Genetic Susceptibility to Cognitive Decline Following Craniospinal Irradiation for Pediatric Central Nervous System Tumors

Authors

Austin L Brown
Pagna Sok
Kimberly P Raghubar
Philip J Lupo
Melissa A Richard
Alanna C Morrison
Jun J Yang
Clinton F Stewart
Mehmet Fatih Okcu
Murali M Chintagumpala
Amar Gajjar
Lisa S Kahalley
Heather Conklin
Michael E Scheurer

Publication Date

9-5-2023

Journal

Neuro-Oncology

Abstract

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.

Keywords

Child, Male, Humans, Female, Brain Neoplasms, Craniospinal Irradiation, Genetic Predisposition to Disease, Genome-Wide Association Study, Intelligence, Central Nervous System Neoplasms, Cognitive Dysfunction, cognitive impairment, craniospinal irradiation, genetics, intelligence, pediatric brain tumor

Comments

Supplementary Materials

Data Availability Statement

PMID: 37038335