Table 3 - uploaded by Ingolf Juhasz-Böss
Content may be subject to copyright.
Association of allele and genotype frequencies of OPG, RANK and RANKL in patients with breast cancer and healthy controls
Source publication
Background
The receptor activator of NF-κB (RANK), its ligand (RANKL) and osteoprotegerin (OPG) have been reported to play a role in the pathophysiological bone turnover and in the pathogenesis of breast cancer. Based on this we investigated the role of single nucleotide polymorphisms (SNPs) within RANK, RANKL and OPG and their possible association...
Contexts in source publication
Context 1
... genotype distributions for all seven SNPs were in the Hardy-Weinberg equilibrium. Table 3 summarizes the results of all SNP analyses in the genes encoding for OPG (rs3102735, rs2073618), RANK (rs1805034, rs35211496) and RANKL (rs9533156, rs2277438, rs1054016). Allelic and genotype frequencies in breast cancer patients were compared to healthy controls. ...
Context 2
... minor al- lele C was more frequent in breast cancer patients (18.4%) compared to the control group (13.0%). In addition, the homozygous genotype CC of the minor allele as well as the heterozygous genotype CT were more frequent in the breast cancer group (3.3% and 30.3%) compared to the controls (1.3% and 23.5%) ( Table 3). The power analysis revealed a power of 0.79 for the allele frequency and 0.72 for the genotype distribution to detect dependencies (α = 0.05) (Additional file 1: Figure S1). ...
Similar publications
Although calcium metabolism during pregnancy is well described the mechanisms involved in bone metabolism are not quite clear. Increase of osteoprotegerin (OPG) with elevated bone turnover is supposed to be a homeostatic mechanism limiting bone loss. The aim of the study was to assess bone turnover in pregnancy in relation to serum osteoprotegerin...
Objective
Osteoporosis is a common disease in postmenopausal women. Several studies have analysed the associations between dietary supplementation with probiotics and bone health in postmenopausal women, but the results are still controversial. We conducted this meta-analysis to assess the effects of probiotics supplement on bone mineral density (B...
Juvenile Paget's disease (JPD), a rare genetic skeletal disorder characterized by accelerated bone turnover with elevated levels of serum alkaline phosphatase, presents in early childhood. We report a female patient with typical features of JPD with dental finding who remained undiagnosed until 18 years of age. Scarcity of this disease in the India...
Paget's disease of bone (PDB) is a common disorder which may affect one or many bones. Although many patients are asymptomatic, a variety of symptoms and complications may occur. PDB is a focal disorder of bone turnover characterized by excessive bone resorption coupled with bone formation. PDB begins with a period of increased osteoclastic activit...
Patients with solid cancer frequently develop bone metastases (BM). Zoledronic acid (Zometa®, ZA), routinely used to treat patients with BM, acts on osteoclasts and also has antitumor properties. We aimed to assess the effect of ZA over time in novel bone turnover markers (RANK/receptor activator of nuclear factor-k B ligand (RANK-L)/ Osteoproteger...
Citations
... The OPG gene variants C950T (promoter), C1181G (exon 1), and myeloma bone disease were also investigated [26]. They discovered that allele 1181 G/950 T and genotypes 950 TT/1181 GG may lead to development of bone disease [27], as well as OPG rs3102735 and rs2073618 polymorphisms, which may have role in the development of breast cancer. The rs3102735 variant has been linked to a higher risk of breast cancer. ...
... Genetic factors may predispose the probability of breast cancer metastasize to bone [8]. The discovery of the apoptosis regulator receptor activator NF-κB ligand (RANKL) and osteoclastogenesis inhibitor OPG signaling pathway exhibited major regulatory system for osteoclast formation and also OPG/RANKL alliance controlled the bone remodeling [9,10], contributed significantly to the physiological bone turnover and also involved in osteoclast differentiation and activation [11]. ...
... RANKL rs9533156 (T>C) causes DNA hypermethylation leading to gene silencing and transcriptional inactivation, that affects the binding of transcriptional factors [22,23]. OPG rs2073618 influence secretions from the cells and drastically affect the secretory kinetics [10]. ...
... RANKL/OPG pathway suggests an important effect on the pathogenesis of breast cancer due to functional properties of genes. Genetic variation within OPG (rs3102735) promoter region and RANKL (rs9533156) near 5' region could have an effect on the expression of genes and may have an influence on the development of tumors [10,12]. Various studies conducted have elucidated the association of RANKL and OPG polymorphism with the breast cancer to bone metastasis risk in different ethnicities [24]. ...
Introduction:
The receptor activator NF-κB ligand (RANKL) and Osteoprotegrin (OPG) single nucleotide polymorphisms (SNPs) have been associated with the risk of breast cancer to bone metastasis. This study was designed to investigate the association of RANKL and OPG gene polymorphisms with breast to bone metastasis in Pashtun population of Khyber Pakhtunkhwa, Pakistan.
Materials and methods:
A total of 215 participants were enrolled containing 106 breast cancer patients, 58 breast to bone metastasis and 51 age and gender matched healthy controls. RANKL (rs9533156) and OPG (rs2073618, rs3102735) polymorphisms were genotyped in genomic DNA, using Tetra-ARMS PCR protocol. The results were analyzed among the three groups and P-value less then 0.05 were considered statistically significant.
Results:
Our results displayed significant association of OPG (rs3102735) risk allele and corresponding genotypes in breast cancer vs healthy controls, bone metastasis vs healthy controls and breast cancer vs breast to bone metastasis as a disease risk. However, there was no association observed for OPG (rs2073618) risk allele and corresponding genotypes with the diseases risk. Similarly, RANKL (rs9533156) risk allele and corresponding genotypes in breast cancer vs healthy controls, bone metastasis vs healthy controls and breast cancer vs breast to bone metastasis exhibited significant association except for the risk allele carrying genotypes in breast to bone metastasis.
Conclusion:
OPG (rs3102735) and RANKL (rs9533156) exhibited significant association with breast to bone metastasis while OPG (rs2073618) didn't show significant association with breast to bone metastasis in Pashtun population of Pakistan. However, this study unlocks more questions to investigate the exact scenario of genetic predisposition of breast to bone metastasis.
... The TNFSF11 gene structure is highly conserved among mammals, consisting of five exons that span 33.9 kb in humans (10). SNPs located near TNFSF11, TNFRSF11A, and TNFRSF11B have been reported to be closely associated with Paget's disease (20), osteoporotic fractures (21), cardiovascular diseases (22), ankylosing spondylitis (11), and breast (23), and esophageal cancers (24). In this study, we showed that subjects who carried the rs9525641-C allele were more likely to develop HCV chronicity than those with the rs9525641-T allele. ...
Background: Recently, several studies have reported that the host immune response can be related to the RANKL/RANK/OPG signaling pathway. However, the associations of TNFSF11, TNFRSF11A , and TNFRSF11B gene polymorphisms in the RANKL/RANK/OPG pathway with hepatitis C virus (HCV) infection outcomes remain unclear.
Methods: In this case-control study, 768 persistent HCV infection and 503 spontaneous HCV clearance cases, and 1,259 control subjects were included. The Taman-MGB probe method was utilized to detect TNFSF11 rs9525641, TNFRSF11A rs8686340, and TNFRSF11B rs2073618 genotypes. The distribution of three single nucleotide polymorphisms (SNPs) genotypes was analyzed using stata14.0.
Results: SNPs rs9525641, rs8086340, and rs2073618 genotype frequencies followed the Hardy-Weinberg natural population equilibrium ( p = 0.637, 0.250, and 0.113, respectively). Also, rs9525641 was significantly associated with HCV chronicity risk in recessive (OR = 1.203, 95% CI: 1.018–1.420, p = 0.030) and additive models (OR = 1.545, 95% CI: 1.150–2.075, p = 0.004). The stratified analysis showed that rs9525641 variant genotypes were associated with HCV chronicity among people older than 50 years (OR =1.562, 95% CI: 1.079–2.262, p = 0.018), females (OR = 1.667, 95% CI: 1.145–2.429, p = 0.008), ALT <40 U/L (OR = 1.532, 95% CI: 1.074–2.286, p = 0.018), and AST < 40 U/L (OR = 1.552, 95% CI: 1.095–2.201, p = 0.014).
Conclusion: TNFRSF11 rs9525641 was significantly associated with HCV chronicity in the Chinese population.
... Bonifaci et al. [8] revealed that rs7226991 was associated with a risk of breast cancer among the general Spanish population (BRCA1 or BRCA2) along with BRCA2 mutation carriers from different populations, which is consistent with the above observations. In addition, the results of the study exhibited effects parallel to those shown in the CGEMS results [8,25,26]. ...
Modifying genes play an exclusive role in the genetic regulation of the risk of breast cancer development in women with a pathogenic variation of BRCA1 or BRCA2. Therefore, it has been suggested that TNFRSF11A, which is among those modifying genes present in breast cancer development, may have a significant role in patients with positive BRCA1 or BRCA2 variations. In our study, we investigated the probable effects of single nucleotide polymorphisms (SNPs) in the TNFRSF11A gene, such as rs4485469, rs9646629, rs34739845, rs17069904, rs 884205, rs4941129 on the risk of breast cancer in patients with BRCA1 or BRCA2 variations. A total of 23 breast cancer patients with pathogenic variations in the BRCA1 or BRCA2 genes, 28 patients with no pathogenic variations in the BRCA1 or BRCA2 genes, and 55 healthy women as a control group, were included in this study. The SNPs were determined with allelic discrimination analysis through the real-time polymerase chain reaction (qPCR) method. There was no statistically significant difference between the SNPs of the TNFRSF11A gene rs4485469, rs9646629, rs34739845, rs17069904, rs884205, rs4941129 and metas-tasis, estrogen receptor, progesterone receptor and CerB2 receptor positivity between patient and control group (p >0.05). However, the rs4485469 SNP was found to be borderline significant between the patient groups with and without BRCA1 or BRCA2 mutations (p = 0.059). In patients with BRCA1 or BRCA2 pathogenic variations living in the Trakya region of Turkey, we could not determine the relationship between TNFRSF11 SNPs with breast cancer risk.
... Bonifaci et al. [8] revealed that rs7226991 was associated with a risk of breast cancer among the general Spanish population (BRCA1 or BRCA2) along with BRCA2 mutation carriers from different populations, which is consistent with the above observations. In addition, the results of the study exhibited effects parallel to those shown in the CGEMS results [8,25,26]. ...
Modifying genes play an exclusive role in the genetic regulation of the risk of breast cancer development in women with a pathogenic variation of BRCA1 or BRCA2. Therefore, it has been suggested that TNFRSF11A, which is among those modifying genes present in breast cancer development, may have a significant role in patients with positive BRCA1 or BRCA2 variations. In our study, we investigated the probable effects of single nucleotide polymorphisms (SNPs) in the TNFRSF11A gene, such as rs4485469, rs9646629, rs34739845, rs17069904, rs 884205, rs4941129 on the risk of breast cancer in patients with BRCA1 or BRCA2 variations. A total of 23 breast cancer patients with pathogenic variations in the BRCA1 or BRCA2 genes, 28 patients with no pathogenic variations in the BRCA1 or BRCA2 genes, and 55 healthy women as a control group, were included in this study. The SNPs were determined with allelic discrimination analysis through the real-time polymerase chain reaction (qPCR) method. There was no statistically significant difference between the SNPs of the TNFRSF11A gene rs4485469, rs9646629, rs34739845, rs17069904, rs884205, rs4941129 and metastasis, estrogen receptor, progesterone receptor and CerB2 receptor positivity between patient and control group (p >0.05). However, the rs4485469 SNP was found to be borderline significant between the patient groups with and without BRCA1 or BRCA2 mutations (p = 0.059). In patients with BRCA1 or BRCA2 pathogenic variations living in the Trakya region of Turkey, we could not determine the relationship between TNFRSF11 SNPs with breast cancer risk.
... The rs2073618 OPG SNP (major allele G, minor allele C) is in the first exon of OPG with the minor allele C causing the third amino acid in the OPG protein to change from Lysine to Asparagine (11). Ney et al. (12) studied the frequency of two OPG gene SNPs (rs3102735 and rs2073618) in 614 breast cancer patients and 784 healthy subjects. They found that the minor allele C of SNP rs3102735 was associated with a 1.5-fold increased risk for breast cancer. ...
... They found that the minor allele C of SNP rs3102735 was associated with a 1.5-fold increased risk for breast cancer. They did not find an association between the OPG gene SNP rs2073618 and breast cancer risk, but did establish that the major allele G was more likely to be found in invasive vs. noninvasive breast cancer cases (12). Ney et al. did not measure OPG protein serum levels, but studies on the same SNPs for different disease states did not find differences in OPG serum levels associated with SNPs rs3102735 or rs2073618 (13,14). ...
Osteoprotegerin (OPG) is a secreted member of the Tumor Necrosis Factor (TNF) receptor superfamily (TNFRSF11B), that was first characterized and named for its protective role in bone remodeling. In this context, OPG binds to another TNF superfamily member Receptor Activator of NF-kappaB Ligand (RANKL; TNFSF11) and blocks interaction with RANK (TNFRSF11A), preventing RANKL/RANK stimulation of osteoclast maturation, and bone breakdown. Further studies revealed that OPG protein is also expressed by tumor cells and led to investigation of the role of OPG in tumor biology. An increasing body of data has demonstrated that OPG modulates breast tumor behavior. Initially, research was focused on OPG in the bone microenvironment as a potential inhibitor of RANKL-driven osteolysis. More recently, attention has shifted to include OPG expression and interactions in the primary breast tumor independent of RANKL. In the primary tumor, OPG may interact with another TNF superfamily member, TNF-Related Apoptosis Inducing Ligand (TRAIL; TNFSF10) to prevent apoptosis induction. Additional interest in OPG in breast cancer has been stimulated by the tumor-promoting role of its binding partner RANKL in association with BRCA1 gene mutations. We and others have previously summarized the functional studies on OPG and breast cancer (1, 2). After basic research studies on the in vitro role for OPG (and RANKL) in breast cancer, the field now expands to assess the in vivo role for OPG by examining the correlation between OPG expression and breast cancer risk or patient prognosis. However, the data reported so far is conflicting, since OPG expression appears linked to both good and poor patient survival. In the current review we will summarize these studies. Our goal is to provide stimulus for further research to bridge the basic research findings and clinical data regarding OPG in breast cancer.
... Our finding confirms other studies on literature because we found CC genotype and C allele were significantly increased in both patients groups. Conversely, in another study, they found no correlation between OPG rs2073618 polymorphism and breast cancer (31). ...
Objective: Triple negative breast cancer (TNBC) is a sub-type of breast cancer with the worst prognosis and highest risk of mortality. Bone metastasis is the most common metastasis type among women with breast cancer. RANK and OPG, are the members of the family of tumor necrosis factor (TNF), which is effective on osteoblastic and osteoclastic mechanisms. RANKL, interacts with RANK and leads to bone resorption, whereas it inhibits bone destruction when it interacts with OPG.Methods: In this study, we investigated the polymorphisms of RANK, RANKL and OPG genes and their effects on bone metastasis in 45 patients with triple negative breast cancer and 30 healthy controls, using PCR, RFLP and agarose gel electrophoresis techniques.Results: The RANKL genotype and allele distribution analysis revealed a significantly increased CC genotype incidence in patients with TNBC and bone metastasis (p=0.011) and in those without bone metastasis (p=0.004) compared to the control group. The OPG genotype and allele distribution analysis revealed significantly increased C allele incidence in patients with TNBC and bone metastasis (p=0.004) compared to the control group. Likewise, the CC genotype (p=0.001) and C allele incidences (p=0.001) were observed to be significantly increased in patients with TNBC compared to healthy controls.Conclusion: This study is one of the first studies investigating all three RANK/RANKL/OPG gene polymorphisms and the relationship between breast cancer and bone metastasis in our country. We believe that our study will shed light onto further studies to be conducted on triple negative breast cancer and bone metastasis.
... Moreover, it has the second- degree risk of 1.5 % [7]. For ER-PR parameter patients were classified according to their level of ER/PR into three groups, ER/PR below 1%, ER/PR 1-5% and ER/PR 6-10%, for ER/PR positivity was?10 fmol/mg cytosol protein and negative breast cancers otherwise [8], LAPTM-4B [9], RANKL [10], T950C [11], YKL-40 [12], Diabetes [13], hypertension [14], OPG G1181C [15], tumor type [16] and tumor size [17]. ...
Computerized classification plays an important role in the classification of cancer stage. Hence, there is a growing need for automatic classification of cancer data. In this paper, a new model for stage classification of cancer data is developed. The proposed model use decision tree data mining technique that is trained on medical data to classify cancer data into several stages based on the weights of the most significant features. Hence, this paper proposes boost strapping approach for generating data oversampling to solve the problems of medical data scarcity. Ultimately, the proposed model improve the gain ratio technique to predict the weights of the factors (attributes) that affected in the staging of each patient case before and after oversampling. The performance of the proposed model is evaluated to develop more cost-effective and easy to use systems that support clinicians. The experimental results show that the proposed model precision is 94% for the original dataset and 90% for the oversampling dataset. The result illustrates the promising capabilities of the model for detecting breast cancer stages by minimum data set and minimum attributes.
... Moreover, it has the second- degree risk of 1.5 % [7]. For ER-PR parameter patients were classified according to their level of ER/PR into three groups, ER/PR below 1%, ER/PR 1-5% and ER/PR 6-10%, for ER/PR positivity was≥10 fmol/mg cytosol protein and negative breast cancers otherwise [8], LAPTM-4B [9], RANKL [10], T950C [11], YKL-40 [12], Diabetes [13], hypertension [14], OPG G1181C [15], tumor type [16] and tumor size [17]. ...
Computerized classification plays an important role in the classification of cancer stage. Hence, there is a growing need for automatic classification of cancer data. In this paper, a new model for stage classification of cancer data is developed. The proposed model use decision tree data mining technique that is trained on medical data to classify cancer data into several stages based on the weights of the most significant features. Hence, this paper proposes boost strapping approach for generating data oversampling to solve the problems of medical data scarcity. Ultimately, the proposed model improve the gain ratio technique to predict the weights of the factors (attributes) that affected in the staging of each patient case before and after oversampling. The performance of the proposed model is evaluated to develop more cost-effective and easy to use systems that support clinicians. The experimental results show that the proposed model precision is 94% for the original data-set and 90% for the oversampling data-set. The result illustrates the promising capabilities of the model for detecting breast cancer stages by minimum data set and minimum attributes.
... Remarkably, two SNPs in OPG (rs3102735 and rs2073618), two SNPs in RANKL (rs9533156, rs1054016), and two SNPs in RANK (rs1805034 and rs35211496) have been shown to have a high allelic Research Paper frequency in BC patients [16][17][18]. Amongst these only SNP rs1054016 in RANKL has been shown to have prognostic value, being associated with increased bone metastasis-free survival [18]. It was also shown that in patients with early stage, hormone-sensitive BC who were receiving therapy with aromatase inhibitors, the OPG SNP rs2073618 plus the RANKL SNP rs7984870 were associated with aromatase inhibitor-related musculoskeletal adverse events, a finding thought to be mediated by an increased RANKL/OPG ratio, higher levels of serum biomarkers of bone turnover, and a lower lumbar spine BMD [19]. ...
Receptor activator of NF-kB (RANK) pathway regulates bone remodeling and is involved in breast cancer (BC) progression. Genetic polymorphisms affecting RANK-ligand (RANKL) and osteoprotegerin (OPG) have been previously associated with BC risk and bone metastasis (BM)-free survival, respectively. In this study we conducted a retrospective analysis of the association of five missense RANK SNPs with clinical characteristics and outcomes in BC patients with BM. SNP rs34945627 had an allelic frequency of 12.5% in BC patients, compared to 1.2% in the control group (P = 0.005). SNP rs34945627 was not associated with any clinicopathological characteristics, but patients presenting SNP rs34945627 had decreased disease-free survival (DFS) (log-rank P = 0.039, adjusted HR 2.29, 95% CI 1.04-5.08, P = 0.041), and overall survival (OS) (log-rank P = 0.019, adjusted HR 4.32, 95% CI 1.55-12.04, P = 0.005). No differences were observed regarding bone disease-free survival (log-rank P = 0.190, adjusted HR 1.68, 95% CI 0.78-3.66, P = 0.187), time to first skeletal-related event (log-rank P = 0.753, adjusted HR 1.28, 95% CI 1.42-3.84; P = 0.665), or time to bone progression (log-rank P = 0.618, adjusted HR 0.511, 95% CI 0.17-1.51; P = 0.233). Our analysis shows that RANK SNP rs34945627 has a high allelic frequency in patients with BC and BM, and is associated with decreased DFS and OS.
