Dataset Information

Host Genome Variation is Associated with Neurocognitive Outcome in Survivors of Pediatric Medulloblastoma.

ABSTRACT: Host genome analysis is a promising source of predictive information for long-term morbidity in cancer survivors. However, studies on genetic predictors of long-term outcome, particularly neurocognitive function following chemoradiation in pediatric oncology, are limited. Here, we evaluated variation in host genome of long-term survivors of medulloblastoma and its association with neurocognitive outcome. Whole-genome sequencing was conducted on peripheral blood of long-term survivors of pediatric medulloblastoma who also completed neuropsychological testing. Cognitively impaired and less impaired survivors did not differ in exposure to chemoradiation therapy or age at treatment. Unsupervised consensus clustering yielded two distinct variant clusters that were significantly associated with neurocognitive outcome. Interestingly, 34 of the 36 significant variants were found in noncoding DNA regions with unknown regulatory function. A separate unsupervised cluster analysis of variants within DNA repair genes identified discrete variant groups that were not associated with neurocognitive outcome, suggesting that variations in genes corresponding to a single functional group may be insufficient to predict long-term outcome alone. These findings are supportive of the presence of a genetic diathesis for treatment-related neurocognitive morbidity in medulloblastoma that may be driven by variation in noncoding regulatory elements.

SUBMITTER: Siegel BI

PROVIDER: S-EPMC6515414 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Host Genome Variation is Associated with Neurocognitive Outcome in Survivors of Pediatric Medulloblastoma.

Siegel Benjamin I BI King Tricia Z TZ Rupji Manali M Dwivedi Bhakti B Carter Alexis B AB Kowalski Jeanne J MacDonald Tobey J TJ

Translational oncology 20190509 7

Host genome analysis is a promising source of predictive information for long-term morbidity in cancer survivors. However, studies on genetic predictors of long-term outcome, particularly neurocognitive function following chemoradiation in pediatric oncology, are limited. Here, we evaluated variation in host genome of long-term survivors of medulloblastoma and its association with neurocognitive outcome. Whole-genome sequencing was conducted on peripheral blood of long-term survivors of pediatri ...[more]

PMID: 31078964

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Project description:BackgroundChildhood intracranial germ cell tumor (GCT) survivors are prone to radiotherapy-related neurotoxicity, which can lead to neurocognitive dysfunctions. Diffusion kurtosis imaging (DKI) is a diffusion MRI technique that is sensitive to brain microstructural changes. This study aimed to investigate the association between DKI metrics versus cognitive and functional outcomes of childhood intracranial GCT survivors.MethodsDKI was performed on childhood intracranial GCT survivors (n = 20) who had received cranial radiotherapy, and age and gender-matched healthy control subjects (n = 14). Neurocognitive assessment was performed using the Hong Kong Wechsler Intelligence Scales, and functional assessment was performed using the Lansky/Karnofsky performance scales (KPS). Survivors and healthy controls were compared using mixed effects model. Multiple regression analyses were performed to determine the effects of microstructural brain changes of the whole brain as well as the association between IQ and Karnofsky scores and the thereof.ResultsThe mean Intelligence Quotient (IQ) of GCT survivors was 91.7 (95% CI 84.5 - 98.8), which was below the age-specific normative expected mean IQ (P = 0.013). The mean KPS score of GCT survivors was 85.5, which was significantly lower than that of controls (P < 0.001). Cognitive impairments were significantly associated with the presence of microstructural changes in white and grey matter, whereas functional impairments were mostly associated with microstructural changes in white matter. There were significant correlations between IQ versus the mean diffusivity (MD) and mean kurtosis (MK) of specific white matter regions. The IQ scores were negatively correlated with the MD of extensive grey matter regions.ConclusionOur study identified vulnerable brain regions whose microstructural changes in white and grey matter were significantly associated with impaired cognitive and physical functioning in survivors of pediatric intracranial GCT.

Project description:AimTo examine whether anesthesia exposure is associated with neurocognitive decline in pediatric medulloblastoma.MethodsPatients were treated at St. Jude Children's Research Hospital and completed ≥2 protocol-directed neurocognitive assessments (n = 107) as part of a multisite clinical trial for pediatric medulloblastoma (NCT00085202). Patients received risk-adapted craniospinal photon irradiation, followed by four cycles of high-dose chemotherapy and stem cell rescue. Neurocognitive testing was completed at study baseline (after surgery and <2 weeks of starting radiation therapy) and annually for 5 years. Data on anesthesia exposure during treatment was abstracted from medical records.ResultsPatients were 10.2 years at diagnosis on average (SD = 4.5; 37% female, 73% average-risk). Mean cumulative anesthesia duration was 20.4 h (SD = 15.2; range 0.7-55.6 h). In the overall group, longer anesthesia duration was associated with greater declines in IQ (Estimate = -0.08, P < 0.001), attention (Estimate = -0.10, P < .001) and processing speed (Estimate = -0.13, P < 0.001). Similar results were shown in subgroups of patients who were <7 years at diagnosis (IQ = -0.14, P = 0.027; Attention = -0.25: P = 0.011), ≥7 years at diagnosis (Attention = -0.07, P = 0.039; Processing Speed = -0.08, P = 0.022), treated for high-risk disease (IQ = -0.09, P = 0.024; Attention = -0.11, P = 0.034; Processing Speed = -0.13, P = 0.001), or treated for average-risk disease (IQ = -0.05, P = .022; Attention = -0.08, P = 0.011; Processing Speed = -0.10, P < 0.001).ConclusionGreater anesthesia exposure is a risk factor for clinically significant neurocognitive decline, in addition to factors of age at diagnosis and treatment risk arm. This result is notable as there are evidence-based strategies that can limit the need for anesthesia. Limiting anesthesia exposure, as feasible, may mitigate neurocognitive late effects, and thus, improve quality of life for survivors.

Dataset Information

Host Genome Variation is Associated with Neurocognitive Outcome in Survivors of Pediatric Medulloblastoma.

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Host Genome Variation is Associated with Neurocognitive Outcome in Survivors of Pediatric Medulloblastoma.

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