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Comprehensive molecular profiling of children with recurrent cancer II

ABSTRACT: Comprehensive molecular profiling of children with recurrent cancer II

PROVIDER: PRJNA422439 | ENA |

REPOSITORIES: ENA

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Project description:Preschool children with recurrent wheezing are heterogeneous, with differing responses to respiratory viral infections. Although neutrophils are crucial for host defense, their function has not been studied in this population. We performed functional immunophenotyping on isolated blood neutrophils from 52 preschool children with recurrent wheezing (aeroallergen sensitization, n=16; no sensitization, n=36). Blood neutrophils were purified and cultured overnight with polyinosinic:polycytidylic acid (poly(I:C)) as a viral analog stimulus. Neutrophils underwent next-generation sequencing with Reactome pathway analysis and were analyzed for cytokine secretion, apoptosis, myeloperoxidase and extracellular DNA release. CD14+ monocytes were also exposed to neutrophil culture supernatant and analyzed for markers of M1 and M2 activation. 495 genes, related largely to the innate immune system and neutrophil degranulation, were differently expressed in children with versus without aeroallergen sensitization. Functional experiments identified more neutrophil degranulation and extracellular trap formation (i.e., more myeloperoxidase and extracellular DNA) and less neutrophil pro-inflammatory cytokine secretion in children with aeroallergen sensitization. Neutrophils also shifted CD14+ monocytes to a more anti-inflammatory (i.e., M2) phenotype in sensitized children and a more pro-inflammatory (i.e., M1) phenotype in non-sensitized children. Although both groups experienced viral exacerbations, annualized exacerbation rates prompting unscheduled healthcare were also higher in children without aeroallergen sensitization after enrollment. Systemic neutrophil responses to viral infection differ by allergic phenotype and may be less effective in preschool children without allergic inflammation. Further studies of neutrophil function are needed in this population, which often has less favorable therapeutic responses to inhaled corticosteroids and other therapies directed at T2-high inflammation.

Project description:Ependymomas are neuroepithelial tumors of the central nervous system (CNS), presenting in both adults and children but accounting for almost 10% of all pediatric CNS tumors and up to 30% of CNS tumors in children under 3 years (Bouffet et al., 2009; McGuire et al., 2009; Rodriguez et al., 2009). In children, most ependymomas arise in the posterior fossa, while most adult ependymomas present around the lower spinal cord and spinal nerve roots. Ependymomas display a wide range of morphological features, and several variants are listed in the World Health Organization (WHO) classification (Ellison et al., 2016). These variants are assigned to three WHO grades (I-III), but the clinical utility of this classification is acknowledged to be limited (Ellison et al., 2011). An increasing understanding of the genomic landscape of ependymoma and the discovery of distinct molecular groups by DNA methylation or gene expression profiling have begun to refine approaches to disease classification and prognostication, but have yet to be translated into clinical routine (Hoffman et al., 2014; Mack et al., 2014; Pajtler et al., 2017; Pajtler et al., 2015; Parker et al., 2014; Wani et al., 2012; Witt et al., 2011). Our comprehensive study of DNA methylation profiling across the entire disease demonstrated three molecular groups for each major anatomic compartment: supratentorial (ST), posterior fossa (PF), and spinal (SP) (Pajtler et al., 2015). In the ST compartment, two molecular groups (ST-EPN-RELA and ST-EPN-YAP1) align with tumors harboring specific genetic alterations, RELA and YAP1 fusion genes, which were initially discovered in a whole genome sequencing study (Parker et al., 2014). Among PF ependymomas, two of three molecular groups, PFA (PF-EPN-A) and PFB (PF-EPN-B), account for nearly all tumors; PF-SE tumors are rare, generally showing the morphology of a subependymoma (Pajtler et al., 2015). PFA tumors are found mainly in infants and young children (median age ≈ 3yrs) and have a relatively poor outcome, while PFB tumors are generally found in young adults (median age ≈ 30yrs) and are associated with a better prognosis (Pajtler et al., 2015; Witt et al., 2011). PFA tumors show few copy number alterations (CNAs), while PFB tumors harbor multiple CNAs that tend to affect entire chromosomes. While recurrent structural variants (SVs) are found in ST ependymomas, recurrent SVs or other mutations, such as single nucleotide variants (SNVs) and insertions or deletions (indels), have not been identified in PF ependymomas to date (Mack et al., 2014; Parker et al., 2014).

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Comprehensive molecular profiling of children with recurrent cancer II

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