ED-17 * GENETIC MODULATION OF NEUROCOGNITIVE FUNCTION AND OUTCOMES IN GLIOMA PATIENTS

Abstract

BACKGROUND: Genetic polymorphisms associated with neurocognitive function (NCF) in glioma patients have not been studied. Determining such markers may help identify patients at increased risk for treatment related neurotoxicity, suggesting possible targets for treatment, and facilitate development of new neuroprotective therapies to improve the patients' quality of life. METHODS: To identify the effect of genetic variants on NCF, we compared the genotype frequencies of 10,967 SNPs mapping to 580 genes from five pathways: Inflammation, DNA repair, Metabolism, Neurocognitive, and TERT, in 233 newly diagnosed glioma patients with neurocognitive evaluations before surgical resection. Five neuropsychological tests that measured memory (Hopkins Verbal Learning Test – Revised [HVLT-R]), processing speed (Trail Making Test A [TMTA]), and executive function (Controlled Oral Word Association [COWA], and Trail Making Test B (TMTB]) were examined. RESULTS: Nineteen SNPs were associated with TMTA, 12 SNPs with TMTB, two SNPs (MCPH1 rs6999296 and TANK rs270952) were associated with COWA, and one SNP (RAD51L1 rs9323505) was associated with HVLT-R Total Recall (FDR ≤ 0.05). For TMTA, the strongest signals were in IRS1 rs6725330 in the inflammation pathway (P = 2.59E-10; P adjusted = 1.21E-06), ERCC4 rs1573638 in DNA repair pathway (P = 3.46E-07; P adjusted = 0.00036), and ABCC1 rs8187858 in metabolism pathway (P = 6.63E-07; P adjusted = 0.0001). For TMTB, the strongest associations were in NOS1 rs11611788 in inflammation pathway (P = 1.85E-8; P adjusted = 8.63E-05), POLE rs5744761 in DNA repair pathway (P = 6.06E-07; P adjusted = 0.0013), and IL16 rs1912124 in inflammation pathway (P = 6.06E-07; P adjusted = 0.0014). Joint effect analysis found significant gene-dosage effects for TMTA (P trend = 9.46e -16) and TMTB (P trend =6.69e-15). CONCLUSION: Genetic polymorphisms in the Inflammation, DNA repair, Metabolism, Neurocognitive, and TERT pathways are associated with neurocognitive impairment in glioma patients and may affect clinical outcomes.