Comprehensive analysis of the role of DNA repair gene polymorphisms on risk of glioma

Abstract

Much of the variation in inherited risk of glioma is likely to be explained by combinations of common low risk variants. The established relationship between glioma risk and exposure to ionizing radiation led us to examine whether variants in the DNA repair genes contribute to disease susceptibility. We evaluated 1127 haplotype-tagging single-nucleotide polymorphisms (SNPs) supplemented with 388 putative functional SNPs to capture most of the common variation in 136 DNA repair genes, in five unique case-control series from four different countries (1013 cases, 1016 controls). We identified 16 SNPs associated with glioma risk at the 1% significance level. The highest association observed across the five independent case-control datasets involved rs243356, which maps to intron 3 of CHAF1A (trend odds ratio, 1.32; 95% confidence interval 1.14-1.54; P = 0.0002; false-positive report probability = 0.055, based on a prior probability of 0.01). Our results provide additional support for the hypothesis that low penetrance variants contribute to the risk of developing glioma and suggest that a genetic variant located in or around the CHAF1A gene contributes to disease risk.

Histone Chaperone CHAF1A Inhibits Differentiation and Promotes Aggressive Neuroblastoma

“…Expression of CAF-1 has been associated with cell proliferation in breast cancer (31), deregulation of DNA repair in squamous cell carcinoma (32), and genomic instability and cancer susceptibility in the recessively inherited Bloom syndrome (14). Furthermore, activating single nucleotide polymorphisms within the CHAF1A gene strongly correlate with glioma tumorigenesis (33).…”

Cyclin D1 Gene G870A Variants and Primary Brain Tumors

“…Although none of these results are sufficient to propose "accurate" risk factors as in familial syndromes, they represent a new era in understanding brain tumor formation. Variants of DNA repair genes such as ERCC1, ERCC2, GLTSCR1, PRKDC, MGMT and CHAF1A have been shown to be significantly associated with glioma and/or glioma subtypes (Wei et al, 1997;Hegi et al, 2005;Wiencke et al, 2005;Yang et al, 2005;Bethke et al, 2007;Felini et al, 2007). ATM and cell cycle genes have been reported to be associated with meningioma and glioblastoma and BRIP-1 was associated with meningioma (Malmer et al, 2007;Rajaraman et al, 2007; Bethke et al, 2008).…”

Pathway Analysis of Single-Nucleotide Polymorphisms Potentially Associated with Glioblastoma Multiforme Susceptibility Using Random Forests

“…A recent study showed that another SNP (rs243356) of CHAF1A was associated with glioma risk (32). This suggests that CHAF1A may contribute to gliomagenesis and warrants further investigation.…”