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1.
Artigo em Inglês | MEDLINE | ID: mdl-31624068

RESUMO

Ultra-hypermutation (>100 mutations/Mb) is rare in childhood cancer genomes and has been primarily reported in patients with constitutional mismatch repair deficiency (CMMRD) caused by biallelic germline mismatch repair (MMR) gene mutations. We report a 5-yr-old child with classic clinical features of CMMRD and an ultra-hypermutated medulloblastoma with retained MMR protein expression and absence of germline MMR mutations. Mutational signature analysis of tumor panel sequencing data revealed a canonical DNA polymerase-deficiency-associated signature, prompting further genetic testing that uncovered a germline POLE p.A456P missense variant, which has previously been reported as a recurrent somatic driver mutation in cancers. This represents the earliest known onset of malignancy in a patient with a germline mutation in the POLE proofreading polymerase. The clinical features in this child, virtually indistinguishable from those of CMMRD, suggest that polymerase-proofreading deficiency should be considered in the differential diagnosis of CMMRD patients with retained MMR function.

2.
Cancer Epidemiol ; 59: 71-74, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30703618

RESUMO

INTRODUCTION: Methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) has been identified as a potential prognostic biomarker of outcomes in various cancers. We evaluated the prognostic value of blood-derived mdNLR within a retrospective cohort of pediatric medulloblastoma patients. MATERIALS AND METHODS: DNA methylation was measured in archival peripheral blood samples collected on 56 pediatric medulloblastoma patients. Hazard ratios (HR) and 95% confidence intervals (CI) for the association between mdNLR and survival were evaluated using Cox proportional hazard models. RESULTS: Compared to patients who were alive at last follow-up (n = 43), the mean mdNLR value was slightly higher in deceased patients (n = 13) (12.3 vs. 5.2,P = 0.163). Elevated log-transformed mdNLR was suggestively associated with an increased likelihood of death in unadjusted models (HR=1.43, 95%CI: 0.92-2.22) and significantly associated with mortality in adjusted models (HR=1.61, 95%CI: 1.01-2.58). DISCUSSION: Future work is warranted to investigate the relationship between mdNLR outcomes in specific pediatric medulloblastoma molecular subgroups.

3.
Curr Opin Pediatr ; 31(1): 41-47, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30531401

RESUMO

PURPOSE OF REVIEW: A significant proportion of pediatric cancer occurs in children with hereditary cancer predisposition syndromes. Their survival may be significantly improved and/or late effects diminished through screening for their greatly elevated cancer risks. Here, an overview of new developments in the field of pediatric cancer surveillance is provided. RECENT FINDINGS: Consensus-based screening guidelines have been developed for most syndromes associated with childhood cancer risks. Studies evaluating the clinical utility of these screening regimens have also been emerging. This review focuses on three conditions for which consensus screening recommendations have been evolving in response to new evidence: Beckwith-Wiedemann syndrome, Li-Fraumeni syndrome, and constitutional mismatch repair deficiency syndrome. For each condition, recently proposed screening guidelines and relevant evidence are described and potential future directions for improving cancer surveillance practices are anticipated. Also, the implications of several recent studies exploring the psychosocial aspects of screening in these conditions are discussed. SUMMARY: Significant strides have been made in cancer surveillance for children with hereditary cancer predisposition syndromes. A continued emphasis on consensus-driven screening guidelines and collaborative research evaluating the clinical utility of recommended screening methodologies will lead to further improvements in the clinical outcomes of these vulnerable children.

5.
Genet Med ; 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30190611

RESUMO

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

6.
Ther Adv Endocrinol Metab ; 9(9): 299-301, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30181857

RESUMO

Individuals with PTEN Hamartoma Tumor Syndrome (PHTS) are at greatly increased risk for developing well-differentiated thyroid cancer. Specific circumstances in which total thyroidectomies should be considered have not been defined. A 14-year-old macrocephalic female with history of developmental delay and lipoma over her left flank presented with neck swelling and was found have multinodular goiter and auto-immune thyroiditis. Asymptomatic tracheal narrowing was also detected on her initial diagnostic imaging. Later on, she developed positional dyspnea during sleep. Genetic testing revealed a heterozygous pathogenic variant in the PTEN gene (c.463T>A). A total thyroidectomy was performed. In addition to addressing the symptomology in our case, a total thyroidectomy also fortuitously eliminated the thyroid cancer risk. This case spurred us on further to identify specific clinical scenarios where total thyroidectomy may be considered as a true prophylactic measure to manage thyroid cancer risk in PHTS patients.

7.
Am J Hum Genet ; 101(4): 503-515, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28942966

RESUMO

Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.


Assuntos
Anormalidades Múltiplas/genética , Antígenos Nucleares/genética , Anormalidades Craniofaciais/genética , Regulação da Expressão Gênica no Desenvolvimento , Haploinsuficiência/genética , Transtornos do Desenvolvimento da Linguagem/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/patologia , Adolescente , Animais , Antígenos Nucleares/metabolismo , Sistemas CRISPR-Cas , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Montagem e Desmontagem da Cromatina , Estudos de Coortes , Anormalidades Craniofaciais/patologia , Feminino , Edição de Genes , Haploinsuficiência/fisiologia , Humanos , Transtornos do Desenvolvimento da Linguagem/patologia , Larva/genética , Larva/crescimento & desenvolvimento , Masculino , Microcefalia/patologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Fenótipo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
8.
JAMA Oncol ; 3(12): 1634-1639, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28772291

RESUMO

Importance: Guidelines for clinical management in Li-Fraumeni syndrome, a multiple-organ cancer predisposition condition, are limited. Whole-body magnetic resonance imaging (WBMRI) may play a role in surveillance of this high-risk population. Objective: To assess the clinical utility of WBMRI in germline TP53 mutation carriers at baseline. Data Sources: Clinical and research surveillance cohorts were identified through the Li-Fraumeni Exploration Research Consortium. Study Selection: Cohorts that incorporated WBMRI for individuals with germline TP53 mutations from January 1, 2004, through October 1, 2016, were included. Data Extraction and Synthesis: Data were extracted by investigators from each cohort independently and synthesized by 2 investigators. Random-effects meta-analysis methods were used to estimate proportions. Main Outcomes and Measures: The proportions of participants at baseline in whom a lesion was detected that required follow-up and in whom a new primary malignant neoplasm was detected. Results: A total of 578 participants (376 female [65.1%] and 202 male [34.9%]; mean [SD] age, 33.2 [17.1] years) from 13 cohorts in 6 countries were included in the analysis. Two hundred twenty-five lesions requiring clinical follow-up were detected by WBMRI in 173 participants. Sixty-one lesions were diagnosed in 54 individuals as benign or malignant neoplasms. Overall, 42 cancers were identified in 39 individuals, with 35 new localized cancers treated with curative intent. The overall estimated detection rate for new, localized primary cancers was 7% (95% CI, 5%-9%). Conclusions and Relevance: These data suggest clinical utility of baseline WBMRI in TP53 germline mutation carriers and may form an integral part of baseline clinical risk management in this high-risk population.

9.
Clin Cancer Res ; 23(13): e115-e122, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28674120

RESUMO

A number of genetic syndromes have been linked to increased risk for Wilms tumor (WT), hepatoblastoma (HB), and other embryonal tumors. Here, we outline these rare syndromes with at least a 1% risk to develop these tumors and recommend uniform tumor screening recommendations for North America. Specifically, for syndromes with increased risk for WT, we recommend renal ultrasounds every 3 months from birth (or the time of diagnosis) through the seventh birthday. For HB, we recommend screening with full abdominal ultrasound and alpha-fetoprotein serum measurements every 3 months from birth (or the time of diagnosis) through the fourth birthday. We recommend that when possible, these patients be evaluated and monitored by cancer predisposition specialists. At this time, these recommendations are not based on the differential risk between different genetic or epigenetic causes for each syndrome, which some European centers have implemented. This differentiated approach largely represents distinct practice environments between the United States and Europe, and these guidelines are designed to be a broad framework within which physicians and families can work together to implement specific screening. Further study is expected to lead to modifications of these recommendations. Clin Cancer Res; 23(13); e115-e22. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.


Assuntos
Detecção Precoce de Câncer , Predisposição Genética para Doença/epidemiologia , Hepatoblastoma/diagnóstico , Tumor de Wilms/diagnóstico , Europa (Continente)/epidemiologia , Hepatoblastoma/epidemiologia , Hepatoblastoma/genética , Humanos , Lactente , Masculino , Oncologia , Fatores de Risco , Estados Unidos/epidemiologia , Tumor de Wilms/epidemiologia , Tumor de Wilms/genética
10.
Clin Cancer Res ; 23(13): e123-e132, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28674121

RESUMO

Children and adolescents who present with neuroendocrine tumors are at extremely high likelihood of having an underlying germline predisposition for the multiple endocrine neoplasia (MEN) syndromes, including MEN1, MEN2A and MEN2B, MEN4, and hyperparathyroid-jaw tumor (HPT-JT) syndromes. Each of these autosomal dominant syndromes results from a specific germline mutation in unique genes: MEN1 is due to pathogenic MEN1 variants (11q13), MEN2A and MEN2B are due to pathogenic RET variants (10q11.21), MEN4 is due to pathogenic CDKN1B variants (12p13.1), and the HPT-JT syndrome is due to pathogenic CDC73 variants (1q25). Although each of these genetic syndromes share the presence of neuroendocrine tumors, each syndrome has a slightly different tumor spectrum with specific surveillance recommendations based upon tumor penetrance, including the age and location for which specific tumor types most commonly present. Although the recommended surveillance strategies for each syndrome contain similar approaches, important differences do exist among them. Therefore, it is important for caregivers of children and adolescents with these syndromes to become familiar with the unique diagnostic criteria for each syndrome, and also to be aware of the specific tumor screening and prophylactic surgery recommendations for each syndrome. Clin Cancer Res; 23(13); e123-e32. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.


Assuntos
Adenoma/genética , Fibroma/genética , Hiperparatireoidismo/genética , Neoplasias Maxilomandibulares/genética , Neoplasia Endócrina Múltipla/genética , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética , Adenoma/diagnóstico , Adenoma/epidemiologia , Adolescente , Criança , Fibroma/diagnóstico , Fibroma/epidemiologia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Humanos , Hiperparatireoidismo/diagnóstico , Hiperparatireoidismo/epidemiologia , Neoplasias Maxilomandibulares/diagnóstico , Neoplasias Maxilomandibulares/epidemiologia , Neoplasia Endócrina Múltipla/diagnóstico , Neoplasia Endócrina Múltipla/epidemiologia , Neoplasia Endócrina Múltipla Tipo 2b/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2b/epidemiologia , Neoplasia Endócrina Múltipla Tipo 2b/genética , Fatores de Risco
11.
Clin Cancer Res ; 23(12): e68-e75, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28620007

RESUMO

Von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition syndrome that places affected individuals at risk for multiple tumors, which are predominantly benign and generally occur in the central nervous system or abdomen. Although the majority of tumors occur in adults, children and adolescents with the condition develop a significant proportion of vHL manifestations and are vulnerable to delayed tumor detection and their sequelae. Although multiple tumor screening paradigms are currently being utilized for patients with vHL, surveillance should be reassessed as the available relevant clinical information continues to expand. We propose a new vHL screening paradigm similar to existing approaches, with important modifications for some tumor types, placing an emphasis on risks in childhood. This includes advancement in the timing of surveillance initiation and increased frequency of screening evaluations. Another neuroendocrine-related familial condition is the rapidly expanding hereditary paraganglioma and pheochromocytoma syndrome (HPP). The tumor spectrum for patients with HPP syndrome includes paragangliomas, pheochromocytomas, renal cancer, and gastrointestinal stromal tumors. The majority of patients with HPP syndrome harbor an underlying variant in one of the SHDx genes (SDHA, SDHB, SDHC, SDHD, SDHA, and SDHAF2), although other genes also have been described (MAX and TMEM127). Annual screening for elevated plasma or urine markers along with complete blood count and biennial whole-body MRI accompanied by focal neck MRI is recommended for older children and adults with HPP syndrome to detect tumors early and to decrease morbidity and mortality from HPP-related tumors. Clin Cancer Res; 23(12); e68-e75. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Doença de von Hippel-Lindau/diagnóstico , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/patologia , Detecção Precoce de Câncer , Humanos , Mutação , Proteínas de Neoplasias/genética , Paraganglioma/epidemiologia , Paraganglioma/genética , Paraganglioma/patologia , Feocromocitoma/epidemiologia , Feocromocitoma/genética , Feocromocitoma/patologia , Fatores de Risco , Doença de von Hippel-Lindau/epidemiologia , Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/patologia
12.
Clin Cancer Res ; 23(12): e76-e82, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28620008

RESUMO

PTEN hamartoma tumor syndrome (PHTS), DICER1 syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumor predisposition syndromes that include benign and malignant neoplasms affecting adults and children. PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma. Thyroid cancer represents the predominant cancer risk under age 20 years. DICER1 syndrome includes risk for pleuropulmonary blastoma, cystic nephroma, ovarian sex cord-stromal tumors, and multinodular goiter and thyroid carcinoma as well as brain tumors including pineoblastoma and pituitary blastoma. Individuals with HLRCC may develop multiple cutaneous and uterine leiomyomas, and they have an elevated risk of renal cell carcinoma. For each of these syndromes, a summary of the key syndromic features is provided, the underlying genetic events are discussed, and specific screening is recommended. Clin Cancer Res; 23(12); e76-e82. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.


Assuntos
RNA Helicases DEAD-box/genética , Fumarato Hidratase/genética , Síndrome do Hamartoma Múltiplo/genética , Leiomiomatose/genética , Síndromes Neoplásicas Hereditárias/genética , PTEN Fosfo-Hidrolase/genética , Ribonuclease III/genética , Neoplasias Cutâneas/genética , Neoplasias Uterinas/genética , Criança , Detecção Precoce de Câncer , Síndrome do Hamartoma Múltiplo/epidemiologia , Síndrome do Hamartoma Múltiplo/patologia , Humanos , Leiomiomatose/epidemiologia , Leiomiomatose/patologia , Síndromes Neoplásicas Hereditárias/epidemiologia , Síndromes Neoplásicas Hereditárias/patologia , Fatores de Risco , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Neoplasias Uterinas/epidemiologia , Neoplasias Uterinas/patologia
13.
Neuro Oncol ; 19(10): 1372-1379, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28444219

RESUMO

Background: Ototoxicity is a common adverse side effect of platinum chemotherapy and cranial radiation therapy; however, individual susceptibility is highly variable. Therefore, our objective was to conduct an epigenome-wide association study to identify differentially methylated cytosine-phosphate-guanine (CpG) sites associated with ototoxicity susceptibility among cisplatin-treated pediatric patients with embryonal tumors. Methods: Samples were collected for a discovery cohort (n = 62) and a replication cohort (n = 18) of medulloblastoma and primitive neuroectodermal tumor patients. Posttreatment audiograms were evaluated using the International Society of Paediatric Oncology (SIOP) Boston Ototoxicity Scale. Genome-wide associations between CpG methylation and ototoxicity were examined using multiple linear regression, controlling for demographic and treatment factors. Results: The mean cumulative dose of cisplatin was 330 mg/m2 and the mean time from end of therapy to the last available audiogram was 6.9 years. In the discovery analysis of 435233 CpG sites, 6 sites were associated with ototoxicity grade (P < 5 × 10-5) after adjusting for confounders. Differential methylation at the top CpG site identified in the discovery cohort (cg14010619, PAK4 gene) was replicated (P = 0.029) and reached genome-wide significance (P = 2.73 × 10-8) in a combined analysis. These findings were robust to a sensitivity analysis evaluating other potential confounders. Conclusions: We identified and replicated a novel CpG methylation loci (cg14010619) associated with ototoxicity severity. Methylation at cg14010619 may modify PAK4 activity, which has been implicated in cisplatin resistance in malignant cell lines.


Assuntos
Neoplasias Cerebelares/terapia , Cisplatino/uso terapêutico , Metilação de DNA/fisiologia , Meduloblastoma/terapia , Quinases Ativadas por p21/metabolismo , Adolescente , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Perda Auditiva/induzido quimicamente , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Adulto Jovem , Quinases Ativadas por p21/genética
14.
J Neurosurg Pediatr ; 19(1): 102-107, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27689246

RESUMO

Neurofibrosarcoma is rare in the pediatric age group. A malignant tumor of the sacrum presents significant challenges, especially if the goals are to resect with wide and clean surgical margins and to achieve acceptable functional outcomes. The authors report a case of this rare tumor affecting the sacrum and sacral nerve roots of a 7-year-old girl and review the role of total hemisacrectomy sparing the contralateral sacral nerve roots and lumbopelvic reconstruction in the treatment of this disease. This patient is, to the best of the authors' knowledge, the youngest to be treated in this manner.


Assuntos
Neurofibrossarcoma/cirurgia , Ossos Pélvicos/cirurgia , Procedimentos Cirúrgicos Reconstrutivos/métodos , Articulação Sacroilíaca/cirurgia , Sacro/cirurgia , Raízes Nervosas Espinhais/cirurgia , Criança , Feminino , Seguimentos , Humanos , Neurofibrossarcoma/diagnóstico por imagem , Ossos Pélvicos/diagnóstico por imagem , Articulação Sacroilíaca/diagnóstico por imagem , Sacro/diagnóstico por imagem , Raízes Nervosas Espinhais/diagnóstico por imagem
15.
Cancer Epidemiol ; 44: 161-166, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27607585

RESUMO

AIM: Medulloblastoma is the most frequent malignant pediatric brain tumor. While survival rates have improved due to multimodal treatment including cisplatin-based chemotherapy, there are few prognostic factors for adverse treatment outcomes. Notably, genes involved in the nucleotide excision repair pathway, including ERCC2, have been implicated in cisplatin sensitivity in other cancers. Therefore, this study evaluated the role of ERCC2 DNA methylation profiles on pediatric medulloblastoma survival. METHODS: The study population included 71 medulloblastoma patients (age <18years at diagnosis) and recruited from Texas Children's Cancer Center between 2004 and 2009. DNA methylation profiles were generated from peripheral blood samples using the Illumina Infinium Human Methylation 450 Beadchip. Sixteen ERCC2-associated CpG sites were evaluated in this analysis. Multivariable regression models were used to determine the adjusted association between DNA methylation and survival. Cox regression and Kaplan-Meier curves were used to compare 5-year overall survival between hyper- and hypo-methylation at each CpG site. RESULTS: In total, 12.7% (n=9) of the patient population died within five years of diagnosis. In our population, methylation of the cg02257300 probe (Hazard Ratio=9.33; 95% Confidence Interval: 1.17-74.64) was associated with death (log-rank p=0.01). This association remained suggestive after correcting for multiple comparisons (FDR p<0.2). No other ERCC2-associated CpG site was associated with survival in this population of pediatric medulloblastoma patients. CONCLUSION: These findings provide the first evidence that DNA methylation within the promoter region of the ERCC2 gene may be associated with survival in pediatric medulloblastoma. If confirmed in future studies, this information may lead to improved risk stratification or promote the development of novel, targeted therapeutics.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Cerebelares/mortalidade , Metilação de DNA , DNA de Neoplasias/genética , Meduloblastoma/mortalidade , Proteína Grupo D do Xeroderma Pigmentoso/genética , Adolescente , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Ilhas de CpG/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Meduloblastoma/genética , Meduloblastoma/patologia , Regiões Promotoras Genéticas/genética , Texas
16.
Cancer Med ; 4(11): 1679-86, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26400460

RESUMO

Manganese superoxide dismutase (MnSOD), encoded by the SOD2 gene, is involved in the detoxification of superoxide anion. Superoxide is likely a source of oxidative stress in the cochlea following treatment with platinum agents and radiation. Therefore, we examined SOD2 variants in association with ototoxicity among cisplatin-treated childhood medulloblastoma patients. Blood samples were obtained from 71 eligible patients treated for pediatric medulloblastoma at Texas Children's Cancer Center (1987-2010). Ototoxicity was defined as requiring the use of a hearing aid sometime after the initiation of therapy. DNA was genotyped on the Illumina HumanOmni-1 Quad BeadChip. A linkage disequilibrium (LD)-based single-nucleotide polymorphism (SNP) selection strategy was used to identify a minimal set of informative variants. Associations between SNPs and ototoxicity were assessed using logistic regression. Of the 71 eligible patients, 26 (37%) suffered from cisplatin-related ototoxicity. Study participants were primarily male (73%) and non-Hispanic white (42%). Five SOD2 variants (rs7855, rs5746151, rs5746136, rs2758331, and rs4880) identified by the LD-based selection strategy were genotyped. After correcting for multiple comparisons, the C-allele of the rs4880 variant was significantly associated with ototoxicity (odds ratio = 3.06, 95% confidence interval: 1.30-7.20) in adjusted models. The rs4880 T > C substitution results in a Val > Ala amino acid change at position 16 of the MnSOD mitochondrial targeting sequence. The Ala variant, which has been associated with increased MnSOD activity, was associated with hearing damage in this study. Platinum-based therapies increase the expression of MnSOD, which may result in an abundance of hydrogen peroxide, a reactive oxygen species. Therefore, oxidative stress may be an important mechanism in therapy-related cochlear damage.


Assuntos
Neoplasias Cerebelares/complicações , Neoplasias Cerebelares/genética , Otopatias/etiologia , Predisposição Genética para Doença , Variação Genética , Meduloblastoma/complicações , Meduloblastoma/genética , Superóxido Dismutase/genética , Adolescente , Alelos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Estudos de Casos e Controles , Neoplasias Cerebelares/tratamento farmacológico , Criança , Pré-Escolar , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Meduloblastoma/tratamento farmacológico , Polimorfismo de Nucleotídeo Único
17.
Acta Neuropathol ; 128(4): 583-95, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25022261

RESUMO

Germ-line RB-1 mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line DICER1 mutation in a child with a PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of DICER1 mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for DICER1 mutations; three patients were known carriers of germ-line DICER1 mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify DICER1 mutations in blood gDNA and/or tumour gDNA. Testing for somatic DICER1 mutations was also conducted on one case with a known germ-line DICER1 mutation. From the eighteen PinBs, we identified four deleterious DICER1 mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic DICER1 RNase IIIb mutations were identified. One PinB arising in a germ-line DICER1 mutation carrier was found to have LOH. This study suggests that germ-line DICER1 mutations make a clinically significant contribution to PinB, establishing DICER1 as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line DICER1 mutation. The means by which the second allele is inactivated may differ from other DICER1-related tumours.


Assuntos
Neoplasias Encefálicas/genética , RNA Helicases DEAD-box/genética , Mutação em Linhagem Germinativa/genética , Glândula Pineal/patologia , Pinealoma/genética , Ribonuclease III/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Saúde da Família , Feminino , Humanos , Lactente , Masculino , Adulto Jovem
18.
Pediatr Blood Cancer ; 60(4): 593-8, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23065688

RESUMO

BACKGROUND: Glutathione S-transferase (GST) enzymes are involved in detoxifying chemotherapy and clearing reactive oxygen species formed by radiation. We explored the relationship between the host GSTP1 105 A > G polymorphism (rs1695), tumor GSTpi protein expression, and clinical outcomes in pediatric medulloblastoma. We hypothesized that the GSTP1 105 G-allele and increased tumor GSTpi expression would be associated with lower progression-free survival and fewer adverse events. PROCEDURE: The study included 106 medulloblastoma/primitive neuroectodermal tumor (PNET) patients seen at Texas Children's Cancer Center. Genotyping was performed using an Illumina HumanOmni1-Quad BeadChip and GSTpi expression was assessed using immunohistochemistry. We used the Kaplan-Meier method for survival analyses and logistic regression for toxicity comparisons. RESULTS: Patients with a GSTP1 105 AG/GG genotype (vs. AA) or who had received high dose craniospinal radiation (≥34 Gy vs. <26 Gy) had a greater risk of requiring hearing aids than their counterparts (OR 4.0, 95% CI 1.2-13.6, and OR 3.1, 95% CI 1.1-8.8, respectively, n = 69). Additionally, there was a statistically significant interaction between these variables. Compared with the lowest risk group (GSTP1 105 AA-low dose radiation), patients with a GSTP1 105 AG/GG genotype who received high dose radiation were 8.4 times more likely to require hearing aids (95% CI 1.4-49.9, p-trend = 0.005, n = 69). When adjusted for age, cumulative cisplatin dose, and amifostine use, the association remained. CONCLUSIONS: The GSTP1 105 G-allele is associated with permanent ototoxicity in pediatric medulloblastoma/PNET and strongly interacts with radiation dose. Patients with this allele should be considered for clinical trials employing radiation dose modifications and cytoprotectant strategies.


Assuntos
Neoplasias Cerebelares/radioterapia , Predisposição Genética para Doença/genética , Glutationa S-Transferase pi/genética , Perda Auditiva/etiologia , Meduloblastoma/radioterapia , Polimorfismo de Nucleotídeo Único , Radioterapia/efeitos adversos , Adolescente , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/mortalidade , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Imuno-Histoquímica , Lactente , Estimativa de Kaplan-Meier , Masculino , Meduloblastoma/genética , Meduloblastoma/mortalidade , Tumores Neuroectodérmicos Primitivos/genética , Tumores Neuroectodérmicos Primitivos/mortalidade , Tumores Neuroectodérmicos Primitivos/radioterapia
19.
J Pediatr Hematol Oncol ; 33(5): 387-9, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20829717

RESUMO

Pediatric oral squamous cell carcinoma is an extremely rare occurence. In our report, we describe a 6-year-old White female with sensorineural hearing loss found to have a Connexin 26 gene mutation who developed a well-differentiated squamous cell carcinoma of the hard palate with metastatic disease to submandibular lymph nodes and the lungs. This association emphasizes the need to consider Connexin 26 gene mutations in children who develop oral squamous cell carcinoma and to monitor for oral squamous cell carcinoma in children with Connexin 26 gene mutations.


Assuntos
Carcinoma de Células Escamosas/genética , Conexinas/genética , Neoplasias Orofaríngeas/genética , Neoplasias Palatinas/genética , Carcinoma de Células Escamosas/secundário , Criança , Conexina 26 , Evolução Fatal , Feminino , Perda Auditiva Neurossensorial/genética , Humanos , Metástase Linfática , Mutação , Neoplasias Orofaríngeas/secundário , Neoplasias Palatinas/patologia
20.
Pediatr Blood Cancer ; 54(7): 1041-4, 2010 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-20162687

RESUMO

We describe a male with a large abdominal mass, most likely originating from the liver, with capsule rupture and tumor dissemination into the abdominal cavity. Adherence of the tumor to the diaphragm and lower right colon also were noted. A comprehensive evaluation of the mass revealed no tumor-defining histopathologic, immunocytochemical, ultrastructural, cytogenetic, or translocation features. The malignant tumor was found to have a novel translocation (X;19)(q13;13.3), which has not been reported in small round cell tumors of childhood or adults. The final diagnosis rendered was an undifferentiated small round cell tumor of uncertain cell of origin.


Assuntos
Neoplasias Abdominais/genética , Neoplasias Abdominais/patologia , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , Cromossomos Humanos Par 19/genética , Cromossomos Humanos X/genética , Neoplasias Abdominais/metabolismo , Carcinoma de Células Pequenas/metabolismo , Criança , Humanos , Imuno-Histoquímica , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Translocação Genética
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