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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.

SUBMITTER: Liu Y

PROVIDER: S-EPMC4506227 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Genetic Modulation of Neurocognitive Function in Glioma Patients.

Liu Yanhong Y Zhou Renke R Sulman Erik P EP Scheurer Michael E ME Boehling Nicholas N Armstrong Georgina N GN Tsavachidis Spiridon S Liang Fu-Wen FW Etzel Carol J CJ Conrad Charles A CA Gilbert Mark R MR Armstrong Terri S TS Bondy Melissa L ML Wefel Jeffrey S JS

Clinical cancer research : an official journal of the American Association for Cancer Research 20150422 14

<h4>Purpose</h4>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.<h4>Experimental design</h4>To identify the effect of genetic variants on neurocognitive function, we examined the relationship between the genotype frequencies of 10,967 single-nucl ...[more]

PMID: 25904748

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Project description: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.

Project description:Background: Neuropsychological deficits frequently occur in diffuse lower-grade glioma (DLGG) patients, but their relationship with molecular subgroups based on the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) is unclear. Methods: All patients enrolled for this study were divided into different subgroups according to the molecular-integrated 2016 CNS WHO and morphology-centric 2007 CNS WHO to compare their neurocognitive function (NCF) dysfunction. Univariate and multivariate analyses were used to assess the independent factors for NCF decline. The performance of NCF changes for discrimination of IDH and 1p19q status was evaluated by receiver operating characteristic (ROC). Results: There was no significant difference in the clinical characteristics among the molecular and morphologic subgroups. In the molecular subgroups, significant differences in NCF alterations were found in terms of attention function, working memory and executive function in grade II glioma patients; in addition to these changes in NCF, memory function and abstract thinking were also significantly different in grade III glioma patients. The pairwise comparison further confirmed that patients with astrocytoma (A)/anaplastic astrocytoma (AA) with isocitrate dehydrogenase wild-type (IDHwt) glioma were more susceptible to severe cognitive decline in terms of the NCF performance described above. For the morphologic subgroups, only working memory was significantly different in grade III glioma patients. The distribution proportion was significantly different among each subgroup of DLGG (grade II, P = 0.001; grade III, P = 0.002). The proportion of extensive NCF decline (≥5 tests) was 4, 12, and 50% in the IDH mutant oligodendroglioma (IDHm-O), IDHm-A, and IDHwt-A subgroups, and this proportion was 33, 60, and 93% in the IDHm-AO, IDHm-AA, and IDHwt-AA subgroups, respectively. In multivariate regression analysis, molecular types were independent factors for NCF alterations after adjusted the factors of tumor and demographics (p < 0.05). ROC curves suggested combined NCF tests model showed an advantage in the differentiation of IDH status. Conclusions: NCF alteration is closely related to molecular-integrated subgroups with varying degrees and frequencies in DLGG. Patients with IDHwt gliomas are more susceptible to suffer from severe and extensive NCF decline than other subgroups.

Project description:BackgroundCognitive impairment is a common and debilitating symptom in patients with diffuse glioma, and is the result of multiple factors. We hypothesized that molecular tumor characteristics influence neurocognitive functioning (NCF), and aimed to identify tumor-related markers of NCF in diffuse glioma patients.MethodsWe examined the relation between cognitive performance (executive function, memory, and psychomotor speed) and intratumoral expression levels of molecular markers in treatment-naive patients with diffuse glioma. We performed a single-center study in a consecutive cohort, through a two-step design: (1) hypothesis-free differential expression and gene set enrichment analysis to identify candidate oncogenetic markers for cognitive impairment. Nineteen molecular markers of interest were derived from this set of genes, as well as from prior knowledge; (2) correlation of cognitive performance to intratumoral expression levels of these nineteen molecular markers, measured with immunohistochemistry.ResultsFrom 708 included patients with immunohistochemical data, we performed an in-depth analysis of neuropsychological data in 197, and differential expression analysis in 65 patients. After correcting for tumor volume and location, we found significant associations between expression levels of CD3 and IDH-1 and psychomotor speed; between IDH-1, ATRX, NLGN3, BDNF, CK2Beta, EAAT1, GAT-3, SRF, and memory performance; and between IDH-1, P-STAT5b, NLGN3, CK2Beta, and executive functioning. P-STAT5b, CD163, CD3, and Semaphorin-3A were independently associated after further correction for histopathological grade.ConclusionMolecular characteristics of glioma can be independent determinants of patients' cognitive functioning. This suggests that besides tumor volume, location, and histological grade, variations in glioma biology influence cognitive performance through mechanisms that include perturbation of neuronal communication. These results pave the way towards targeted cognition improving therapies in neuro-oncology.

Dataset Information

Genetic Modulation of Neurocognitive Function in Glioma Patients.

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Genetic Modulation of Neurocognitive Function in Glioma Patients.

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