identify and characterize this emerging category and become mandatory when targeted treatment is considered.


Asunto(s)
Receptores ErbB , Humanos , Masculino , Femenino , Receptores ErbB/genética , Niño , Preescolar , Adolescente , Lactante , Estudios Retrospectivos , Mutación , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/enzimología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Metilación de ADN , Inmunohistoquímica
4.
ACR Open Rheumatol ; 6(8): 454-462, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38695166

RESUMEN

OBJECTIVE: In 2019, the EULAR/American College of Rheumatology developed classification criteria for systemic lupus erythematosus (SLE). A positive correlation between summary score at diagnosis and SLE disease activity at five years has been noted in adult patients with lupus, but little is known among the pediatric population. We evaluated the prognostic value of higher summary scores and number of extrarenal domains at diagnosis (low/moderate number [1-5] vs high number [6-9]) to renal outcomes after one year of treatment in pediatric patients with lupus nephritis (LN). METHODS: This retrospective, single-center cohort study included 74 pediatric patients with LN. Published pediatric renal response definitions were used for our outcome measure (no, partial, and complete response). Descriptive statistics were reported, and an ordinal logistic regression estimated adjusted odds ratios (ORs) for renal response including 95% confidence intervals (CIs). RESULTS: Patients with high extrarenal domains had OR 1.47 (95% CI 0.55-2.91) of having a complete renal response compared to patients with low/moderate domains. Patients with a summary score <30 had OR 1.31 (95% CI 0.50-3.44) of having a complete renal response relative to a summary score ≥30, though a larger proportion of patients with a summary score of ≥30 had no renal response after one year of treatment. CONCLUSION: More extrarenal domains at diagnosis did not have a statistically significant impact on renal response at one year, nor did a higher summary score. However, a larger portion of patients with a summary score <30 achieved complete renal response compared to patients with a score ≥30.

6.
NPJ Precis Oncol ; 8(1): 92, 2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38637626

RESUMEN

In vitro models of pediatric brain tumors (pBT) are instrumental for better understanding the mechanisms contributing to oncogenesis and testing new therapies; thus, ideally, they should recapitulate the original tumor. We applied DNA methylation (DNAm) and copy number variation (CNV) profiling to characterize 241 pBT samples, including 155 tumors and 86 pBT-derived cell cultures, considering serum vs serum-free conditions, late vs early passages, and dimensionality (2D vs 3D cultures). We performed a t-SNE classification and identified differentially methylated regions in tumors compared to cell models. Early cell cultures recapitulate the original tumor, but serum media and 2D culturing were demonstrated to significantly contribute to the divergence of DNAm profiles from the parental ones. All divergent cells clustered together acquiring a common deregulated epigenetic signature suggesting a shared selective pressure. We identified a set of hypomethylated genes shared among unfaithful cells converging on response to growth factors and migration pathways, such as signaling cascade activation, tissue organization, and cellular migration. In conclusion, DNAm and CNV are informative tools that should be used to assess the recapitulation of pBT-cells from parental tumors.

7.
Cancer Lett ; 588: 216711, 2024 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-38423245

RESUMEN

Five-year glioblastoma (GBM) survivors (LTS) are the minority of the isocitrate dehydrogenase (IDH)-wild-type GBM patients, and their molecular fingerprint is still largely unexplored. This multicenter retrospective study analyzed a large LTS-GBM cohort from nine Italian institutions and molecularly characterized a subgroup of patients by mutation, DNA methylation (DNAm) and copy number variation (CNV) profiling, comparing it to standard survival GBM. Mutation scan allowed the identification of pathogenic variants in most cases, showing a similar mutational spectrum in both groups, and highlighted TP53 as the most commonly mutated gene in the LTS group. We confirmed DNAm as a valuable tool for GBM classification with a diagnostic refinement by using brain tumor classifier v12.5. LTS were more heterogeneous with more cases classified as diffuse pediatric high-grade glioma subtypes and having peculiar CNVs. We observed a global higher methylation in CpG islands and in gene promoters of LTS with methylation levels of distinct gene promoters correlating with prognosis.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Niño , Glioblastoma/patología , Estudios Retrospectivos , Isocitrato Deshidrogenasa/genética , Variaciones en el Número de Copia de ADN , Neoplasias Encefálicas/patología , Mutación , Pronóstico , Metilación de ADN , Sobrevivientes
8.
Clin Epigenetics ; 16(1): 9, 2024 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-38178234

RESUMEN

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) account for 3-10% of pediatric sarcomas, 50% of which occur in neurofibromatosis type 1 (NF1). Sporadic MPNSTs diagnosis may be challenging due to the absence of specific markers, apart from immunohistochemical H3K27me3 loss. DNA methylation (DNAm) profiling is a useful tool for brain and mesenchymal neoplasms categorization, and MPNSTs exhibit a specific DNAm signature. An MPNST-like group has recently been recognized, including pediatric tumors with retained H3K27me3 mark and clinical/histological features not yet well explored. This study aims to characterize the DNAm profile of pediatric/juvenile MPNSTs/MPNST-like entities and its diagnostic/prognostic relevance. RESULTS: We studied 42 tumors from two groups. Group 1 included 32 tumors histologically diagnosed as atypical neurofibroma (ANF) (N = 5) or MPNST (N = 27); group 2 comprised 10 tumors classified as MPNST-like according to Heidelberg sarcoma classifier. We performed further immunohistochemical and molecular tests to reach an integrated diagnosis. In group 1, DNAm profiling was inconclusive for ANF; while, it confirmed the original diagnosis in 12/27 MPNSTs, all occurring in NF1 patients. Five/27 MPNSTs were classified as MPNST-like: Integrated diagnosis confirmed MPNST identity for 3 cases; while, the immunophenotype supported the change to high-grade undifferentiated spindle cell sarcoma in 2 samples. The remaining 10/27 MPNSTs variably classified as schwannoma, osteosarcoma, BCOR-altered sarcoma, rhabdomyosarcoma (RMS)-MYOD1 mutant, RMS-like, and embryonal RMS or did not match with any defined entity. Molecular analysis and histologic review confirmed the diagnoses of BCOR, RMS-MYOD1 mutant, DICER1-syndrome and ERMS. Group 2 samples included 5 high-grade undifferentiated sarcomas/MPNSTs and 5 low-grade mesenchymal neoplasms. Two high-grade and 4 low-grade lesions harbored tyrosine kinase (TRK) gene fusions. By HDBSCAN clustering analysis of the whole cohort we identified two clusters mainly distinguished by H3K27me3 epigenetic signature. Exploring the copy number variation, high-grade tumors showed frequent chromosomal aberrations and CDKN2A/B loss significantly impacted on survival in the MPNSTs cohort. CONCLUSION: DNAm profiling is a useful tool in diagnostic work-up of MPNSTs. Its application in a retrospective series collected during pre-molecular era contributed to classify morphologic mimics. The methylation group MPNST-like is a 'hybrid' category in pediatrics including high-grade and low-grade tumors mainly characterized by TRK alterations.


Asunto(s)
Neoplasias Óseas , Neurofibrosarcoma , Rabdomiosarcoma , Sarcoma , Humanos , Niño , Neurofibrosarcoma/diagnóstico , Neurofibrosarcoma/genética , Neurofibrosarcoma/patología , Histonas/metabolismo , Metilación de ADN , Estudios Retrospectivos , Variaciones en el Número de Copia de ADN , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/patología , Proteínas Tirosina Quinasas , Ribonucleasa III , ARN Helicasas DEAD-box
9.
Mod Pathol ; 37(2): 100387, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38007157

RESUMEN

PATZ1-rearranged sarcomas are well-recognized tumors as part of the family of round cell sarcoma with EWSR1-non-ETS fusions. Whether PATZ1-rearranged central nervous system (CNS) tumors are a distinct tumor type is debatable. We thoroughly characterized a pediatric series of PATZ1-rearranged CNS tumors by chromosome microarray analysis (CMA), DNA methylation analysis, gene expression profiling and, when frozen tissue is available, optical genome mapping (OGM). The series consisted of 7 cases (M:F=1.3:1, 1-17 years, median 12). On MRI, the tumors were supratentorial in close relation to the lateral ventricles (intraventricular or iuxtaventricular), preferentially located in the occipital lobe. Two major histologic groups were identified: one (4 cases) with an overall glial appearance, indicated as "neuroepithelial" (NET) by analogy with the corresponding methylation class (MC); the other (3 cases) with a predominant spindle cell sarcoma morphology, indicated as "sarcomatous" (SM). A single distinct methylation cluster encompassing both groups was identified by multidimensional scaling analysis. Despite the epigenetic homogeneity, unsupervised clustering analysis of gene expression profiles revealed 2 distinct transcriptional subgroups correlating with the histologic phenotypes. Interestingly, genes implicated in epithelial-mesenchymal transition and extracellular matrix composition were enriched in the subgroup associated to the SM phenotype. The combined use of CMA and OGM enabled the identification of chromosome 22 chromothripsis in all cases suitable for the analyses, explaining the physical association of PATZ1 to EWSR1 or MN1. Six patients are currently disease-free (median follow-up 30 months, range 12-92). One patient of the SM group developed spinal metastases at 26 months from diagnosis and is currently receiving multimodal therapy (42 months). Our data suggest that PATZ1-CNS tumors are defined by chromosome 22 chromothripsis as causative of PATZ1 fusion, show peculiar MRI features (eg, relation to lateral ventricles, supratentorial frequently posterior site), and, although epigenetically homogenous, encompass 2 distinct histologic and transcriptional subgroups.


Asunto(s)
Cromotripsis , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Niño , Factores de Transcripción/genética , Sarcoma/genética , Proteína EWS de Unión a ARN/genética , Sistema Nervioso Central/patología , Transcriptoma , Neoplasias de los Tejidos Blandos/genética , Proteínas Represoras/genética , Factores de Transcripción de Tipo Kruppel/genética
10.
Front Oncol ; 11: 689833, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34262872

RESUMEN

BACKGROUND AND OBJECTIVES: The treatment of asymptomatic patients with congenital pulmonary malformations (CPMs) remains controversial, partially because the relationship between congenital lung malformations and malignancy is still undefined. Change in methylation pattern is a crucial event in human cancer, including lung cancer. We therefore studied all differentially methylated regions (DMRs) in a series of CPMs in an attempt to find methylation anomalies in genes already described in association with malignancy. METHODS: The DNA extracted from resected congenital lung malformations and control lung tissue was screened using Illumina MethylationEPIC arrays. Comparisons between the group of malformed samples or the malformed samples of same histology or each malformed sample and the controls and between a pleuropulmonary blastoma (PPB) and controls were performed. Moreover, each malformed sample was pairwise compared with its respective control. All differentially methylated regions (DMRs) with an adjusted p-value <0,05 were studied. RESULTS: Every comparison highlighted a number of DMRs closed to genes involved either in cell proliferation or in embryonic development or included in the Cancer Gene Census. Their abnormal methylation had been already described in lung tumors. CONCLUSIONS: Methylation anomalies already described in lung tumors and also shared by the PPB were found in congenital lung malformations, regardless the histology. The presence of methylation abnormalities is suggestive of a correlation between congenital lung malformations and some step of malignant transformation.

11.
J Pediatric Infect Dis Soc ; 10(5): 650-658, 2021 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-33595081

RESUMEN

BACKGROUND: Third-generation cephalosporin-resistant urinary tract infections (UTIs) often have limited oral antibiotic options with some children receiving prolonged parenteral courses. Our objectives were to determine predictors of long parenteral therapy and the association between parenteral therapy duration and UTI relapse in children with third-generation cephalosporin-resistant UTIs. METHODS: We conducted a multisite retrospective cohort study of children <18 years presenting to acute care at 5 children's hospitals and a large managed care organization from 2012 to 2017 with a third-generation cephalosporin-resistant UTI from Escherichia coli or Klebsiella spp. Long parenteral therapy was ≥3 days and short/no parenteral therapy was 0-2 days of concordant parenteral antibiotics. Discordant therapy was antibiotics to which the pathogen was non-susceptible. Relapse was a UTI from the same organism within 30 days. RESULTS: Of the 482 children included, 81% were female and the median age was 3.3 years (interquartile range: 0.8-8). Fifty-four children (11.2%) received long parenteral therapy (median duration: 7 days). Predictors of long parenteral therapy included age <2 months (adjusted odds ratio [aOR] 67.3; 95% confidence interval [CI]: 16.4-275.7), limited oral antibiotic options (aOR 5.9; 95% CI: 2.8-12.3), and genitourinary abnormalities (aOR 5.4; 95% CI: 1.8-15.9). UTI relapse occurred in 1 of the 54 (1.9%) children treated with long parenteral therapy and in 6 of the 428 (1.5%) children treated with short/no parenteral therapy (P = .57). Of the 105 children treated exclusively with discordant antibiotics, 3 (2.9%, 95% CI: 0.6%-8.1%) experienced UTI relapse. CONCLUSIONS: Long parenteral therapy was associated with age <2 months, limited oral antibiotic options, and genitourinary abnormalities. UTI relapse was rare and not associated with duration of parenteral therapy. For UTIs with limited oral options, further research is needed on the effectiveness of continued discordant therapy.


Asunto(s)
Farmacorresistencia Bacteriana , Infecciones Urinarias , Antibacterianos/uso terapéutico , Cefalosporinas , Niño , Preescolar , Escherichia coli , Femenino , Humanos , Lactante , Estudios Retrospectivos , Infecciones Urinarias/tratamiento farmacológico
12.
Pediatrics ; 145(2)2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31953316

RESUMEN

OBJECTIVES: To describe the initial clinical response and care escalation needs for children with urinary tract infections (UTIs) resistant to third-generation cephalosporins while on discordant antibiotics. METHODS: We performed a retrospective study of children <18 years old presenting to an acute care setting of 5 children's hospitals and a large managed care organization from 2012 to 2017 with third-generation cephalosporin-resistant UTIs (defined as the growth of ≥50 000 colony-forming units per mL of Escherichia coli or Klebsiella spp. nonsusceptible to ceftriaxone with a positive urinalysis). We included children started on discordant antibiotics who had follow-up when culture susceptibilities resulted. Outcomes were escalation of care (emergency department visit, hospital admission, or ICU transfer while on discordant therapy) and clinical response at follow-up (classified as improved or not improved). RESULTS: Of the 316 children included, 78% were girls and the median age was 2.4 years (interquartile range 0.6-6.5). Children were evaluated in the emergency department (56%) or clinic (43%), and 90% were started on a cephalosporin. A total of 7 of 316 children (2.2%; 95% confidence interval 0.8%-4.5%) experienced escalation of care. For the 230 children (73%) with clinical response recorded, 192 of 230 (83.5%; 95% confidence interval 78.0%-88.0%) experienced clinical improvement. In children with repeat urine testing while on discordant therapy, pyuria improved or resolved in 16 of 19 (84%) and urine cultures sterilized in 11 of 17 (65%). CONCLUSIONS: Most children with third-generation cephalosporin-resistant UTIs started on discordant antibiotics experienced initial clinical improvement, and few required escalation of care. Our findings suggest that narrow-spectrum empiric therapy is appropriate while awaiting final urine culture results.


Asunto(s)
Antibacterianos/uso terapéutico , Resistencia a las Cefalosporinas , Infecciones Urinarias/tratamiento farmacológico , Carga Bacteriana , Niño , Preescolar , Intervalos de Confianza , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Femenino , Humanos , Lactante , Klebsiella/efectos de los fármacos , Klebsiella/crecimiento & desarrollo , Masculino , Estudios Retrospectivos , Infecciones Urinarias/microbiología
13.
Neurobiol Aging ; 84: 239.e9-239.e14, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31000212

RESUMEN

Variants in tank-binding kinase 1 (TBK1) are responsible for a significant proportion of amyotrophic lateral sclerosis (ALS) cases. In the present study, we analyzed variants in TBK1 extracted by targeted sequencing of 32 genes in a group of 406 Italian patients with ALS. We identified 7 different TBK1 variants in 7 sporadic cases, resulting in a frequency of 1.7%. Three patients had missense variants (p.R357Q, p.R358H, and p.R724C), one patient had a small deletion (p.E618del), and 3 had truncating variants (p.Y482*, p.R229*, and p.N681*). Notably, we found that 4 patients had an additional variant in ALS-related genes: 2 in OPTN and 2 in the 3'UTR region of FUS. By studying an independent group of 7 TBK1-mutated patients previously reported, we found another variant in the 3'UTR region of FUS in one patient. The presence of a second variant in TBK1 variant carriers is an interesting finding that needs to be investigated in larger cohorts of patients. These findings suggest that TBK1 belongs to the category of genes conferring a significantly increased risk but not sufficient to cause disease.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Variación Genética , Proteínas Serina-Treonina Quinasas/genética
14.
Am J Med Genet A ; 176(2): 455-459, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29226580

RESUMEN

KAT6B sequence variants have been identified in both patients with the Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and in the genitopatellar syndrome (GPS). In SBBYSS, they were reported to affect mostly exons 16-18 of KAT6B, and the predicted mechanism of pathogenesis was haploinsufficiency or a partial loss of protein function. Truncating variants in KAT6B leading to GPS appear to cluster within the proximal portion of exon 18, associated with a dominant-negative effect of the mutated protein, most likely. Although SBBYSS and GPS have been initially considered allelic disorders with distinctive genetic and clinical features, there is evidence that they represent two ends of a spectrum of conditions referable as KAT6B-related disorders. We detected a de novo truncating variant within exon 7 of KAT6B in a 8-year-old female who presented with mild intellectual disability, facial dysmorphisms highly consistent with SBBYSS, and skeletal anomalies including exostosis, that are usually considered component manifestations of GPS. Following the clinical diagnosis driven by the striking facial phenotype, we analyzed the KAT6B gene by NGS techniques. The present report highlights the pivotal role of clinical genetics in avoiding clear-cut genotype-phenotype categories in syndromic forms of intellectual disability. In addition, it further supports the evidence that a continuum exists within the clinical spectrum of KAT6B-associated disorders.


Asunto(s)
Blefarofimosis/genética , Hipotiroidismo Congénito/genética , Anomalías Craneofaciales/genética , Cardiopatías Congénitas/genética , Histona Acetiltransferasas/genética , Discapacidad Intelectual/genética , Inestabilidad de la Articulación/genética , Riñón/anomalías , Rótula/anomalías , Trastornos Psicomotores/genética , Escroto/anomalías , Anomalías Urogenitales/genética , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Alelos , Blefarofimosis/fisiopatología , Niño , Hipotiroidismo Congénito/fisiopatología , Anomalías Craneofaciales/fisiopatología , Exones , Facies , Femenino , Estudios de Asociación Genética , Haploinsuficiencia/genética , Cardiopatías Congénitas/fisiopatología , Humanos , Discapacidad Intelectual/fisiopatología , Inestabilidad de la Articulación/fisiopatología , Riñón/fisiopatología , Mutación , Rótula/fisiopatología , Fenotipo , Trastornos Psicomotores/fisiopatología , Escroto/fisiopatología , Anomalías Urogenitales/fisiopatología
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