Combinational Polymorphisms of Seven CXCL12-Related Genes Are Protective against Breast Cancer in Taiwan

Abstract

Many single nucleotide polymorphisms (SNPs) have been found to be associated with breast cancer, but their SNP interactions are seldom addressed. In this study, we focused on the joint effect for SNP combinations of seven CXCL12-related genes involved in major cancer-related pathways. SNP genotyping was determined by PCR-restriction fragment length polymorphism (RFLP) in this study (case = 220, control = 334). Different numbers of combinational SNPs with genotypes called the SNP barcodes from different chromosomes were used to evaluate their joint effect on breast cancer risk. Except for vascular endothelial growth factor (VEGF) rs3025039-CT, none of these SNPs were found to individually contribute to breast cancer risk. However, for two combined SNPs, the proportion of subjects with breast cancer was significantly low in the SNP barcode with CC-GG genotypes in rs2228014-1801157 (CXCR4-CXCL12) compared to those with non-CC-GG genotypes. Similarly, the SNP barcode of rs12812942-rs2228014-rs3025039 (CD4-CXCR4-VEGF) and rs12812942-rs3136685-rs2228014-rs1801157 (CD4- CCR7-CXCR4-CXCL12) with specific genotype patterns (AT-CC-CC and AT-AG-CC-GG) among three and four combinational SNPs were significantly low in breast cancer occurrence. More SNP combinations larger than five SNPs were also addressed, and these showed similar effects. After controlling for age, and comparing their corresponding non-SNP barcodes, the estimated odds ratios for breast cancer ranged between 0.20 and 0.71 for specific SNP barcodes with two to seven SNPs. In conclusion, we have associated the potential combined CXCL12-related SNPs with genotypes that were protective against breast cancer, and that may contribute to identification of a low-risk population for the development of breast cancer.

VEGF 936C>T polymorphism and breast cancer risk: evidence from 5,729 cases and 5,868 controls

“…In addition, for studies in which controls were matched on the bias of age, six were population-based and only one study was hospital-based. The distribution of genotypes in the controls was consistent with Hardy-Weinberg equilibrium in all studies except for one study [26].…”

“…However, there are only two studies of Asian populations reported [22,26]. Therefore, additional studies are warranted to further validate ethnic differences in the effect of the 936C[T polymorphism on breast cancer risk, especially among Asians.…”

“…A total of eight eligible studies involving 5,729 cases and 5,868 controls were included in the pooled analyses [14,15,17,[22][23][24][25][26]. The characteristics of the selected studies are summarized in Table 1.…”

Association of a vascular endothelial growth factor gene 936 C/T polymorphism with breast cancer risk: a meta-analysis

“…Renner et al [15] reported three novel polymorphisms (C702T, C936T, and G1612A) in the 3 0 -untranslated region and found that carriers of the 936T allele had significantly lower VEGF plasma levels than non-carriers, and Krippl et al [16] reported that carriers of the VEGF 936T allele are at decreased risk for breast cancer. However, subsequent reports have shown that the VEGF 936T allele is not associated with breast cancer risk [17][18][19][20][21][22]. The inconclusive nature of these results might be explained by the possible small effect of the polymorphism on breast cancer risk and the relatively small sample size in each of the published studies.…”

CXCL12 rs1801157 polymorphism in patients with breast cancer, hodgkin's lymphoma, and non‐hodgkin's lymphoma

“…Most studies have addressed the effects of some SNPs, categorizing them as ''not associated,'' and thus concluded that they are not important in cancer or disease risks. It is possible that some SNPs without main effects, or with main effects too small to detect, may interact with others and confer a changed risk for cancers, as demonstrated by Lin et al (64). Especially concerning the influence of CXCL12 genotype rs1801157 on cancer progression, as long as the functional importance of rs1801157 in the expression of the CXCL12 transcript and protein are still unclear.…”