Genetic advances in glioma: susceptibility genes and networks

Abstract

Recent advances in human genome studies have opened new avenues for the identification of susceptibility genes for many complex genetic disorders, especially in the field of rare cancers such as glioma. To date, eight glioma susceptibility loci have been identified by candidate gene-association studies: PRKDC G6721T, XRCC1 W399R, PARP1 A762V, MGMT F84L, ERCC1 A8092C, ERCC2 Q751K, EGF +61 A/G, and IL13 R110G. Five loci have been identified by genome-wide association studies: TERT rs2736100, CCDC26 rs4295627, CDKN2A-CDKN2B rs4977756, PHLDB1 rs498872, and RTEL1 rs6010620. Using the Ingenuity Pathway Analysis tool, we investigated whether these 13 susceptibility genes are biologically related. Our data provide not only networks for understanding the biological properties of gliomagenesis but also useful pathway maps for future understanding of disease.

Figure 1. Biological networks for selected glioma susceptibility genes

Interactions among the glioma susceptibility genes (green emblems) were analyzed using Ingenuity Pathway Analysis (http://www.ingenuity.com). This diagram shows the direct (solid lines) and indirect (dashed lines) interactions among the 21 genes. The red solid lines are the direct two-way interactions, and blue dashed lines are the indirect two-way interactions. For clarity, we do not show all of the interactions identified but focus primarily on direct interactions that link glioma.

Figure 2. Functional annotations of the glioma susceptibility genes

The annotations show that the key bio-function of these susceptibility genes is related to DNA replication, recombination and repair pathway. The 21 network genes associated with biological functions in the Ingenuity Pathways Knowledge Base were considered for the analysis. Fisher’s exact test was used to calculate a p-value determining the probability that each biological function assigned to that network is due to chance alone. Threshold bar shows cut-off point of significance P < 0.05, −log(P-value) of 1.3.