br Category Protein Interaction With Genes br
Category Protein Interaction With Genes
Count % P-Value Benjamini
Analysis was performed by David Bioinformatics Resources 6.8, National Institute of Allergy and Infectious Diseases/National Institutes of Health via Gene ID Conversion Tool. List of 4 studied genes was introduced, and protein interaction option by UCSC_TFBS genome browser was chosen.
Notably, the C allele of OPG-rs2073617 was associated with decreased risk of advanced prostate cancer.52 A possible explanation is that rs2073617 SNP is associated with an altered secondary structure, which may cause differences in OPG messenger RNA expression.31 However, the OPG-rs2073617 T/C 56-85-9 had no effect on serum OPG in prostate cancer.52 Thus, the mechanism of the protective effect of OPG-rs2073617 should be further investigated.
Reports about the association of CHI3L1 polymorphisms with BC were few. We found significant association between CHI3L1-rs4950928 and BC, where the minor homozygote GG genotype was associated with increased BC risk, whereas the CG heterozygote was protective. In contrast, CHI3L1-rs4950928 was not a significant predisposing factor of BC in a large caseecontrol study.25 Further-more, no association was found for CHI3L1-rs4950928 with glio-blastoma,53 uterine cancer,54 or hepatocellular carcinoma.55 On the other hand, the C allele of CHI3L1-rs4950928 was significantly higher in patients with rectal cancer than those with colon cancer in an Egyptian population.33 These discordant results may be attributable to different tumors, sample sizes, and populations studied.
We observed significant interactions between RANKL-rs9533156 and OPG SNPs with CHI3L1-rs4950928 in relation to BC risk. These interactions are consistent with the link between these genes and diseases characterized by inflammation and tissue
remodeling. High serum YKL-40 level is a nonspecific inflamma-tory marker and was associated with poor prognosis in BC.56,57 Genetic variants of CHI3L1 and RANK/RANKL genes were asso-ciated with inflammatory diseases such as rheumatoid arthritis.58,59 Genetic variants in the OPG locus have been implicated in anky-losing spondylitis.60 RANKL might induce CHI3L1 indirectly e230 - Clinical Breast Cancer February 2019
through NF-kB signaling.43,44 A cross-talk between OPG and YKL-40 could be through enhancing angiogenesis; both stimulate endothelial cell survival and tube formation by inducing ERK1/2 and Akt phosphorylation.17,61
We demonstrated association of VDR FokI and BsmI poly-morphisms with BC predisposition, with the minor BsmI A (B) allele and AG genotype associated with increased BC risk whereas the minor FokI C (F) allele and the presence of CTþCC genotypes were protective in our studied population. Other genetic variants in VDR, ApaI and TaqI, also conferred high BC susceptibility, particularly in Egyptian women.62 Together, these results support the notion that breast carcinogenesis may be affected by vitamin D/VDR signaling. Previous reports demonstrated inconsistent re-sults about association of FokI and BsmI with BC risk among different populations.22,26-29 This variability among different
studies was suggested to be due to different proportions of patients with a family history of BC.26,29
The observed interaction of VDR polymorphisms and RANKL/ OPG SNPs could be explained by the idea that vitamin D through VDR regulates RANKL and OPG gene expression.45-47 A direct relationship between VDR and RANKL gene expression has been reported. The 1,25(OH)2D3 activated human RANKL promoter through vitamin Deresponsive elements located at distal regions 1584/ 1570 by binding VDR and RXR-a heterodimers in a ligand-dependent manner.63 Furthermore, an interplay between low plasma RANKL and VDR-FokI polymorphism in lumbar disc herniation has also been demonstrated.64 Higher RANKL and lower plasma OPG levels were observed with the VDR-FokI F allele compared to the f allele and were linked to T-cell activation in multiple sclerosis patients.65 As VDR and RANKL/RANK/OPG
have identified roles in immune system modulation, interactions between several immune-related genes were demonstrated to be associated with susceptibility to breast invasive ductal carcinoma.66 Notably, 88.7% of our patients had invasive duct tumors. Together, these results implicate that interaction of certain genotypes of spe-cific functional SNPs could predispose cancer through cross-talk of their proteins.
We carried out a haplotype analysis in BC subgroups to identify haplotypes associated with BC prognosis. Our results revealed that TCCCTG haplotype stratified patients according ER/PR status. TCTCTG and TGTCTG haplotypes were inversely correlated, whereas TCTCTA was positively associated with bone metastasis. Our results indicate that some combinations of these selected SNPs could contribute to BC progression and poor prognosis. In line with our results, the VDR-BsmI polymorphism was linked to BC metastasis, with women carried the minor homozygote had almost a 4 times higher risk of developing metastases than women carrying the major homozygote genotype.67 CHI3L1-rs4950928 may be a potential candidate for predicting poor hepatocellular carcinoma prognosis and clinical status, where CGþGG genotype carriers among hepatocellular carcinoma patients indicated a greater risk of vascular invasion.55 The OPG-rs2073618 stratified BC patients into invasive or noninvasive tumors.24 The OPG-rs2073617 C allele was negatively correlated with metastatic prostate cancer.52 Although the genotype distributions of the studied RANKL and OPG SNPs were not significantly different between bone metastatic and nonmetastatic BC in an Egyptian study,23 elevated serum RANKL, OPG, and vitamin D, but not YKL-40, were significantly associated with bone metastasis in BC in Egyptian patients.68