Shuting Jia

Folate metabolism gene polymorphisms MTHFR C677T and A1298C and risk for Down syndrome offspring: a meta-analysis.

OBJECTIVES MTHFR C677T and A1298C have been associated with the risk of having an infant with Down syndrome (DS), but results were conflicting. We performed this meta-analysis to derive a more precise estimation of the association between maternal MTHFR polymorphisms and DS. STUDY DESIGN An electronic search of PubMed and Chinese Biomedicine database was conducted to select studies for meta-analysis. Twenty-eight case-control studies containing MTHFR C677T and A1298C gene polymorphisms were chosen, and odds ratio (OR) with confidence interval (CI) was used to assess the strength of this association. RESULTS Case-control studies including 2806 cases and 4597controls for MTHFR C677T were identified. The overall results suggested that the variant genotypes MTHFR C677T were associated with DS risk (TT+CT vs. CC: OR=1.305, 95% CI: 0.125-1.514, p=0). In the stratified analysis, individuals with the T-carriers genotype in the dominant model had increased risk of DS (OR=1.171, 95% CI: 0.976-1.405, p=0.09) in Caucasian subjects and in Asian subjects (OR=1.749, 95% CI: 1.084-2.824, p=0.022). In addition, case-control studies including 1854 cases and 2364 controls for MTHFR A1298C were chosen. Associations between MTHFR A1298C and the risk of having a child with DS were not found. A symmetric funnel plot, the Eggers test (p=0.126) suggested a lack of publication bias. CONCLUSION This meta-analysis supports the idea that MTHFR C677T genotype is associated with increased risk for DS offspring.

The MTHFR C677T Polymorphism and Risk of Acute Lymphoblastic Leukemia: an Updated Meta-analysis Based on 37 Case-control Studies

BACKGROUND The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) has been associated with acute lymphoblastic leukemia (ALL). However, results were conflicting. The aim of this study was to quantitatively summarize the evidence for the MTHFRC677T polymorphism and ALL risk. METHODS Electronic searches of PubMed and the Chinese Biomedicine database were conducted to select case-control studies containing available genotype frequencies of C677T and the odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of any association. RESULTS Case-control studies including 6,371 cases and 10,850 controls were identified. The meta-analysis stratified by ethnicity showed that individuals with the homozygous TT genotype had decreased risk of ALL (OR= 0.776, 95% CI: 0.687~0.877, p< 0.001) in Caucasians (OR= 0.715, 95% CI: 0.655~0.781, p= 0.000). However, results among Asians (OR=0.711, 95% CI: 0.591~1.005, p= 0.055) and others (OR=0.913, 95% CI: 0.656~1.271, p= 0. 590) did not suggest an association. A symmetric funnel plot, the Eggers test (P=0.093), and the Begg- test (P=0.072) were all suggestive of the lack of publication bias. CONCLUSION This meta-analysis supports the idea that the MTHFR C677T genotype is associated with risk of ALL in Caucasians. To draw comprehensive and true conclusions, further prospective studies with larger numbers of participants worldwide are needed to examine associations between the MTHFRC677T polymorphism and ALL.

Association of p53 Arg72Pro polymorphism with bladder cancer: a meta-analysis.

BACKGROUND p53 tumor suppressor gene Arg72Pro polymorphism has been associated with bladder cancer. However, results were inconsistent. We performed this meta-analysis to estimate the association between p53 Arg72Pro polymorphism and bladder cancer. METHODS Electronic search of PubMed was conducted to select studies. Studies containing available genotype frequencies of Arg72Pro were chosen, and pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the association. RESULTS The final meta-analysis included 14 published studies with 2176 bladder cancer cases and 2798 controls. The results suggested that the variant genotype was associated with the bladder cancer risk (additive model: OR=1.72, 95% CI: 1.036-1.325, P=0.011; dominant model: OR=1.268, 95% CI: 1.003-1.602, P=0.047) in Asian subgroup. However, the association was not significant between this polymorphism and bladder cancer risk in Caucasian (additive model: OR=0.773, 95% CI: 0.564-1.059, P=0.109; dominant model: OR=0.685, 95% CI: 0.418-1.124, P=0.134). CONCLUSION This meta-analysis suggests that p53 Arg72Pro polymorphism is associated with increased risk of bladder cancer in Asians. To validate the association between this polymorphism and bladder cancer, further studies with larger participants worldwide are needed.

The Gain of Function of p53 Mutant p53S in Promoting Tumorigenesis by Cross-talking with H-RasV12

The loss of wild type p53 tumor suppressive function and oncogenic gain-of-function of p53 mutants have been showing important implications in tumorigenesis. The p53N236S (p53N239S in human, p53S) mutation has been shown to lose wild type p53 function by yeast assay. However, its gain of function is still not clear. By gel shift assay, we showed that mutant p53S had lost its DNA binding ability to its target promoters. Further real-time PCR data confirmed that p53S had lost the function of regulating the transcription of p21 Cip1/Waf1, cyclin G, PUMA, and Bax in response to 10Gy irradiation. These data confirmed the loss of function of p53S in mammalian cells. By xenograft assay, we showed that the p53S per se was not oncogenic enough to form tumor, however, cooperating with H-RasV12, p53S could dramatically promote tumorigenesis in p53 null MEFs. Further study showed that co-expression of p53S and H-RasV12 could increase the expression level of H-RasV12 and partially eliminate the elevation of stress response proteins such as Chk2, γ-H2AX, Hsp70, Rb, p16Ink4a caused by either p53S or H-RasV12. These data suggested that p53S cross-talked with H-RasV12 and reduced the cellular stress response to oncogenic signals, which facilitated the cell growth and tumorigenesis. Together these data provided the molecular basis for the cooperation of p53S and H-RasV12 and revealed the gain of function of p53S in cross-talking with H-RasV12. This study revealed an important aspect of gain of function for p53 mutant, therefore might shed light on the clinical strategy in targeting p53 mutant.

Association Between rs1344706 of ZNF804A and Schizophrenia: A Meta-analysis

Schizophrenia is one of the most serious mental diseases found in humans. Previous studies indicated that the single nucleotide polymorphism (SNP) rs1344706 in the gene ZNF804A encoding zinc finger protein 804A was associated with schizophrenia in Caucasian population but not in Chinese Han population. However, current results are conflicting in Asian population. In the present study, a meta-analysis was performed to revisit the association between rs1344706 and the risk of schizophrenia in Asian, Caucasian and other populations. Electronic search of PubMed database identified 25 case–control studies with available genotype frequencies of rs1344706 for the meta-analysis, involving a total of 15,788 cases and 22,654 controls. A pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the association. The current meta-analysis showed an association between rs1344706 and schizophrenia in Caucasian populations (P = 0.028, OR = 1.138, 95% CI: 1.014–1.278; P = 0.004 for heterogeneity) and Asian populations (P = 0.008, OR = 1.092, 95% CI: 1.023–1.165; P = 0.001 for heterogeneity), but not in other populations (P = 0.286, OR = 1.209, 95% CI: 0.853–1.714, P = 0.120 for heterogeneity). Egger’s test (P > 0.05) and Begg’s test (P > 0.05) are both suggestive of the lack of publication bias for the included studies. Thus, the absence of association in other populations suggests a genetic heterogeneity in the susceptibility of schizophrenia and demonstrates the difficulties in replicating genome-wide association study findings regarding schizophrenia across different ethnic populations. To validate the association between rs1344706 and schizophrenia, further studies with larger participant populations worldwide are needed.

Two mechanisms underlying the loss of p16Ink4a function are associated with distinct tumorigenic consequences for WS MEFs escaping from senescence

Werner syndrome (WS) mouse embryonic fibroblasts (MEFs) can spontaneously escape from senescence and become immortalized, either tumorigenic or non-tumorigenic. Our data revealed a single p53(N236S) point mutation in the tumorigenic cell lines, which was correlated with the down-regulation of p21(Waf1/Cip1). p16(Ink4a) expression was significantly decreased in all immortalized cell lines. Bisulfate sequencing indicated that the p16(Ink4a) gene was methylated in the tumorigenic cells. Exogenous overexpression of p21(Waf1/Cip1) demethylated p16(Ink4a) and restored its expression, which induced cell growth arrest and senescence. While in non-tumorigenic immortalized cells, the Ink4a loci and adjacent genomic DNA were found to be deleted. These data suggest that the loss of p16(Ink4a) function by either genomic DNA deletion or methylation have been adopted by senescent WS MEFs escaping from senescence, with distinct tumorigenic consequences. The fact that cells that had escaped senescence via the spontaneous biallelic deletion of the Ink4a loci could not form tumors suggests that the functional loss of p16(Ink4a)per se might not be sufficient for tumorigenesis; most likely, it is a byproduct and passenger mutation. The mutations in factors regulating p16(Ink4a) methylation might be the driver mutation. These findings shed light on the strategy of anti-aging by regulating p16(Ink4a) expression.

Bisphosphonates in the Treatment of Patients With Metastatic Breast, Lung, and Prostate Cancer: A Meta-Analysis.

AbstractThe purpose of this meta-analysis was to investigate whether bisphosphonates are a key therapy for bone metastases in lung cancer, breast cancer, and prostate cancer by comparing all randomized controlled trials that appraised the effects of bisphosphonates on risk of skeletal-related events (SREs).PubMed, Embase, and Medline databases (up to December 2014) were used to search all related articles. Using the data from 19 available publications, the authors examined the efficacy in treating or reducing the risk of SREs in lung cancer, breast cancer, and prostate cancer by meta-analysis.Bisphosphonates have demonstrated efficacy in treating or reducing the risk of SREs in lung cancer [odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.69–0.95, P = 0.008], breast cancer (OR = 0.62, 95% CI = 0.54–0.71, P = 0.000), and prostate cancer (OR = 0.62, 95% CI = 0.45–0.86, P = 0.004).This meta-analysis suggests that bisphosphonates have demonstrated efficacy in treating or reducing the risk of SREs in lung cancer, breast cancer, and prostate cancer.

Gain of function in the mouse model of a recurrent mutation p53N236S promotes the formation of double minute chromosomes and the oncogenic potential of p19ARF

The mutation p53N236S (p53S) has been identified as one of the recurrent mutations in human cancers by TCGA database. Our in vitro data revealed the oncogenic gain of function of p53S. To understand the function of p53S in vivo, we generated the p53S knock‐in mouse. The p53S/S mice manifested highly invasive lymphomas and metastatic sarcomas with dramatically increased double minute chromosomes. The survival curve, the incidence of tumors and the tumor spectrum of p53S/S mice is very similar to the p53R172H mouse model. The p53S/+ mice showed delayed onset of tumorigenesis and a high metastasis rate (40%) and low loss of heterozygosity rate (2/16). The activation of CDKN2A pathway in p53S/S MEF and tumors, and the accumulation of p19ARF protein in tumor tissues suggested p19ARF might contribute to the accumulation of mutant p53S protein in the tumor and promote tumorigenesis. The high expression of p19ARF correlated with mutant p53 accumulation and tumor progression, suggesting a dual role of p19ARF in tumor promotion or suppression that might depend on the p53 mutation status in tumor cells. The oncogenic gain of function of this recurrent mutation p53S prompts the reconsideration of p53 mutations function that occurs at a low frequency.

The relationship between RASSF1A gene promoter methylation and the susceptibility and prognosis of melanoma: A meta-analysis and bioinformatics.

Background The function of the tumor suppressor gene RASSF1A in cancer cells has been detailed in many studies. However, due to the methylation of its promoter, the expression of RASSF1A is missing in most cancers. In the literature, we found that the conclusion regarding the relationship between RASSF1A gene promoter methylation and the susceptibility and prognosis of melanoma was not unified. This study adopts the use of a meta-analysis and bioinformatics to explore the relationship between RASSF1A gene promoter methylation and the susceptibility and prognosis of melanoma. Methods Data on melanoma susceptibility were downloaded from the PubMed, Cochrane Library, Web of Science and Google Scholar databases, which were analyzed via a meta-analysis. The effect sizes were estimated by measuring an odds ratio (OR) with a 95% confidence interval (CI). We also used a chi-squared-based Q test to examine the between-study heterogeneity, and used funnel plots to evaluate publication bias. The data on melanoma prognosis, which were analyzed by bioinformatics methods, were downloaded from The Cancer Genome Atlas (TCGA) project. The effect sizes were estimated by measuring the hazard ratios (HRs) with a 95% confidence interval (CI). Results Our meta-analysis included 10 articles. We found that RASSF1A gene promoter methylation was closely related to melanoma susceptibility (OR = 12.67, 95% CI: 6.16 ∼ 26.05, z = 6.90, P<0.0001 according to a fixed effects model and OR = 9.25, 95% CI: 4.37 ∼ 19.54, z = 5.82, P<0.0001 according to a random effects model). The results of the meta-analysis did not reveal any heterogeneity (tau2 = 0.00; H = 1 [1; 1.55]; I2 = 0% [0%; 58.6%], P = 0.5158) or publication bias (t = 0.87, P = 0.4073 by Egger’s test; Z = 0.45, P = 0.6547 by Begg’s test); therefore, we believe that the results of our meta-analysis were more reliable. To explore the relationship between RASSF1A gene methylation, the prognosis of melanoma and the clinical features of this cancer type, we used the melanoma DNA methylation data and clinical data from TCGA project. We found that RASSF1A gene promoter methylation and melanoma prognosis did not demonstrate any relationship (HR was 0.94 (95% CI = [0.69; 1.27], P = 0.694) with disease-free survival and 0.74 (95% CI = [0.53; 1.05], P = 0.106) for overall survival), and no significant difference was observed between RASSF1A gene promoter methylation and the clinical-pathological features of melanoma. Conclusions In conclusion, the meta-analysis of the data in these articles provides strong evidence that the methylation status of the RASSF1A gene promoter was strongly related to melanoma susceptibility. Our bioinformatics analysis revealed no significant difference between RASSF1A gene promoter methylation and the prognosis and clinical-pathological features of melanoma.

Loss of p21 promoted tumorigenesis in the background of telomere dysfunctions induced by TRF2 and Wrn deficiency

Werner syndrome (WS) is a rare autosomal recessive progeria disease with genetic instability/cancer predisposition, thus a good model in understanding aging related carcinogenesis. Telomere dysfunction induced cellular senescence is essential in the manifestation of the WS phenotype. Our previous data has shown that p21 (encoded by Cdkn1a gene) could induce cellular senescence and suppress cellular growth of ALT (alternative lengthening of telomere) tumors derived from WS, suggested that p21 might play a key role in maintaining senescence of WS cells. To confirm the role of p21 in suppressing telomere dysfunction induced tumorigenesis, we overexpressed dominant negative protein TRF2ΔBΔM in p21-/- mouse embryonic fibroblasts (MEFs). To further stress the cell, we crossed Wrn-/-mice with p21-/- mice to obtained p21-/-Wrn-/- MEFs, and overexpressed TRF2ΔBΔM in these MEFs to induce telomere dysfunction similar to that in WS cells. Our data showed that, in the context of p21-/-TRF2ΔBΔM, loss of p21 function rescued cellular senescence, and induced p53 mutation, but did not induce tumorigenesis. However, in the set of p21-/-Wrn-/-TRF2ΔBΔM, loss of p21 function induced p53 mutation and tumorigenesis. To further verify the role of p21 in suppressing telomere dysfunction related tumorigenesis, we knocked down p21 in non-tumorigenic immortalized cells derived from WS MEFs (mTerc-/-Wrn-/-), and found that loss of p21 could induce ALT tumorigenesis, which displayed typical smear pattern of telomere length and arc-shaped telomeric DNA. In another hand, recovering telomerase activity in these MEFs could also induce tumorigenesis without affecting p21 expression level. Together our data suggested that p21 controlled cell cycle regulation played an essential role in suppressing telomere dysfunction-related tumorigenesis. These data also suggested that the genetic context is essential in determining the role of p21 in cancer prevention. Therefore, targeting p21 in the treatment of human degenerative diseases would require a personalized genetic background screen.