Genetic Variants, Neurocognitive Outcomes, and Functional Neuroimaging in Survivors of Childhood Acute Lymphoblastic Leukemia.

Abstract

Genetic predispositions may modulate risk for developing neurocognitive late effects in childhood acute lymphoblastic leukemia (ALL) survivors. Long-term ALL survivors (n = 212; 14.3[4.77] years, mean[SD]; 49% female) treated with chemotherapy completed neurocognitive testing and task-based functional neuroimaging (fMRI). Based on previous work from our team, genetic variants related to the folate pathway, glucocorticoid regulation, drug metabolism, oxidative stress, and attention were included as predictors of neurocognitive performance, using multivariable models adjusted for age, race, and sex. Subsequent analyses evaluated the impact of these variants on task-based fMRI. Statistical tests were two-sided. Survivors exhibited higher rates of impaired attention(20.8%), motor skills(42.2%), visuo-spatial memory(49.3-58.3%), processing speed(20.1%), and executive function(24.3-26.1%) relative to population norms (10%; p's < 0.001). Genetic variants implicated in attention deficit phenotypes predicted impaired attention span (synaptosome associated protein 25 [SNAP25rs3746544], F(2,172)=4.07, p = 0.019) and motor skills (monoamine oxidase A, [MAOArs1137070], F(2,125)=5.25, p = 0.007). Visuo-spatial memory and processing speed varied as a function of genetic variants in the folate pathway (methylenetetrahydrofolate reductase [MTHFRrs1801133], F(2,165)=3.48, p = 0.033; methylenetetrahydrofolate dehydrogenase 1 [MTHFD1rs2236225], F(2,135)=3.8, p = 0.025; respectively). Executive function performance was modulated by genetic variants in the folate pathway (MTHFD1rs2236225, F(2,158)=3.95, p = 0.021; MTHFD1rs1950902, F(2,154)=5.55, p = 0.005) and glucocorticoid regulation (vitamin D receptor [VDRrs154410], F(2,158)=3.29, p = 0.039; FKBP prolyl isomerase 5 [FKBP5rs1360780], F(2,154)=5.6, p = 0.005). Additionally, MTHFD1rs2236225 and FKBP5rs1360780 were associated with altered brain function during attention and working memory (p < 0.05; FWE corrected). Results extend previous findings of genetic risk of neurocognitive impairment following ALL therapy and highlight the importance of examining genetic modulators in relation to neurocognitive deficits.