Characterization and risk association of polymorphisms in Aurora kinases A, B and C with genetic susceptibility to gastric cancer development.
ABSTRACT: BACKGROUND:Single nucleotide polymorphisms (SNPs) in genes encoding mitotic kinases could influence development and progression of gastric cancer (GC). METHODS:Case-control study of nine SNPs in mitotic genes was conducted using qPCR. The study included 116 GC patients and 203 controls. In silico analysis was performed to evaluate the effects of polymorphisms on transcription factors binding sites. RESULTS:The AURKA rs1047972 genotypes (CT vs. CC: OR, 1.96; 95% CI, 1.05-3.65; p?=?0.033; CC?+?TT vs. CT: OR, 1.94; 95% CI, 1.04-3.60; p?=?0.036) and rs911160 (CC vs. GG: OR, 5.56; 95% CI, 1.24-24.81; p?=?0.025; GG?+?CG vs. CC: OR, 5.26; 95% CI, 1.19-23.22; p?=?0.028), were associated with increased GC risk, whereas certain rs8173 genotypes (CG vs. CC: OR, 0.60; 95% CI, 0.36-0.99; p?=?0.049; GG vs. CC: OR, 0.38; 95% CI, 0.18-0.79; p?=?0.010; CC?+?CG vs. GG: OR, 0.49; 95% CI, 0.25-0.98; p?=?0.043) were protective. Association with increased GC risk was demonstrated for AURKB rs2241909 (GG?+?AG vs. AA: OR, 1.61; 95% CI, 1.01-2.56; p?=?0.041) and rs2289590 (AC vs. AA: OR, 2.41; 95% CI, 1.47-3.98; p?=?0.001; CC vs. AA: OR, 6.77; 95% CI, 2.24-20.47; p?=?0.001; AA+AC vs. CC: OR, 4.23; 95% CI, 1.44-12.40; p?=?0.009). Furthermore, AURKC rs11084490 (GG?+?CG vs. CC: OR, 1.71; 95% CI, 1.04-2.81; p?=?0.033) was associated with increased GC risk. A combined analysis of five SNPs, associated with an increased GC risk, detected polymorphism profiles where all the combinations contribute to the higher GC risk, with an OR increased 1.51-fold for the rs1047972(CT)/rs11084490(CG?+?GG) to 2.29-fold for the rs1047972(CT)/rs911160(CC) combinations. In silico analysis for rs911160 and rs2289590 demonstrated that different transcription factors preferentially bind to polymorphic sites, indicating that AURKA and AURKB could be regulated differently depending on the presence of particular allele. CONCLUSIONS:Our results revealed that AURKA (rs1047972 and rs911160), AURKB (rs2241909 and rs2289590) and AURKC (rs11084490) are associated with a higher risk of GC susceptibility. Our findings also showed that the combined effect of these SNPs may influence GC risk, thus indicating the significance of assessing multiple polymorphisms, jointly. The study was conducted on a less numerous but ethnically homogeneous Bosnian population, therefore further investigations in larger and multiethnic groups and the assessment of functional impact of the results are needed to strengthen the findings.
Project description:Wilms tumor is the most common type of renal malignancy in children. Previous studies have demonstrated that single nucleotide polymorphisms (SNPs) in the AURKA gene could predispose to several human malignancies. We recruited 145 cases and 531 cancer-free controls to investigate whether AURKA gene variants modify Wilms tumor susceptibility. Three AURKA SNPs (rs1047972 C>T, rs2273535 T>A, and rs8173 G>C) were genotyped by the Taqman methodology. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of association between AURKA SNPs and Wilms tumor risk. We found that only the rs8173 G>C polymorphism was significantly associated with Wilms tumor risk (GC vs. GG: adjusted OR (AOR)?=?0.50, 95% CI?=?0.35-0.73, P=0.0002; GC/CC vs. GG: AOR?=?0.60, 95% CI?=?0.42-0.88, P=0.008). Stratification analysis revealed that rs8173 GC/CC genotypes were associated with Wilms tumor risk among children aged >18?months (AOR?=?0.56, 95% CI?=?0.34-0.93, P=0.024), male children (AOR?=?0.54, 95% CI?=?0.33-0.90, P=0.017), and children with clinical stage III?+?IV diseases (AOR?=?0.56, 95% CI?=?0.35-0.90, P=0.017). Haplotype analysis indicated that the CAG haplotype was significantly associated with increased Wilms tumor risk. In conclusion, our findings indicated that the AURKA rs8173 G>C polymorphism was associated with decreased Wilms tumor risk in Chinese children.
Project description:OBJECTIVE:Previous studies have reported an association between cyclooxygenase-2 (COX-2) polymorphism and gastric cancer (GC) susceptibility, but their results are controversial. This meta-analysis was intended to evaluate the relationship between the COX-2 rs20417 polymorphism and GC susceptibility in different ethnic groups. METHODS:We searched PubMed, EMBASE, Web of Knowledge, and the Chinese Biomedical Database (CBM) for relevant case-control studies published up to October 6, 2018, which reported an association between the COX-2 rs20417 polymorphism and gastric cancer risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of this association. RESULTS:15 papers detailing case-control studies were included in the analysis, which included a total of 2848 GC cases and 4962 healthy controls. The meta-analysis results indicated that the COX-2 rs20417 polymorphism was associated with increased GC susceptibility under allele (G vs C: OR?=?1.67, 95%CI?=?1.19-2.35, P?=?.003), heterozygous (GG vs CG: OR?=?1.44, 95%CI?=?1.03-2.02, P?=?.034), dominant (GC+CC vs GG: OR?=?1.66, 95%CI?=?1.18-2.34, P?=?.004), homozygous (GG vs CC:OR?=?2.20, 95%CI?=?1.07-4.54, P?=?.033), and recessive models (CC vs GG+CG:OR?=?2.05, 95%CI?=?1.09-3.85, P?=?.025). An analysis of ethnic subgroups revealed that the COX-2 rs20417 polymorphism was significantly associated with GC susceptibility in Asians under all 5 models (G vs C: OR?=?2.22, 95%CI?=?1.66-2.96, P?<?.001; GG vs CC: OR?=?4.29, 95%CI?=?1.94-9.50, P?<?.001; GG vs CG: OR?=?1.86, 95%CI?=?1.34-2.58, P?<?.001; CC vs GG+CG: OR?=?3.73, 95%CI?=?1.92-7.24, P?<?.001; GC+CC vs GG: OR?=?2.20, 95%CI?=?1.65-2.93, P?<?.001). Helicobacter pylori positive patients suffered a high risk of GC, compared to H pylori negative patients under the dominant model (OR?=?3.09, 95%CI?=?1.80-5.32, P?<?.001). CONCLUSION:This meta-analysis of 15 case-control studies provides strong evidence that the COX-2 rs20417 polymorphism increases the risk of GC susceptibility in general populations, especially in Asians. Helicobacter pylori positive patients and those with the COX-2 rs20417 polymorphism had a higher risk of developing GC.
Project description:The TOB1 (ErbB-2,1) gene is an anti-proliferative factor that has the potential to regulate cell growth and encodes a member of the transducer of erbB-2/B-cell translocation gene protein. The association between the polymorphisms of the TOB1 gene and gastric cancer (GC) risk is still unclear. In this study, 506 GC cases and 548 healthy controls (HCs) were collected to evaluate the association between the eleven SNPs (rs35220381, rs12950561, rs7221352, rs61482741, rs9303568, rs34700818, rs12949115, rs9903822, rs12601477, rs11656976 and rs4626) of the TOB1 gene and GC risk in the population of northeast China. The results showed that there were significant associations of haplotype GCCTTGC, haplotype ATCTTGG, and haplotype GCCACGC with GC risk (P < 0.05, P < 0.001, and P <0.001, respectively). The association between rs12601477 GA+AA genotypes and GC risk was significant among individuals older than 58 (adjusted OR=1.53, 95% CI=1.05-2.22, P< 0.05). The association between rs4626 AG+GG genotypes and GC risk was significant among individuals older than 58 (adjusted OR=1.54, 95% CI = 1.03-2.28, P<0.05). The rs34700818 CT+TT genotypes were associated with a significantly increased risk of T3-T4 (CT+TT vs CC, adjusted OR=1.71, 95% CI= 1.01-2.88, P<0.05) and TNM stage II (CT+TT vs CC, adjusted OR=2.40, 95% CI =1.27-4.52, P<0.01). The rs61482741 CG+GG genotypes were also associated with a significantly increased risk of T3-T4 (CG+GG vs CC, adjusted OR=1.71, 95% CI = 1.01-2.88, P<0.05) and TNM stage II (CG+GG vs CC, adjusted OR=2.40, 95% CI=1.27-4.52, P<0.01). The results suggest that four SNPs (rs12601477, rs4626, rs34700818 and rs61482741) of the TOB1 gene play an important role in the occurrence and development of GC in the Chinese Han population of northeast China.
Project description:Purpose:Triple-negative breast cancer (TNBC) is more than a single disease. Identifying biomarkers to further subdivide TNBC patients with distinct outcome is of great importance. It has been reported that single-nucleotide polymorphisms (SNPs) in Aurora kinase A (AURKA) or Aurora kinase B (AURKB) are associated with the risk and survival of several cancers. But till now, there is no research about these polymorphisms in TNBC patients. Materials and methods:In this study, we investigated the association between polymorphisms in AURKA or AURKB gene and prognosis of TNBC patients treated with taxane-based adjuvant chemotherapy. A total of 273 TNBC patients were enrolled. Haploview 4.2 software was used to identify Tag SNPs. Genotyping was conducted using the MassARRAY MALDI-TOF system. Results:We found that AURKA rs6099128 GG genotype carriers had significantly worse overall survival (OS) than TT+ TG genotype carriers (P = 0.003, HR = 12.499, 95% CI = 2.357-66.298). AURKB rs11651993 TT genotype carriers had better disease-free survival (DFS) than TC + CC genotype carriers (P = 0.018, HR = 1.876, 95% CI = 1.116-3.154). AURKB rs2289590 CC genotype carriers had worse DFS than CA + AA genotype carriers (P = 0.021, HR = 0.536, 95% CI = 0.315-0.912). After subgroup analysis, rs11651993 TC + CC genotype predicted worse DFS in subgroups of age ? 50, post-menopausal, grade unknown (UK), tumor size >2 cm, and lymph node negative. Rs2289590 CA + AA genotype could predict favorable DFS in pre-menopausal, grade 3 and lymph node-positive patients. Conclusion:We first demonstrated that polymorphisms in AURKA or AURKB gene might predict the OS or DFS of TNBC patients treated with taxane-based adjuvant chemotherapy.
Project description:BACKGROUND:Published data on the association between AURKA polymorphisms and breast cancer (BC) risk are inconclusive. This meta-analysis was performed to derive a more precise estimation on the relationship between AURKA polymorphisms (rs2273535 and rs1047972) and BC risk. METHODS:PubMed, Web of Knowledge and Embase were searched for relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of associations. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were performed for allele contrast genetic model, homozygous genetic model, heterozygote genetic model, dominant model, and recessive model, respectively. RESULTS:A total of 13 studies (16,349 BC patients and 20,872 case-free controls) were involved in this meta-analysis. Meta-analysis showed that there was significant association between rs2273535 and BC risk in three genetic models in the overall population (A vs. T: OR?=?1.08, 95% CI?=?1.01-1.15, P = 0.02; AA vs. TT: OR?=?1.36, 95% CI?=?1.06-1.73, P?<?0.00001; AA vs. TT?+?TA: OR?=?1.15, 95% CI?=?1.01-1.31, P?=?0.04). In the subgroup analysis by ethnicity, the effects remained in Asians (allele contrast genetic model: OR?=?1.12, 95% CI?=?1.00-1.26, P?=?0.04 and homozygote comparison: OR?=?1.22, 95% CI?=?1.06-1.41, P?=?0.007). However, no genetic models reached statistical association in Cauasians. Rs1047972 polymorphism was associated with BC risk in the overall population based on homozygote comparison (AA vs. GG: OR?=?0.81, 95% CI?=?0.66-0.99, P?=?0.04). When stratified by ethnicity, rs1047972 polymorphism had a decreased association with BC risk in Caucasians based on allele contrast genetic model, homozygote comparison, the dominant model and the recessive model. However, there was no association in any genetic model in Asians. CONCLUSIONS:This meta-analysis suggests that AURKA rs2273535 polymorphism has an increased risk with BC, especially in Asians. However, rs1047972 polymorphism has a decreased BC risk in Caucasians. Further large scale multicenter epidemiological studies are warranted to confirm this finding.
Project description:The study purpose was to examine the correlation between SNP in the regulatory region (c.-521G>C, rs4855883) of APEH gene as well as the incidence and severity of radiotherapy (RTH) induced oral mucositis (OM) and overall survival (OS) in head and neck cancer (HNC) patients.OM in 62 HNC patients subjected to irradiation was assessed using RTOG/EORTC scale. DNA was isolated from whole blood of HNC patients. Mini-sequencing method (SNaPshot PCR) was used to determine the genotype.The following frequency of occurrence of APEH gene was observed: CC: 37.1%, CG: 43.6% and GG: 19.3%. It was established that the presence of CC genotype reduced the risk of occurrence of grade 2 and 3 OM symptoms: 3-fold in RTH week 2 (in case of CC vs GC or GG it was: 26.8% vs 73.2% patients, respectively, OR = 0.27, 95 CI: 0.09-0.83; p = 0.0222), 6-fold in RTH week 3 (in case of CC vs GC or GG it was: 29.4% vs 70.6% patients, respectively, OR = 0.16, 95 CI: 0.04-0.67; p = 0.0125) and grade 3 OM symptoms 4-fold in RTH week 6 (in case of CC vs GC or GG it was: 19.2% vs 80.8% patients, respectively, OR = 0.23, 95 CI: 0.07-0.77; p = 0.0166). CC genotype was associated with lower OS (CC vs GG or GC: 29 months vs 38 months; HR = 2.48, 95% CI: 0.90-6.85; p = 0.0266).CC genotype of APEH gene was correlated with the risk of more severe radiotherapy-induced OM in HNC patients and lower rates of survival.
Project description:MiR-124 functions as a tumor suppressor and plays an important role in tumorigenesis. A common polymorphism (rs531564, C>G) in the pri-miR-124 has been recently studied in connection with cancer risk. The aim of the present study was to investigate the association between pri-miR-124 rs531564 polymorphism and the risk and clinicopathological characteristics of colorectal cancer (CRC). Two case-control studies involving 900 CRC patients and 1110 cancer-free controls showed that pri-miR-124 rs531564 polymorphism was significantly associated with the decreased risk of CRC in Xuzhou population [GG vs. CC: OR = 0.25, 95%CI = 0.09-0.67, P = 0.003; (CG+GG) vs. CC: OR = 0.73, 95%CI = 0.56-0.94, P = 0.01; GG vs. (CC+CG): OR = 0.27, 95%CI = 0.10-0.70, P = 0.004; G vs. C: OR = 0.70, 95%CI = 0.56-0.89, P = 0.003], Bengbu population [GG vs. CC: OR = 0.20, 95%CI = 0.04-0.90, P = 0.02; GG vs. (CC+CG): OR = 0.21, 95%CI = 0.05-0.95, P = 0.03; G vs. C: OR = 0.72, 95%CI = 0.54-0.98, P = 0.03] and pooled population [GG vs. CC: OR = 0.26, 95%CI = 0.11-0.59, P<0.001; (CG+GG) vs. CC: OR = 0.76, 95%CI = 0.62-0.93, P = 0.008; GG vs. (CC+CG): OR = 0.27, 95%CI = 0.12-0.62, P < 0.001; G vs. C: OR = 0.71, 95%CI = 0.59-0.85, P<0.001]. Additionally, pri-miR-124 rs531564 polymorphism was significantly associated with the decreased risk of poor differentiation and lymph node metastasis of CRC. Our results suggest that pri-miR-124 rs531564 polymorphism may be a genetic modifier for developing CRC. However, further studies are needed to validate our findings.
Project description:IL-18 polymorphisms influence the transcriptional activity of the IL-18 gene and associated with various diseases. However, their relationships with hepatitis B virus-related liver diseases had not reached a consensus. So we conducted this case-control study with a view to clarifying the association. We included four groups: healthy controls, chronic hepatitis B virus (CHB) carriers, liver cirrhosis (LC) and hepatocellular carcinoma (HCC) groups with each group of 250 persons. Odd ratios (ORs) and 95% confidence intervals (95%CIs) with or without adjustment were calculated. Haplotype analysis was also performed. The results showed people carrying rs187238 CG genotype had a lower risk of LC (CG vs. CC: OR = 0.59, 95%CI = 0.38-0.91, P = 0.02), while GG genotype carriers had a higher risk of HCC (GG vs. CC+CG: OR = 4.73, 95%CI = 1.01-22.1, P = 0.03) than those with CC and CG genotypes in healthy group. Rs187238 GG genotype increased the risk from CHB to LC status (GG vs. CC: OR = 4.81, 95%CI = 1.03-22.6; GG vs. CC+CG: OR = 4.73, 95%CI = 1.01-22.1), meanwhile the trend also existed by controlling confounding factors (GG vs. CC: OR = 6.25, 95%CI = 1.09-35.8; GG vs. CC+CG: OR = 5.91, 95%CI = 1.04-33.7). Haplotype Crs187238Trs1946518 moderately decreased the risk of CHB carriers developing into HCC (OR = 0.69, 95%CI = 0.50-0.96, P = 0.03) after adjustment. In conclusion, IL-18 rs187238 GG genotype may increase the risk of HCC in healthy population and the risk of LC in CHB carriers.
Project description:The melatonin receptor 1B (MTNR1B) polymorphism rs10830963 C>G has been reported to be associated with the risk of gestational diabetes mellitus (GDM) with inconsistent results. To clarify the effect of the polymorphism on the risk of GDM, a meta-analysis therefore was performed. Pooled OR with its corresponding 95%CI was used to estimate the strength of the association. Totally 14 eligible studies with a number of 5033 GDM patients and 5614 controls were included in this meta-analysis. Results indicated that the variant G allele was significantly associated with an increased GDM risk (CG vs. CC: OR = 1.25, 95% CI = 1.11-1.40, P < 0.001; GG vs. CC: OR = 1.78, 95% CI = 1.45-2.19, P < 0.001; G vs. C: OR = 1.33, 95% CI = 1.21-1.47, P < 0.001). In the stratified analysis by ethnicity, similar results were found in Asians (CG vs. CC: OR = 1.15, 95%CI = 1.02-1.28, P = 0.020; GG vs. CC: OR = 1.52, 95% CI = 1.23-1.89, P < 0.001; G vs. C: OR = 1.23, 95% CI = 1.10-1.37, P < 0.001) and in Caucasians (CG vs. CC: OR = 1.40, 95% CI = 1.16-1.70, P < 0.001; GG vs. CC: OR = 2.21, 95% CI = 1.54-3.17, P < 0.001; G vs. C: OR = 1.47, 95% CI = 1.24-1.73, P < 0.001). FPRP and TSA analyses confirmed findings support that the rs10830963 G allele increases the risk of GDM, and further functional experimental studies are warranted to explore and clarify the potential mechanism.
Project description:Common single-nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) have been shown to be associated with susceptibility to several types of human cancer. We evaluated the association between three SNPs (rs11614913, rs2910164 and rs3746444) in pre-miRNAs (miR-196a2, miR-146a and miR-499) and various clinicopathological characteristics, including CpG island hypermethylation (CIHM) status and overall survival in gastric cancer (GC) patients. rs11614913 (T>C), rs2910164 (C>G) and rs3746444 (A>G) SNPs were genotyped in 127 GC patients. CIHM of p14, p16, DAP-kinase and CDH1 genes was determined by methylation-specific polymerase chain reaction in the cancer tissues. A significant marginal association was found between the rs11614913 CC genotype and polypoid or elevated type morphology in early-stage GC (OR=6.29, 95% CI 1.18-33.47, p=0.03). The rs2910164 CC and CG genotypes were associated with increased susceptibility to CIHM of DAP-kinase (CC+CG, OR=5.48, 95% CI 1.30-23.10, p=0.02; CC, OR=6.93, 95% CI 1.37-35.02, p=0.02; CG, OR=4.24, 95% CI 0.87-20.78, p=0.07). The 11614913 TT and TC genotypes were associated with a higher number of CIHM (no. of CIHM 0-1 vs. 2-4; TT+TC, OR=3.67, 95% CI 0.98-13.72, p=0.05; TC, OR=4.08, 95% CI 1.04-15.97, p=0.04). When the subjects were divided according to age group, the combined rs11614913 TT+TC genotype tended to be associated with worse overall survival than the CC genotype in patients younger than 65 years of age (p=0.05). The combined rs2910164 CG+GG genotype also tended to be associated with worse overall survival than the CC genotype in the same age group (p=0.09). It appears that rs11614913 and rs2910164 SNPs in pre-miRNAs (miR-196a2 and miR-146a) affect the clinicopathological characteristics of GC, including its morphological appearance, CIHM status and overall survival.