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1.
Neuro Oncol ; 25(7): 1331-1342, 2023 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-36541551

RESUMEN

BACKGROUND: To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available. METHODS: We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n = 40/579) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on pediatric high-grade gliomas (pHGGs) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations. RESULTS: ALT is common in pHGGs (n = 24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ pHGGs and in 30% of ALT- pHGGs. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT. CONCLUSIONS: We demonstrate that ATRX is mutated in only a subset of ALT+ pHGGs, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with the development of ALT in patients with pHGG.


Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Niño , Reparación de la Incompatibilidad de ADN , Homeostasis del Telómero/genética , Proteína Nuclear Ligada al Cromosoma X/genética , Glioma/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Mutación , Telómero/genética , Telómero/patología
2.
Cancer Causes Control ; 27(10): 1209-18, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27541142

RESUMEN

PURPOSE: Neuroblastoma is a childhood cancer of the sympathetic nervous system with embryonic origins. Previous epidemiologic studies suggest maternal vitamin supplementation during pregnancy reduces the risk of neuroblastoma. We hypothesized offspring and maternal genetic variants in folate-related and choline-related genes are associated with neuroblastoma and modify the effects of maternal intake of folate, choline, and folic acid. METHODS: The Neuroblastoma Epidemiology in North America (NENA) study recruited 563 affected children and their parents through the Children's Oncology Group's Childhood Cancer Research Network. We used questionnaires to ascertain pre-pregnancy supplementation and estimate usual maternal dietary intake of folate, choline, and folic acid. We genotyped 955 genetic variants related to folate or choline using DNA extracted from saliva samples and used a log-linear model to estimate both child and maternal risk ratios and stratum-specific risk ratios for gene-environment interactions. RESULTS: Overall, no maternal or offspring genotypic results met criteria for a false discovery rate (FDR) Q-value <0.2. Associations were also null for gene-environment interaction with pre-pregnancy vitamin supplementation, dietary folic acid, and folate. FDR-significant gene-choline interactions were found for offspring SNPs rs10489810 and rs9966612 located in MTHFD1L and TYMS, respectively, with maternal choline dietary intake dichotomized at the first quartile. CONCLUSION: These results suggest that variants related to one-carbon metabolism are not strongly associated with neuroblastoma. Choline-related variants may play a role; however, the functional consequences of the interacting variants are unknown and require independent replication.


Asunto(s)
Colina/administración & dosificación , Ácido Fólico/administración & dosificación , Neuroblastoma/epidemiología , Neuroblastoma/genética , Preescolar , Colina/metabolismo , Suplementos Dietéticos/estadística & datos numéricos , Femenino , Ácido Fólico/metabolismo , Interacción Gen-Ambiente , Variación Genética , Genotipo , Humanos , Lactante , Masculino , Neuroblastoma/metabolismo , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Embarazo , Sistema de Registros , Estados Unidos/epidemiología
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