Genetic Modulation of Neurocognitive Function in Glioma Patients

Abstract

Purpose: Accumulating evidence supports the contention that genetic variation is associated with neurocognitive function in healthy individuals and increased risk for neurocognitive decline in a variety of patient populations, including cancer patients. However, this has rarely been studied in glioma patients.

Experimental design: To identify the effect of genetic variants on neurocognitive function, we examined the relationship between the genotype frequencies of 10,967 single-nucleotide polymorphisms in 580 genes related to five pathways (inflammation, DNA repair, metabolism, cognitive, and telomerase) and neurocognitive function in 233 newly diagnosed glioma patients before surgical resection. Four neuropsychologic tests that measured memory (Hopkins Verbal Learning Test-Revised), processing speed (Trail Making Test A), and executive function (Trail Making Test B, Controlled Oral Word Association) were examined.

Results: Eighteen polymorphisms were associated with processing speed and 12 polymorphisms with executive function. For processing speed, the strongest signals were in IRS1 rs6725330 in the inflammation pathway (P = 2.5 × 10(-10)), ERCC4 rs1573638 in the DNA repair pathway (P = 3.4 × 10(-7)), and ABCC1 rs8187858 in metabolism pathway (P = 6.6 × 10(-7)). For executive function, the strongest associations were in NOS1 rs11611788 (P = 1.8 × 10(-8)) and IL16 rs1912124 (P = 6.0 × 10(-7)) in the inflammation pathway, and POLE rs5744761 (P = 6.0 × 10(-7)) in the DNA repair pathway. Joint effect analysis found significant gene polymorphism-dosage effects for processing speed (Ptrend = 9.4 × 10(-16)) and executive function (Ptrend = 6.6 × 10(-15)).

Conclusions: Polymorphisms in inflammation, DNA repair, and metabolism pathways are associated with neurocognitive function in glioma patients and may affect clinical outcomes.