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1.
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
2.
Front Genet ; 11: 679, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754194

RESUMO

Genome-wide association studies (GWAS) have identified several susceptibility loci for gastric cancer (GC), but the majority of identified single-nucleotide polymorphisms (SNPs) fall within the non-coding region and are likely to exert their biological function by modulating gene expression. To systematically estimate expression-associated SNPs (eSNPs) that confer genetic predisposition to GC, we evaluated the associations of 314,203 stomach tissue-specific eSNPs with GC risk in three GWAS datasets (2,631 cases and 4,373 controls). Subsequently, we conducted a gene-based analysis to calculate the cumulative effect of eSNPs through sequence kernel association combined test and Sherlock integrative analysis. At the SNP-level, we identified two novel variants (rs836545 at 7p22.1 and rs1892252 at 6p22.2) associated with GC risk. The risk allele carriers of rs836545-T and rs1892252-G exhibited higher expression levels of DAGLB (P = 3.70 × 10-18) and BTN3A2 (P = 3.20 × 10-5), respectively. Gene-based analyses identified DAGLB and FBXO43 as novel susceptibility genes for GC. DAGLB and FBXO43 were significantly overexpressed in GC tissues than in their adjacent tissues (P = 5.59 × 10-7 and P = 3.90 × 10-6, respectively), and high expression level of these two genes was associated with an unfavorable prognosis of GC patients (P = 1.30 × 10-7 and P = 7.60 × 10-3, respectively). Co-expression genes with these two novel genes in normal stomach tissues were significantly enriched in several cancer-related pathways, including P53, MAPK and TGF-beta pathways. In summary, our findings confirm the importance of eSNPs in dissecting the genetic basis of GC, and the identified eSNPs and relevant genes will provide new insight into the genetic and biological basis for the mechanism of GC development.

3.
BMC Cancer ; 20(1): 465, 2020 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-32448131

RESUMO

BACKGROUND: The association of Helicobacter pylori (H. pylori) babA2 gene with gastric cancer (GC) was reported by several studies, but results were inconsistent. This meta-analysis was performed to investigate the relationship between H. pylori babA2 gene and GC risk. METHODS: Case-control studies involving the association between H. pylori babA2 gene and GC risk were systematically identified from PubMed databases. A meta-analysis was used to pool studies and to estimate odds ratios (ORs) with 95% confidence intervals (CIs) of H. pylori babA2 gene associated with GC risk. RESULTS: Twenty studies were identified with a total of 1289 GC cases and 1081 controls. H. pylori babA2 gene was associated with an increased risk of GC by 2.05 fold (95% CI, 1.30-3.24, P = 0.002). In subgroup analysis, we found that H. pylori babA2 gene was significantly associated with GC risk in Asian population (OR = 2.63, 95% CI: 1.36-5.09 P = 0.004) but not in South American population (OR = 1.35, 95% CI: 0.69-2.64, P = 0.379). CONCLUSIONS: This meta-analysis indicates that H. pylori babA2 gene may be associated with increased risk of GC, especially in Asian population.

4.
Cancer Epidemiol Biomarkers Prev ; 29(2): 487-492, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31748259

RESUMO

BACKGROUND: The association of plasma homocysteine level (PHL) with gastric cancer risk was reported in observational studies. However, the causality is challenging due to confounding factors and the lack of evidence from well-designed cohort studies. Herein, we performed a two-sample Mendelian randomization (MR) analysis to investigate whether PHL is causally related to gastric cancer risk. METHODS: We performed the MR analysis based on the results from genome-wide association studies consisting of 2,631 patients with gastric cancer and 4,373 controls. An externally weighted genetic risk score (wGRS) was constructed with 15 SNPs with well-established associations with PHL. We utilized logistic regression model to estimate associations of PHL-related SNPs and wGRS with gastric cancer risk in total population and in strata by sex, age, and study site, in addition to a series of sensitivity analyses. RESULTS: High genetically predicted PHL was associated with an increased gastric cancer risk (per SD increase in the wGRS: OR = 1.07; 95% confidence interval, 1.01-1.12; P = 0.011), which was consistent in sensitivity analyses. Subgroup analyses provided evidence of a stronger association with gastric cancer risk in women than in men. MR-Egger and weighted median regression suggested that potentially unknown pleiotropic effects were not biasing the association between PHL and gastric cancer risk. CONCLUSIONS: These results revealed that genetically predicted high PHL was associated with an increased gastric cancer risk, suggesting that high PHL may have a causal role in the etiology of gastric cancer. IMPACT: These findings provide causal inference for PHL on gastric cancer risk, suggesting a causal role of high PHL in the etiology of gastric cancer.

5.
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
6.
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
7.
BMC Cancer ; 19(1): 164, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30791881

RESUMO

BACKGROUND: The association of ABO blood groups with gastric cancer risk was proposed decades ago, but the results have been inconsistent. METHODS: We used two single nucleotide polymorphisms to determine ABO genotype in 4932 gastric cancer cases and 6158 controls of Chinese descent, and evaluated the associations of ABO blood groups and genotypes with risk of gastric cancer using multivariable logistic regression models. We also systematically reviewed published literature and performed a meta-analysis of all relevant studies. RESULTS: In the case-control study, compared with blood group O, both blood group A and AB were associated with increased gastric cancer risk (for group A, odds ratio (OR) = 1.13, 95% confidence interval (CI): 1.02-1.24; for group AB, OR = 1.18, 95% CI: 1.02-1.36, respectively). Analyses of ABO genotypes revealed associations of AO and AB with risk of gastric cancer compared with OO genotype. Consistent with the case-control study, meta-analysis of 40 studies including 33,613 cases and 2,431,327 controls demonstrated that blood group A (OR = 1.19, 95% CI: 1.13-1.25) and AB (OR = 1.09, 95% CI: 1.03-1.16) were associated with increased risk of gastric cancer. CONCLUSIONS: Our analyses validated the association of blood group A with risk of gastric cancer, and suggested that blood group AB was also associated with gastric cancer risk. Functional investigations are warranted to elucidate the exact mechanism of ABO blood groups in gastric carcinogenesis.


Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Grupo com Ancestrais do Continente Asiático/genética , Genótipo , Neoplasias Gástricas/genética , Estudos de Casos e Controles , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Polimorfismo de Nucleotídeo Único , Risco
8.
Gastric Cancer ; 22(1): 60-68, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29859005

RESUMO

BACKGROUND: Gastric cancer (GC) is one of the high-incidence and high-mortality cancers all over the world. Though genome-wide association studies (GWASs) have found some genetic loci related to GC, they could only explain a small fraction of the potential pathogenesis for GC. METHODS: We used multi-marker analysis of genomic annotation (MAGMA) to analyze pathways from four public pathway databases based on Chinese GWAS data including 2631 GC cases and 4373 controls. The differential expressions of selected genes in certain pathways were assessed on the basis of The Cancer Genome Atlas database. Immunohistochemistry was also conducted on 55 GC and paired normal tissues of Chinese patients to localize the expression of genes and further validate the differential expression. RESULTS: We identified three pathways including chemokine signaling pathway, potassium ion import pathway, and interleukin-7 (IL7) pathway, all of which were associated with GC risk. NMI in IL7 pathway and RAC1 in chemokine signaling pathway might be two new candidate genes involved in GC pathogenesis. Additionally, NMI and RAC1 were overexpressed in GC tissues than normal tissues. CONCLUSION: Immune and inflammatory associated processes and potassium transporting might participate in the development of GC. Besides, NMI and RAC1 might represent two new key genes related to GC. Our findings might give new insight into the biological mechanism and immunotherapy for GC.


Assuntos
Biomarcadores Tumorais/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Gástricas/genética , Proteínas rac1 de Ligação ao GTP/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudo de Associação Genômica Ampla , Genômica , Humanos
9.
J Hum Genet ; 63(11): 1159-1168, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30202044

RESUMO

Many features are shared between esophageal cancer (EC) and gastric cancer (GC). This study aimed to explore whether known EC susceptibility loci are also important in the development of GC. A total of 21 genetic variants associated with EC in genome-wide association studies were evaluated with association of GC risk in 2631 cases and 4373 controls of Chinese ancestry. Single variant and weighted genetic scores (WGS) for esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and overall EC were analyzed with GC risk, respectively. Genetic variants of rs2274223 in PLCE1 at 10q23.33 (per G allele: odds ratio (OR) = 1.26, 95% confidence interval (CI): 1.16-1.38, P = 6.51 × 10-8), rs10052657 in PDE4D at 5q11.2 (per C allele: OR = 1.12, 95% CI: 1.01-1.25, P = 3.28 × 10-2) and rs671 in ALDH2 at 12q24.12 (per A-allele: OR = 0.83, 95% CI: 0.75-0.91, P = 1.14 × 10-4) were significantly associated with GC risk. The combined effect of those three variants had stronger influence on GC risk (OR = 1.31, 95% CI: 1.19-1.44, P = 2.34 × 10-8). High WGS of ESCC was also associated with increased risk of GC (P = 5.52 × 10-4 as a continuous variable) (trend test P = 2.71 × 10-4), whereas no statistically significant associations were observed between the WGS of EAC and GC risk (P = 0.66 as a continuous variable) (trend test P = 0.70). ESCC rather than EAC may share genetic susceptibility with GC. Genetic variants at 10q23.33, 5q11.2, and 12q24.12 may be useful as biomarkers to identify individuals with high risk for both ESCC and GC.


Assuntos
Adenocarcinoma/genética , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/genética , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Aldeído-Desidrogenase Mitocondrial/genética , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , China/epidemiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/patologia , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Fosfoinositídeo Fosfolipase C/genética , Prognóstico , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/patologia
10.
Oncotarget ; 8(62): 105312-105319, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29285253

RESUMO

Recently promoter of NR3C1 has been found to be high methylated in gastric cancer tissues which might be involved in the initiation of gastric carcinoma development. To test whether the variants in NR3C1 could modify the risk of gastric cancer, we evaluated the association between four SNPs (rs6194, rs12521436, rs33388 and rs4912913) in NR3C1 and gastric cancer risk in a case-control study with 1,113 gastric cancer cases and 1,848 cancer-free controls in a Chinese population. We found a significant association between rs4912913 and gastric cancer risk (OR=1.18, 95%CI=1.05-1.33, P=5.49×10-3). We also observed that the A-allele of rs12521436 and rs33388 were significantly associated with a decreased risk of gastric cancer (OR=0.84, 95%CI=0.76-0.94, P=2.78×10-3; OR=0.85, 95%CI=0.75-0.97; P=0.018). Finally, we made a joint effect analysis of rs12521436, rs33388 and rs4912913 on risk of gastric cancer (PTrend =2.83×10-5). These findings indicate that the variants rs4912913, rs33388 and rs12521436 of NR3C1 may contribute to gastric cancer susceptibility.

11.
Sci Rep ; 7(1): 11499, 2017 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-28904398

RESUMO

Protein phosphatase 2A (PP2A), a tumor suppressor protein, has been implicated in cell cycle and apoptosis. Additionally, studies have illustrated its crucial roles in transformation of normal human cells to tumorigenic status. PPP2CA, which encodes the alpha isoform of the catalytic subunit of PP2A, has been recently reported to be associated with several types of cancers. Therefore, we hypothesized that genetic variants in PPP2CA might influence susceptibility of gastric cancer. To test this hypothesis, three tagging single nucleotide polymorphisms (SNPs) in PPP2CA were genotyped in a case-control study including 1,113 cases and 1,848 controls in a Chinese population. Three tagging SNPs in PPP2CA were genotyped using Illumina Human Exome BeadChip. We observed that the A allele of rs13187105 was associated with an increased risk of gastric cancer (adjusted odds ratio (OR) = 1.14, 95% confidence interval (CI): 1.02-1.28, P = 0.017). Further analyses showed that rs13187105 [A] was associated with decreased expression of PPP2CA mRNA (P = 5.1 × 10-6), and PPP2CA mRNA was significantly lower in gastric tumor tissues when comparing that in their adjacent normal tissues (P = 0.037). These findings support our hypothesis that genetic variants in PPP2CA may be implicated in gastric cancer susceptibility in Chinese population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Variação Genética , Proteína Fosfatase 2/genética , Alelos , Estudos de Casos e Controles , China/epidemiologia , Bases de Dados Genéticas , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Vigilância da População , Locos de Características Quantitativas
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