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1.
Int J Cancer ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33728681

RESUMO

Notch signaling pathway plays crucial roles in progression of colorectal cancer (CRC), likely affecting overall survival (OS). In a two-stage survival analysis of 1116 CRC patients in East China, we found that one locus at MINAR1 out of 133 genes in the Notch signaling pathway was significantly associated with OS (P < 1 × 10-6 , false discovery rate < 0.01). This locus containing seven single-nucleotide polymorphisms (SNPs) in high linkage disequilibrium (R2 = 1) is located on chromosome 15, of which the MINAR1 rs72430409 G allele was associated with a greater death risk (HR = 1.98, 95% CI = 1.55-2.54, P = 6.8 × 10-8 ). Further analysis of ChIP-sequencing data from the encyclopedia of DNA Elements showed that rs72430409 and rs72630408 were potential cis-regulatory elements for the MINAR1 promoter. Additional expression quantitative trait loci analysis revealed that rs72430409 G>A and rs72630408 A>G were correlated with increased MINAR1 expression levels in both blood cells and colon tissues. Dual luciferase assays revealed that the rs72430409 A allele increased MINAR1 promoter activity. The Cancer Genome Atlas data showed that expression levels of MINAR1 in CRC samples were significantly higher than that in normal colorectal tissue and that high expression of MINAR1 was associated with a shortened OS, likely via activating the epithelial mesenchymal transition (EMT) pathway as shown in the gene-set enrichment analysis. In vitro, RNAi-mediated silencing of MINAR1 led to decreased migration and proliferation in CRC cancer cells, and MINAR1 silencing could downregulate the expression of key effector genes in EMT and glycolysis. Larger cohort studies and further experiments are needed to validate our findings.

2.
Lancet Oncol ; 21(10): 1378-1386, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33002439

RESUMO

BACKGROUND: Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk. METHODS: In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10-4 p=5 × 10-5 p=5 × 10-6 p=5 × 10-7, and p=5 × 10-8) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2-4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor. FINDINGS: The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5 × 10-5) showed the strongest association with gastric cancer risk (p=7·56 × 10-10). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (ptrend<0·0001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio [HR] 1·54 [95% CI 1·22-1·94], p=2·67 × 10-4) and a high genetic risk (2·08 [1·61-2·69], p<0·0001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (ptrend<0·0001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2·03 [1·46-2·83], p<0·0001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0·53 [0·29-0·99], p=0·048), with an absolute risk reduction of 1·12% (95% CI 0·62-1·56). INTERPRETATION: Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.


Assuntos
Predisposição Genética para Doença/genética , Estilo de Vida Saudável , Neoplasias Gástricas/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , China/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/psicologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/psicologia
3.
Cancer Med ; 9(19): 7310-7316, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32777176

RESUMO

Genome-wide association studies (GWAS) have identified some single nucleotide polymorphisms (SNPs) associated with the risk of gastric cancer (GCa). However, currently, there is no published predictive model to assess the risk of GCa. In the present study, risk-associated SNPs derived from GWAS and large meta-analyses were selected to construct a predictive model to assess the risk of GCa. A total of 1115 GCa cases and 1172 controls from the eastern Chinese population were included. Logistic regression models were used to identify SNPs that correlated with the risk of GCa. A predictive model to assess the risk of GCa was established by receiver operating characteristic curve analysis. Multifactor dimensionality reduction (MDR) and classification and regression tree (CART) were applied to calculate the effect of high-order gene-environment interactions on risk of the cancer. A total of 42 SNPs were selected for further analysis. The results revealed that ASH1L rs80142782, PKLR rs3762272, PRKAA1 rs13361707, MUC1 rs4072037, PSCA rs2294008, and PLCE1 rs2274223 polymorphisms were associated with a risk of GCa. The area under curve considering both genetic factors and BMI was 3.10% higher than that of BMI alone. MDR analysis revealed that rs13361707 and rs4072307 variants and BMI had interaction effects on susceptibility to GCa, with the highest predictive accuracy (61.23%) and cross-validation consistency (100/100). CART analysis also supported this interaction model that non-overweight status and a six SNP panel could synergistically increase the susceptibility to GCa. The six SNP panel for predicting the risk of GCa may provide new tools for prevention of the cancer based on GWAS and large meta-analyses derived genetic variants.

4.
Carcinogenesis ; 41(9): 1203-1212, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32614429

RESUMO

Human leukocyte antigen (HLA) is highly polymorphic, driving antigen presentation, complement cascade and leukocyte maturation against cancer cells. Therefore, we extracted genotyping data in the HLA region from an ongoing Chinese genome-wide association study of non-small cell lung cancer (NSCLC). Using deep sequencing data of 10 689 healthy Han Chinese, we imputed for untyped genetic variants in the HLA region, followed by a two-stage survival analysis of 1531 NSCLC patients. In the discovery stage of 758 patients, we identified 301 out of 15 138 single-nucleotide polymorphisms to be independently associated with overall survival [P < 0.05 and Bayesian false-discovery probability < 0.8]. In further validation of another 773 patients, we confirmed chromosome 6p21, rs241424 (located at intron 3 of TAP2) and rs6457642 as two independent survival predictors. In the combined analysis of 1531 NSCLC patients, rs241424 G>A and rs6457642 C>T were associated with a hazards ratio of 1.26 [95% confidence interval (CI) = 1.14-1.40 and P = 4.04 × 10-6] and 0.76 (95% CI = 0.66-0.87 and P = 1.16 × 10-4), respectively. The analysis of publically available ChIP-sequencing and Hi-C data found that the rs241424 locus was involved in potential cis-regulatory element by a long-range interaction with the HLA-DQA1 promoter. Additional expression quantitative trait loci analysis showed that the rs241424 G>A change decreased HLA-DQA1 mRNA expression. Furthermore, expression levels of HLA-DQA1 were lower in lung cancer tissues than in adjacent normal tissues, and the lower expression was associated with a worse prognosis for patients with lung adenocarcinoma. Collectively, HLA genetic variants may modulate OS of NSCLC patients, possibly via a mechanism of long-range promoter interaction regulating HLA-DQA1 expression.

5.
Ann Transl Med ; 8(7): 484, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32395528

RESUMO

Background: Although microsatellite instability (MSI) is a powerful predictive biomarker for the efficacy of immunotherapy, the mechanism of MSI in sporadic gastrointestinal cancer is not fully understood. However, epigenetics, particularly microRNAs, has been suggested as one of the main regulators that contribute to the MSI formation. Methods: We used microRNA expression data of 386 gastric adenocarcinoma samples from The Cancer Genome Atlas (TCGA) database to identify differential microRNA expression profiles by different MSI status. We also obtained putative common target genes of the top differential microRNAs with miRanda online tools, and we analyzed these data by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment (KEGG). Results: We found that 56 and 67 gastric adenocarcinoma samples were positive for low and high MSI, respectively, and that a high MSI status was associated with age, sex and subregion (P=0.049, 0.014 and 0.007, respectively). In the 67 samples with a high MSI status, expression levels of 14 microRNAs were upregulated but five microRNAs were downregulated as assessed by the fold change (FC), compared with that of the 56 samples with a low MSI status (P<0.05, |FC| >2). Further analysis suggested that the expression of miR-210-3p, miR-582-3p, miR-30a-3p and miR-105-5p predicted a high MSI status (P=4.93×10-10, 5.63×10-10, 3.23×10-9 and 7.64×10-4, respectively). Regulation of the transcription pathways ranked the top of lists from both GO and KEGG analyses, and these microRNAs might regulate DNA damage-repair genes that were also associated with a high MSI status. Conclusions: MiR-30a-3p and miR-105-5p are potential biomarkers for the MSI-H gastric adenocarcinoma, possibly by altering expression of DNA damage-repair genes.

6.
Gut ; 69(4): 641-651, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31383772

RESUMO

OBJECTIVE: Although a subset of genetic loci have been associated with gastric cancer (GC) risk, the underlying mechanisms are largely unknown. We aimed to identify new susceptibility genes and elucidate their mechanisms in GC development. DESIGN: We conducted a meta-analysis of four genome-wide association studies (GWASs) encompassing 3771 cases and 5426 controls. After targeted sequencing and functional annotation, we performed in vitro and in vivo experiments to confirm the functions of genetic variants and candidate genes. Moreover, we selected 33 promising variants for two-stage replication in 7035 cases and 8323 controls from other five studies. RESULTS: The meta-analysis of GWASs identified three loci at 1q22, 5p13.1 and 10q23.33 associated with GC risk at p<5×10- 8 and replicated seven known loci at p<0.05. At 5p13.1, the risk rs59133000[C] allele enhanced the binding affinity of NF-κB1 (nuclear factor kappa B subunit 1) to the promoter of PRKAA1, resulting in a reduced promoter activity and lower expression. The knockout of PRKAA1 promoted both GC cell proliferation and xenograft tumour growth in nude mice. At 10q23.33, the rs3781266[C] and rs3740365[T] risk alleles in complete linkage disequilibrium disrupted and created, respectively, the binding motifs of POU2F1 and PAX3, resulting in an increased enhancer activity and expression of NOC3L, while the NOC3L knockdown suppressed GC cell growth. Moreover, two new loci at 3q11.2 (OR=1.21, p=4.56×10- 9) and 4q28.1 (OR=1.14, p=3.33×10- 11) were associated with GC risk. CONCLUSION: We identified 12 loci to be associated with GC risk in Chinese populations and deciphered the mechanisms of PRKAA1 at 5p13.1 and NOC3L at 10q23.33 in gastric tumourigenesis.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/genética , Neoplasias Gástricas/genética , China , Estudo de Associação Genômica Ampla , Humanos
7.
Lancet Respir Med ; 7(10): 881-891, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31326317

RESUMO

BACKGROUND: Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations. METHODS: To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up. FINDINGS: We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10-8, including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53-2·51; ptrend=2·02 × 10-9). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years. INTERPRETATION: We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations. FUNDING: National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Medição de Risco/métodos , Adulto , Idoso , China , Feminino , Loci Gênicos/genética , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco
8.
Int J Cancer ; 144(2): 251-262, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29978580

RESUMO

We previously reported that some single nucleotide polymorphisms (SNPs) of candidate genes involved in the MTOR complex1 (MTORC1) were associated with risk of gastric cancer (GCa). In the present study, we further evaluated associations of eight potentially functional SNPs of MTOR, MLST8 and RPTOR with survival of 1002 GCa patients and also investigated molecular mechanisms underlying such associations. Specifically, we found that the MTOR rs2536 C allele at the microRNA binding site was independently associated with a 26% reduction of death risk (HR = 0.74, 95% CI = 0.57-0.96, p = 0.022). The results remained noteworthy with a prior false positive probability of 0.1. Genotype-phenotype correlation analysis in 144 patients' adjacent normal gastric tissue samples revealed that the MTOR expression levels were lower in rs2536 TC/CC carriers than that in wild-type TT carriers (p = 0.043). Dual luciferase assays revealed that the rs2536 C allele had a higher binding affinity to microRNA-150, leading to a decreased transcriptional activity of MTOR, compared to the rs2536 T allele. Further functional analysis revealed that MTOR knockdown by small interference RNA impaired proliferation, migration, and invasion ability in GCa cell lines. In conclusion, The MTOR rs2536 T > C change may be a biomarker for survival of Chinese GCa patients, likely by modulating microRNA-induced gene expression silencing. Additional studies are needed to validate our findings.


Assuntos
Neoplasias Gástricas/genética , Serina-Treonina Quinases TOR/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Tumorais/genética , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/mortalidade
9.
PLoS One ; 13(10): e0204826, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30273368

RESUMO

Although physicians learn about new medical technologies from their peers, the magnitude and source of peer influence is unknown. We estimate the effect of peer adoption of three first-in-class medications (dabigatran, sitigliptin, and aliskiren) on physicians' own adoption of those medications. We included 11,958 physicians in Pennsylvania prescribing anticoagulant, antidiabetic, and antihypertensive medications. We constructed 4 types of peer networks based on shared Medicare and Medicaid patients, medical group affiliation, hospital affiliation, and medical school/residency training. Instrumental variables analysis was used to estimate the causal effect of peer adoption (fraction of peers in each network adopting the new drug) on physician adoption (prescribing at least the median number prescriptions within 15 months of the new drug's introduction). We illustrate how physician network position can inform targeting of interventions to physicians by computing a social multiplier. Dabigatran was adopted by 25.2%, sitagliptin by 24.5% and aliskiren by 8.3% of physicians. A 10-percentage point increase in peer adoption in the patient-sharing network led to a 5.90% (SE = 1.50%, p<0.001) increase in physician adoption of dabigatran, 8.32% (SE = 1.51%, p<0.001) increase in sitagliptin, and 7.84% increase in aliskiren adoption (SE = 2.93%, p<0.001). Peer effects through shared hospital affiliation were positive but not significant, and medical group and training network effects were not reliably estimated. Physicians in the top decile of patient-sharing network peers were estimated to have nearly 2-fold stronger influence on their peers' adoption compared to physicians in the top decile of prescribing volume. Limitations include lack of detailed clinical information and pharmaceutical promotion, variables which may influence physician adoption but which are unlikely to bias our peer effect estimates. Peer adoption, especially by those with whom physicians share patients, strongly influenced physician adoption of new drugs. Our study shows the potential for using information on physician peer networks to improve technology diffusion.


Assuntos
Prescrições de Medicamentos/estatística & dados numéricos , Uso de Medicamentos/tendências , Padrões de Prática Médica , Amidas/uso terapêutico , Dabigatrana/uso terapêutico , Feminino , Fumaratos/uso terapêutico , Humanos , Masculino , Medicaid , Medicare , Grupo Associado , Pennsylvania , Fosfato de Sitagliptina/uso terapêutico , Estados Unidos
10.
J Cell Mol Med ; 22(10): 4975-4984, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30055028

RESUMO

To identify genetic variants in Notch signalling pathway genes that may predict survival of Han Chinese patients with epithelial ovarian cancer (EOC), we analysed a total of 1273 single nucleotide polymorphisms (SNPs) within 75 Notch genes in 480 patients from a published EOC genomewide association study (GWAS). We found that PSEN1 rs165934 and MAML2 rs76032516 were associated with overall survival (OS) of patients by multivariate Cox proportional hazards regression analysis. Specifically, the PSEN1 rs165934 AA genotype was associated with a poorer survival (adjusted hazards ratio [adjHR] = 1.41, 95% CI = 1.07-1.84, and P = .014), compared with the CC + CA genotype, while MAML2 rs76032516 AA + AC genotypes were associated with a poorer survival (adjHR = 1.58, 95% CI = 1.16-2.14, P = .004), compared with the CC genotype. The combined analysis of these two SNPs revealed that the death risk increased as the number of unfavourable genotypes increased in a dose-dependent manner (Ptrend < .001). Additionally, the expression quantitative trait loci analysis revealed that the SNP rs165932 in the rs165934 LD block (r2 = .946) was associated with expression levels of PSEN1, which might be responsible for the observed association with SNP rs165934. The associations of PSEN1 rs165934 and MAML2 rs76032516 of the Notch signalling pathway genes with OS in Chinese EOC patients are novel findings, which need to be validated in other large and independent studies.


Assuntos
Carcinoma Epitelial do Ovário/genética , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/genética , Presenilina-1/genética , Prognóstico , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário/epidemiologia , Carcinoma Epitelial do Ovário/patologia , China/epidemiologia , Reparo do DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Receptores Notch/genética , Transdução de Sinais/genética , Transativadores
11.
Mol Carcinog ; 57(11): 1553-1565, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30035334

RESUMO

The benefits of platinum-based chemotherapy (PBC) on survival of esophageal squamous cell carcinoma (ESCC) patients are inexplicit due to the varied therapeutic effects. Nucleotide excision repair (NER) pathway plays a vital role in removing platinum-DNA adducts in tumor cells and hence may modulate the therapeutic effect and survival outcome. The present study assessed the associations of 26 potentially functional regulatory single nucleotide polymorphisms (rSNPs) in nine core NER genes with disease-free survival (DFS) and overall survival (OS) in 339 ESCC patients. We found that ERCC2 rs2097215 T and rs3916788 A, ERCC5 rs3759497 A and XPC rs3731054 C alleles were associated with unfavorable DFS. Patients carrying high-risk allele group (HRG, 5-8 risk alleles) had a significantly shorter DFS, compared with those carrying low-risk alleles (LRG, 0-4 risk alleles) [adjusted hazards ratio (HRadj ) = 1.64, 95%CI = 1.23-2.19, Padj < 0.001]. Three of these SNPs (ie, ERCC2 rs2097215 T and rs3916788 A and ERCC5 rs3759497 A) were also significantly associated with a poorer OS (HRG vs LRG: HRadj = 1.75, 95%CI = 1.23-2.47, Padj = 0.002). The expression quantitative trait loci (eQTL) analysis revealed significant genotype-expression correlations for ERCC5 rs3759497 and ERCC2 2097215 and rs3916788, which suggest regulatory roles of these SNPs. It appears that these NER variants may independently or jointly exert an impact on survival outcome of Chinese ESCC patients undergoing adjuvant platinum-based therapy. Large studies are warranted to validate these findings.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Reparo do DNA , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/mortalidade , Variação Genética , Adulto , Idoso , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Feminino , Estudos de Associação Genética , Ligação Genética , Genótipo , Humanos , Estimativa de Kaplan-Meier , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Platina/administração & dosagem , Polimorfismo de Nucleotídeo Único , Prognóstico , Locos de Características Quantitativas , Resultado do Tratamento
12.
Data Brief ; 18: 787-789, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29900238

RESUMO

The transcriptome sequencing data of valproic acid (VPA) model of autism and control rats are presented. VPA model of autism was induced by a single intraperitoneal injection of 600 mg/kg sodium valproic acid to female rats at day 12.5 post-conception, and the control rats were injected with saline. Male offspring of VPA- or saline-injected dams from different litters were sacrificed on PND 35 (n = three rats/three litters/group). Prefrontal cortex was dissected from both hemispheres, and RNA was isolated. Libraries were prepared and RNA Sequencing (RNA-Seq) was performed following Illumina's recommendations. Samples are described in the SRA portal (SRP115258) and FASTQ files have been deposited in Sequence Read Archive (accession numbers: SRR5950172 to SRR5950177). The interpretation of these data is presented in the following research article: "Transcriptional and splicing dysregulation in prefrontal cortex of valproic acid induced rat models of autism" (Zhang et al., 2018) [1].

13.
Reprod Toxicol ; 77: 53-61, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29427782

RESUMO

Gene-environmental interaction could be the major cause of autism. The aim of the current study is to detect the effects of valproic acid on gene expression profiles and alternatively spliced genes in the prefrontal cortex in rat models of autism. Female rats received a single intraperitoneal injection of 600 mg/kg valproic acid at day 12.5 post-conception, and controls were injected with saline. Only male offspring were employed in the current study. RNA sequencing was used to investigate transcriptome in the prefrontal cortex of VPA-exposed rats. There were 3228 differently expressed genes and 637 alternative spliced genes, in VPA rats compared to controls. Pathways enrichment among the differently expressed genes and alternatively spliced genes were associated with neurological diseases and neural system development. The results implied VPA affected transcriptional and splicing events genome-wide and the transcriptional and splicing events may be associated with the autistic behaviors of VPA rats.


Assuntos
Processamento Alternativo/efeitos dos fármacos , Anticonvulsivantes/toxicidade , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/genética , Córtex Pré-Frontal/metabolismo , Transcrição Genética/efeitos dos fármacos , Ácido Valproico/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Masculino , Troca Materno-Fetal , Gravidez , Ratos Sprague-Dawley , Olfato/efeitos dos fármacos , Comportamento Social , Natação , Transcriptoma/efeitos dos fármacos
14.
Int J Cancer ; 142(6): 1218-1229, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29134637

RESUMO

Platinum-based chemotherapy (PBC) in combination with the 3rd generation drugs is the first-line treatment for patients with advanced non-small cell lung cancer (NSCLC); however, the efficacy is severely hampered by grade 3-4 toxicities. Nucleotide excision repair (NER) pathway is the main mechanism of removing platinum-induced DNA adducts that contribute to the toxicity and outcome of PBC. We analyzed data from 710 Chinese NSCLC patients treated with PBC and assessed the associations of 25 potentially functional single nucleotide polymorphisms (SNPs) in nine NER core genes with overall, gastrointestinal and hematologic toxicities. Through a two-phase study, we found that ERCC4 rs1799798 was significantly associated with overall and gastrointestinal toxicities [all patients: GA/AA vs. GG, odds ratio (OR)adj =1.61 and 2.35, 95% confidence interval (CI)=1.11-2.33 and 1.25-4.41, and Padj =0.012 and 0.008, respectively]. Our prediction model for the overall toxicity incorporating rs1799798 demonstrated a significant increase in the area under the curve (AUC) value, compared to that for clinical factors only (all patients: AUC = 0.61 vs. 0.59, 95% CI = 0.57-0.65 vs. 0.55-0.63, P = 0.010). Furthermore, the ERCC4 rs1799798 A allele was associated with lower ERCC4 mRNA expression levels according to the expression quantitative trait loci (eQTL) analysis. Our study provided some new clue in future development of biomarkers for assessing toxicity and outcomes of platinum drugs in lung cancer treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas de Ligação a DNA/genética , Neoplasias Pulmonares/tratamento farmacológico , Compostos Organoplatínicos/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Biologia Computacional , Adutos de DNA/efeitos dos fármacos , Reparo do DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/epidemiologia , Gastroenteropatias/genética , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/epidemiologia , Doenças Hematológicas/genética , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Adulto Jovem
15.
Hum Mol Genet ; 27(1): 199-210, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29040610

RESUMO

Elevated blood pressure (BP) is a major global risk factor for cardiovascular disease. Genome-wide association studies have identified several genetic variants at the NPR3 locus associated with BP, but the functional impact of these variants remains to be determined. Here we confirmed, by a genome-wide association study within UK Biobank, the existence of two independent BP-related signals within NPR3 locus. Using human primary vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) from different individuals, we found that the BP-elevating alleles within one linkage disequilibrium block identified by the sentinel variant rs1173771 was associated with lower endogenous NPR3 mRNA and protein levels in VSMCs, together with reduced levels in open chromatin and nuclear protein binding. The BP-elevating alleles also increased VSMC proliferation, angiotensin II-induced calcium flux and cell contraction. However, an analogous genotype-dependent association was not observed in vascular ECs. Our study identifies novel, putative mechanisms for BP-associated variants at the NPR3 locus to elevate BP, further strengthening the case for targeting NPR-C as a therapeutic approach for hypertension and cardiovascular disease prevention.


Assuntos
Pressão Sanguínea/genética , Hipertensão/genética , Músculo Liso Vascular/fisiologia , Receptores do Fator Natriurético Atrial/genética , Bases de Dados de Ácidos Nucleicos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Frequência do Gene , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hipertensão/metabolismo , Hipertensão/patologia , Desequilíbrio de Ligação , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Polimorfismo de Nucleotídeo Único , Receptores do Fator Natriurético Atrial/metabolismo , Transdução de Sinais
16.
Sci Rep ; 7(1): 10702, 2017 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-28878296

RESUMO

Nucleotide excision repair (NER) plays a vital role in platinum-induced DNA damage during chemotherapy. We hypothesize that regulatory single nucleotide polymorphisms (rSNPs) of the core NER genes modulate clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy (PBS). We investigated associations of 25 rSNPs in eight NER genes with progression free survival (PFS) and overall survival (OS) in 710 NSCLC patients. We found that ERCC1 rs3212924 AG/GG and XPC rs2229090 GC/CC genotypes were associated with patients' PFS (HRadj = 1.21, 95% CI = 1.03-1.43, P adj = 0.021 for ERCC1 and HRadj = 0.80, 95% CI = 0.68-0.94, P adj = 0.007 for XPC), compared with the AA and GG genotypes, respectively. The association of XPC rs2229090 was more apparent in adenocarcinoma than in squamous cell carcinoma patients. Additionally, ERCC4 rs1799798 GA/AA genotypes were associated with poorer OS (HRadj = 1.32, 95% CI = 1.04-1.69, P adj = 0.026), compared with the GG genotype. The expression quantitative trait loci analysis revealed that ERCC1 rs3212924 and XPC rs2229090 might regulate transcription of their genes, which is consistent with their associations with survival. Larger studies are needed to validate our findings with further functional studies to elucidate the mechanisms underlying these observed associations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Variação Genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Progressão da Doença , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Prognóstico , Adulto Jovem
17.
Mol Carcinog ; 56(12): 2706-2717, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28796378

RESUMO

DNA repair protects genomic integrity and may modulate chemotherapy efficacy. Few large-scale studies have evaluated predictive roles of genetic variants of DNA repair genes in survival of Chinese gastric cancer (GCa) patients treated with chemotherapy. Here, we assessed the roles of 35 single nucleotide polymorphisms (SNPs) in DNA repair genes in survival of 1002 GCa patients, of whom 694 received chemotherapy and 308 did not. Among patients receiving chemotherapy, the ERCC1 rs2298881A allele was associated with a better survival [hazards ratio (HR) = 0.82, 95% confidence interval (CI) = 0.69-0.98; P = 0.03], whereas two XRCC4 SNPs were associated with a worse survival (HR = 1.26, 95% CI = 1.03-1.54 for the rs10040363G allele, P = 0.02; and HR = 1.30, 95% CI = 1.06-1.59 for the rs2075685T allele, P = 0.01). These three SNPs were unique survival predictors for patients treated with chemotherapy (P < 0.05 for all) but not for patients without chemotherapy (P > 0.05 for all), suggesting that they modulated chemotherapy efficacy. Patients who received chemotherapy and had haplotypes with at least one death-risk allele in XRCC4 had a poor survival, and the trend for an increase in the number of death-risk alleles adversely affecting the survival was also observed in an allelic dose-dependent manner (Ptrend = 0.001). Further functional analysis revealed that the death-risk alleles up-regulated the gene expression, leading to a worse survival as suggested by our meta-analysis pooling both mRNA microarray data from the GEO database and published data (ERCC1: HR = 1.31 [1.08-1.58]; P = 0.006). These functional genetic variants may independently or jointly affect survival in chemotherapy-treated GCa patients by modulating the gene expression in the tumors.


Assuntos
Proteínas de Ligação a DNA/genética , Endonucleases/genética , Regulação Neoplásica da Expressão Gênica/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/genética , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Frequência do Gene , Genótipo , Haplótipos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia
18.
Hum Mol Genet ; 26(5): 989-1002, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28087731

RESUMO

Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na+/HCO3- co-transporter NBCn1 which regulates intracellular pH (pHi). We conducted a functional study of variants at this locus in primary cultures of vascular smooth muscle and endothelial cells. In both cell types, we found genotype-dependent differences for rs13082711 in DNA-nuclear protein interactions, where the risk allele is associated with increased SLC4A7 expression level, NBCn1 availability and function as reflected in elevated steady-state pHi and accelerated recovery from intracellular acidosis. However, in the presence of Na+/H+ exchange activity, the SLC4A7 genotypic effect on net base uptake and steady-state pHi persisted only in vascular smooth muscle cells but not endothelial cells. We found no discernable effect of the missense polymorphism resulting in the amino acid substitution Glu326Lys. The finding of a genotypic influence on SLC4A7 expression and pHi regulation in vascular smooth muscle cells provides an insight into the molecular mechanism underlying the association of variation at the SLC4A7 locus with blood pressure.


Assuntos
Hipertensão/metabolismo , Músculo Liso Vascular/metabolismo , Simportadores de Sódio-Bicarbonato/genética , Alelos , Substituição de Aminoácidos/genética , Animais , Pressão Sanguínea/genética , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Concentração de Íons de Hidrogênio , Hipertensão/genética , Hipertensão/patologia , Músculo Liso Vascular/patologia , Mutação , Ratos , Sódio/metabolismo , Simportadores de Sódio-Bicarbonato/biossíntese
19.
ACS Nano ; 11(2): 1826-1839, 2017 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-28112893

RESUMO

Autophagy plays a crucial role in the metabolic process. So far, conventional methods are incapable of rapid, precise, and real-time monitoring of autophagy in living objects. Herein, we describe an in situ intracellular self-assembly strategy for quantitative and temporal determination of autophagy in living objectives. The intelligent building blocks (DPBP) are composed by a bulky dendrimer as a carrier, a bis(pyrene) derivative (BP) as a signal molecule, and a peptide linker as a responsive unit that can be cleaved by an autophagy-specific enzyme, i.e., ATG4B. DPBP maintains the quenched fluorescence with monomeric BP. However, the responsive peptide is specifically tailored upon activation of autophagy, resulting in self-aggregation of BP residues which emit a 30-fold enhanced fluorescence. By measuring the intensity of fluorescent signal, we are able to quantitatively evaluate the autophagic level. In comparison with traditional techniques, such as TEM, Western blot, and GFP-LC3, the reliability and accuracy of this method are finally validated. We believe this in situ intracellular self-assembly strategy provides a rapid, effective, real-time, and quantitative method for monitoring autophagy in living objects, and it will be a useful tool for autophagy-related fundamental and clinical research.


Assuntos
Autofagia/efeitos dos fármacos , Oligopeptídeos/farmacologia , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Células MCF-7 , Oligopeptídeos/síntese química , Oligopeptídeos/química , Temperatura , Peixe-Zebra
20.
Oncotarget ; 8(11): 18435-18443, 2017 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-27821817

RESUMO

Literature suggests that genetic variants associated with increased susceptibility to gastric cancer (GCa) are mostly located in genes involved in carcinogenesis and possibly tumor progression. Therefore, we hypothesize that high genetic susceptibility is also associated with prognosis of the patients. To test this hypothesis, we selected a total of 42 common genetic variants that were reportedly associated with GCa risk with a high level of evidence obtained from either genome-wide association studies (GWASs) or meta-analyses and performed survival analysis of patients used in a case-control analysis. We first used 1115 GCa cases and 1172 cancer-free controls of ethnic Han Chinese to construct a weighted genetic risk score (GRS). Then, we included 633 GCa cases with available clinical information, fit GRS in a fractional polynomial Cox proportional hazards regression model to investigate whether there is a dose-dependent effect of GRS on risk of death in survival analysis. Dynamic predictive value of genetic risk for prognosis was also calculated. The results showed that the increase of GRS had no effect on risk of death in these GCa patients. Compared with GCa patients with the medium GRS, there was no significant difference in survival in patients with either a low (P = 0.349) or a high (P = 0.847) GRS. The results unchanged when data were stratified by tumor stage and Lauren's classification. Time-dependent predictive value for prognosis in considering both clinical factors and GRS was comparable with that in considering clinical factors alone, for either all patients (P = 0.986) or stage- and Laruen type-based subgroups (P > 0.05 for all). In conclusion, higher polygenic susceptibility loci for GCa may not indicate worse prognosis of Chinese patients. Additional variants of relevant genes modulating GCa patients' survival need to be further identified.


Assuntos
Neoplasias Gástricas/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Prognóstico , Fatores de Risco , Neoplasias Gástricas/sangue
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