Genetic susceptibility to cognitive decline following craniospinal irradiation for pediatric central nervous system tumors.

Autor:	Brown AL; Department of Pediatrics, Baylor College of Medicine, Houston, Texas., Sok P; Department of Pediatrics, Baylor College of Medicine, Houston, Texas., Raghubar KP; Department of Pediatrics, Baylor College of Medicine, Houston, Texas., Lupo PJ; Department of Pediatrics, Baylor College of Medicine, Houston, Texas., Richard MA; Department of Pediatrics, Baylor College of Medicine, Houston, Texas., Morrison AC; Department of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at Houston, Houston, Texas., Yang JJ; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee., Stewart CF; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee., Okcu MF; Department of Pediatrics, Baylor College of Medicine, Houston, Texas., Chintagumpala MM; Department of Pediatrics, Baylor College of Medicine, Houston, Texas., Gajjar A; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee., Kahalley LS; Department of Pediatrics, Baylor College of Medicine, Houston, Texas., Conklin H; Psychology Department, St. Jude Children's Research Hospital, Memphis, Tennessee., Scheurer ME; Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2023 Sep 05; Vol. 25 (9), pp. 1698-1708.
DOI:	10.1093/neuonc/noad072
Abstrakt:	Background: Survivors of pediatric central nervous system (CNS) tumors treated with craniospinal irradiation (CSI) exhibit long-term cognitive difficulties. Goals of this study were to evaluate longitudinal effects of candidate and novel genetic variants on cognitive decline following CSI. Methods: Intelligence quotient (IQ), working memory (WM), and processing speed (PS) were longitudinally collected from patients treated with CSI (n = 241). Genotype-by-time interactions were evaluated using mixed-effects linear regression to identify common variants (minor allele frequency > 1%) associated with cognitive performance change. Novel variants associated with cognitive decline (P < 5 × 10-5) in individuals of European ancestry (n = 163) were considered replicated if they demonstrated consistent genotype-by-time interactions (P < .05) in individuals of non-European ancestries (n = 78) and achieved genome-wide statistical significance (P < 5 × 10-8) in a meta-analysis across ancestry groups. Results: Participants were mostly males (65%) diagnosed with embryonal tumors (98%) at a median age of 8.3 years. Overall, 1150 neurocognitive evaluations were obtained (median = 5, range: 2-10 per participant). One of the five loci previously associated with cognitive outcomes in pediatric CNS tumors survivors demonstrated significant time-dependent IQ declines (PPARA rs6008197, P = .004). Two variants associated with IQ in the general population were associated with declines in IQ after Bonferroni correction (rs9348721, P = 1.7 × 10-5; rs31771, P = 7.8 × 10-4). In genome-wide analyses, we identified novel loci associated with accelerated declines in IQ (rs116595313, meta-P = 9.4 × 10-9), WM (rs17774009, meta-P = 4.2 × 10-9), and PS (rs77467524, meta-P = 1.5 × 10-8; rs17630683, meta-P = 2.0 × 10-8; rs73249323, meta-P = 3.1 × 10-8). Conclusions: Inherited genetic variants involved in baseline cognitive functioning and novel susceptibility loci jointly influence the degree of treatment-associated cognitive decline in pediatric CNS tumor survivors. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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