Genetic variants in the H2AFX promoter region are associated with risk of sporadic breast cancer in non-Hispanic white women aged ≤55 years

Abstract

The histone protein family member X (H2AFX) is important in maintaining chromatin structure and genetic stability. Genetic variants in H2AFX may alter protein functions and thus cancer risk. In this case-control study, we genotyped four common single nucleotide polymorphisms (i.e., −1654A > G [rs643788], −1420G > A [rs8551], and −1187T > C [rs7759] in the H2AFX promoter region and 1057C > T [rs7350] in the 3′ untranslated region (UTR)) in 467 patients with sporadic breast cancer and 488 cancer-free controls. All female subjects were non-Hispanic whites aged ≤55 years. We found that significantly increased risk of breast cancer was associated with variant genotypes in the H2AFX promoter: adjusted odds ratio [OR] = 1.80, 95% confidence interval [CI] = 1.38-2.34 for −1654AG/GG; OR = 1.40, 95% CI = 1.07-1.83 for −1420GA/AA; and OR = 1.65, 95% CI = 1.26-2.16 for −1187TC/CC. Furthermore, the number of variant alleles in the promoter haplotypes was associated with increased risks of breast cancer in a dose-response manner (OR = 6.08, 95% CI = 3.25-11.38; OR = 6.83, 95% CI = 3.83-12.18; and OR = 23.61, 95% CI = 3.95-140.99 for one, two, and three variant alleles, respectively) (P trend < 0.0001). Age at onset of breast cancer significantly decreased as the number of variant alleles increased (P trend = 0.024). However, these effects were not observed in the 3′UTR 1057C > T polymorphism. Therefore, we believe that H2AFX promoter polymorphisms may contribute to the etiology of

Possible association between genetic variants in the H2AFX promoter region and risk of adult glioma in a Chinese Han population

“…It is known that the promoter and 3 0 -UTR regions of a gene have functions in regulating transcription, messenger RNA (mRNA) stability, and gene production [15] and that single-nucleotide polymorphisms (SNPs) are the common genetic variants in these core and proximal promoter regions [16], and thus searching for functional variants in the promoter and 3 0 -UTR regions or regulatory regions of the gene [17][18][19] becomes important. Recently, two molecular epidemiology studies demonstrated that H2AFX promoter polymorphisms may alter susceptibility to cancers, including non-Hodgkin lymphoma [20] and breast cancer [21]. These findings provide support for the hypothesis that SNPs in the H2AFX promoter region are biologically important.…”

“…The homozygous AA genotype of rs2509049 upstream of the H2AFX start codon was observed to be strongly associated with protection against NHL, this being the first study to establish a correlation between an H2AFX gene polymorphism and risk of human cancer. Another recent study [21] found that three common SNPs (rs643788, rs8511, and rs7759) in the H2AFX promoter were associated with increased risk of breast cancer in non-Hispanic White women aged B55 years. However, no associations were observed for rs643788, rs8511, and rs7350 in a bladder cancer study [26].…”

“…Similarly, gene-age interaction was also observed in breast cancer. In a recent study of 467 breast cancer cases and 488 cancer-free controls, the increased risk of breast cancer for H2AFX variants (rs643788, rs8511, and rs7759) was found to be more evident in those aged B45 years [21]. Furthermore, the increased number of variant alleles was associated with decreased age at onset of breast cancer.…”

“…Several studies have reported the association between H2AFX polymorphisms and risk of cancers [20,21,26], but no study has investigated the association between H2AFX polymorphisms and glioma to date. In this casecontrol study, we analyzed three common SNPs (rs643788, rs8511, and rs2509851) in the H2AFX promoter region in 669 adult glioma patients and 638 cancer-free controls.…”

Genetic variants of H2AX gene were associated with P M 2.5 -modulated DNA damage levels in Chinese Han populations

“…The rs7759 A > G is located at the promoter region of H2AX. Three common tagging SNPs (including rs7759 A > G) in the H2AX promoter region were previously investigated and reported to contribute to the risk of sporadic breast cancer in young non-Hispanic white women, and may regulate the gene expression [27]. In previous studies, the polymorphisms nearby the upstream of H2AX gene were found to regulate the expression of H2AX, modify DNA repair pathway, and influence genetic susceptibility to some diseases by contributing to the maintenance of genome stability [28][29][30].…”