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Transl Oncol. 2019 Jul;12(7):908-916. doi: 10.1016/j.tranon.2019.03.004. Epub 2019 May 9.

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

Author information

1
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.
2
Department of Psychology and Neuroscience Institute, Georgia State University, Atlanta, GA. Electronic address: tzking@gsu.edu.
3
Winship Cancer Institute of Emory University, Atlanta, GA.
4
Department of Pathology and Laboratory Medicine, Children's Healthcare of Atlanta, Atlanta, GA.
5
Winship Cancer Institute of Emory University, Atlanta, GA; Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, GA.
6
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA; Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA.

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.

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