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1.
Medicine (Baltimore) ; 99(41): e22497, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031286

RESUMO

RATIONALE: Paragangliomas (PGLs) are rare neuroendocrine tumors that are strongly influenced by genetics, and succinate dehydrogenase-deficient PGLs appear to constitute one of the most important categories. Interestingly, somatic PGLs only possess genomic alterations involving the SDHB and SDHD subunits, and no SDHA alterations have been described. Here, we are presenting the clinical and genetic analyses of 2 cases with the first somatic SDHA variant identified in PGLs. PATIENT CONCERNS: Here, we reported 2 family members with the diagnosis of PGL. Patient 1 is a 55-year-old woman with a functionally perigastric PGL that co-occurred with a gastric gastrointestinal stromal tumor (GIST), and patient 2 is a 43-year-old woman with a nonfunctionally pericardial PGL, who was the younger sister of the first patient. DIAGNOSES: Imaging surveys of the 2 cases depicted the presence of a perigastric and a pericardial mass, respectively. A diagnosis of paragangliomas was established by immunohistochemistry (IHC). INTERVENTIONS: Both patients underwent single-stage resection of the lesion after preoperative oral α-adrenoceptor therapy for 2 weeks. We later performed comprehensive genomic profiling on the tumor samples, including PGL and GIST from patient 1 and PGL from patient 2, and searched for novel actionable mutations, including in all succinate dehydrogenase subunits, as the IHC results were negative for SDHB. OUTCOMES: Both patients had an uneventful recovery after surgery and the sequencing showed a novel somatic variant in the SDHA gene on chromosome 5q11 (c.1945_1946delTT). Regular follow-up with biochemical testing and image studies showed no evidence of recurrence after a year for patient 1 and 6 years for patient 2. LESSONS: PGLs often lead to considerable diagnostic difficulty due to their multiple anatomical locations and variable symptoms, as presented by our cases. The comprehensive use of images and plasma/urine catecholamine measurement can aid the diagnosis of PGLs. In addition, our findings also demonstrate the usefulness and importance of genetic analysis of SDHA mutations in patients exhibiting SDHB IHC-negative PGL. Additional studies utilizing comprehensive genomic profiling are needed to identify the group of PGLs harboring this SDHA genomic alteration.


Assuntos
Complexo II de Transporte de Elétrons/genética , Tumores do Estroma Gastrointestinal/genética , Neoplasias Primárias Múltiplas/genética , Paraganglioma Extrassuprarrenal/genética , Neoplasias Gástricas/genética , Adulto , Feminino , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/patologia , Testes Genéticos , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação , Paraganglioma Extrassuprarrenal/diagnóstico , Paraganglioma Extrassuprarrenal/patologia , Irmãos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia
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.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(5): 683-692, 2020 May 30.
Artigo em Chinês | MEDLINE | ID: mdl-32897212

RESUMO

OBJECTIVE: To investigate the expression of BUB1 gene in gastric cancer. METHODS: Oncomine, GEPIA, BioGPS and Kaplan-Meier Plotter databases were used to analyze the difference of BUB1 gene expression between gastric cancer tissue and normal gastric tissue. The association of BUB1 expression level with the prognosis of gastric cancer patients was also analyzed. The Cancer Cell Line Encyclopedia (CCLE) was explored to analyze the expression of BUB1 in T cells and B cells in gastric cancer patients, and the String database was used to generate the network map of BUB1-related proteins and functional annotation of gene ontology (GO). The related pathways of KEGG were analyzed. Tumor immune assessment resource (TIMER) database was used to analyze the expression of BUB1 in immune infiltration and its effect on prognosis of gastric cancer patients. To further verify the results of gene chip analysis in Oncomine database, we collected 30 pairs of surgical specimens of gastric adenocarcinoma and adjacent tissues from patients admitted to the First Affiliated Hospital of Chengdu Medical College from March, 2018 to July, 2019. The results of BUB1 gene expression in Oncomine database were verified by PCR and immunohistochemistry. RESULTS: Oncomine, GEPIA and BioGPS analyses showed that BUB1 was highly expressed in gastric cancer compared with normal gastric tissue. Kaplan-Meier survival analysis showed that the progression-free survival time (HR=0.52, 95% CI:0.41-0.67, P < 0.05) and the overall survival time (HR=0.67, 95% CI:0.55-0.82, P < 0.05) were prolonged in gastric cancer patients with a high expression of BUB1. Through String data collection, BUB1-related proteins were mainly enriched in 13 cellular components, 4 molecular functions and 12 biological processes, involving 4 signal pathways. TIMER database analysis showed that CD4+ T cells and macrophages with high expressions of BUB1 mRNA in the immune microenvironment were associated with a favorable 5-year survival outcome of patients with gastric cancer. In the surgical specimens, real-time quantitative PCR showed that the expression level of BUB1 mRNA was significantly higher in gastric cancer tissues than in the adjacent gastric mucosa tissues, and immunohistochemical results demonstrated positive BUB1 staining in the gastric cancer tissues. CONCLUSIONS: BUB1 gene is highly expressed in gastric cancer. BUB1 may reduce tumor immunosuppression and helps to evaluate the prognosis of patients with gastric cancer.


Assuntos
Biologia Computacional , Proteínas Serina-Treonina Quinases/genética , Neoplasias Gástricas , Humanos , Estimativa de Kaplan-Meier , Prognóstico , Neoplasias Gástricas/genética , Microambiente Tumoral
4.
Zhonghua Zhong Liu Za Zhi ; 42(8): 648-652, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867456

RESUMO

Objective: To investigate the relationship between KDM6A mutation or expression and clinicopathological characteristics of gastric cancer. Methods: Fifty-seven cases of gastric cancer tissues were analyzed by second-generation sequencing, and bioinformation database such as Cbioportal, Kaplan Meier-Plotter, and the Human Protein Atlas were used to analyze the relationship between KDM6A mutation and clinicopathological characteristics of gastric cancer. Results: Among 57 gastric cancer samples, 14 were KDM6A mutation, and the mutation proportion was 24.6%. Compared with the non-mutation group, the Borrmann classification, T stage, TNM stage and tumor diameter of KDM6A mutant group were significantly different (all P<0.05). The median survival time of the KDM6A mutant patients was 53.5 months, significantly shorter than 72.0 months of the KDM6A non-mutation patients (P=0.007). The analysis result of Kaplan Meier-Plotter database showed that, among all of the 875 patients, 655 patients had low KDM6A expression and 220 patients had high expression. The median survival time of patients with low expression was 23.5 months, significantly shorter than 30.8 months of patients with high expression (P=0.002). In male, gastric cancer patients with stage Ⅲ, intestinal type, diffuse type, simple surgical treatment and fluorouracil chemotherapy, the expression of KDM6A is related to the patient's overall survival time (all P<0.05). The analysis result of Cbioportal database showed that, among all of the 1 172 gastric cancer patients, 70 patients with KDM6A mutation, 1100 patients with non-mutation. The median overall survival time of mutant patients was 28.9 months, significantly shorter than 35.9 months of non-mutation patients (P<0.001). The analysis result of Human Protein Atlas database showed that, among all of the 355 gastric cancer patients, 97 patients had high KDM6A expression and 258 patients had low KDM6A expression. The median survival time of patients with low expression was 13.7 months, significantly shorter than 19.8 months of patients with high expression (P=0.022). Conclusions: The survival time of gastric cancer patients with KDM6A mutation or low expression is shorter. The mutation and expression of KDM6A are related to clinical pathological factors, which may become a potential target for the diagnosis and treatment of gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Histona Desmetilases/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Histona Desmetilases/genética , Humanos , Metástase Linfática , Masculino , Mutação/genética , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida
5.
Anticancer Res ; 40(10): 5593-5600, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988883

RESUMO

BACKGROUND: Despite improved treatment for gastric cancer (GC), the prognosis of advanced disease remains poor. Further investigation of the oncogenic sequence for GC is needed. MATERIALS AND METHODS: The expression of TYRO3 protein tyrosine kinase in five GC cell lines was confirmed using western blotting. TYRO3 knockdown in GC cells, and bromodeoxyuridine and Transwell assays were used to examine the functions of TYRO3 in tumor proliferation and invasion. Finally, TYRO3 expression in 138 patients who underwent curative gastric resection for advanced GC (Union for International Cancer Control stage II/III) was tested by immunohistochemistry, and the association between prognosis and TYRO3 expression was analyzed. RESULTS: TYRO3 was detected at various levels in all the tested GC cell lines. Deleting TYRO3 significantly suppressed proliferation and invasion. Immunohistochemistry revealed TYRO3 expression was an independent prognostic factor for overall survival in patients with GC. CONCLUSION: TYRO3 appears to mediate tumor progression and predict prognosis of patients with GC.


Assuntos
Biomarcadores Tumorais/genética , Prognóstico , Receptores Proteína Tirosina Quinases/genética , Neoplasias Gástricas/genética , Idoso , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia
6.
Anticancer Res ; 40(10): 5815-5821, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988910

RESUMO

BACKGROUND/AIM: Glioma-associated oncogene 1 (GLI1) is an important transcription factor in the hedgehog signalling pathway and tumour formation. We evaluated the clinical significance of GLI1 expression as a prognostic factor in patients with locally advanced gastric cancer (GC). PATIENTS AND METHODS: GLI1 expression levels were measured by quantitative real-time polymerase chain reaction analysis of cancerous and adjacent normal mucosa specimens obtained from 142 patients with Stage II/III GC administered adjuvant chemotherapy with S-1 after curative resection. The associations of GLI1 expression with clinicopathological features and survival were evaluated. RESULTS: Clinicopathological features and GLI1 expression showed no association. Overall survival was significantly poorer in the high compared to the low GLI1 expression group (p=0.04). Multivariate analysis revealed that GLI1 expression was a significant independent prognostic factor [p=0.019, hazard ratio (HR)=1.94, 95% confidence interval (CI)=1.70-3.38]. CONCLUSION: GLI1 expression may be a useful prognostic marker in patients with locally advanced GC.


Assuntos
Biomarcadores Tumorais/genética , Prognóstico , Neoplasias Gástricas/tratamento farmacológico , Proteína GLI1 em Dedos de Zinco/genética , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Estadiamento de Neoplasias , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Tegafur/administração & dosagem , Tegafur/efeitos adversos
7.
Medicine (Baltimore) ; 99(37): e21963, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925730

RESUMO

This study aims to identify differentially expressed microRNAs (miRNAs) in gastric cancer by comparing gastric cancerous tissues with normal tissues, explore the potential roles.The miRNA expression microarray was employed on gastric cancer tissues, and apparently normal para-cancerous tissues from 3 patients undergoing radical surgery were matched. Quantitative RT-PCR was performed on the other 7 patients to validate the findings of the microarray. Furthermore, Gene Ontology (GO) analysis and enrichment analysis of KEGG Pathway were performed for 5 dysregulated candidate miRNAs, including 3 upregulated (miR-31-3p, miR-6736-3p, and miR-147b) and 2 downregulated (miR-3065-5p and miR-3921) miRNAs, in order to determine the role of miRNAs in tumorigenesis and development.Among these miRNAs, 17 miRNAs were found to be upregulated, and 19 miRNAs were found to be downregulated. The dysregulated expression of 5 candidate miRNAs, including miR-31-3p, miR-147b, miR-6736-3p, miR-3065-5p, and miR-3921, were verified by quantitative RT-PCR in the validation set. Among these miRNAs, miR-31-3p, miR-6736-3p, miR-3065-5p, and miR-3921 had 551 target gene intersections. The GO and KEGG Pathway analyses Revealed that miR-31-3p, miR-6736-3p, miR-3065-5p, and miR-3921 may participate in multiple pathophysiological processes, such as foreign substance metabolism and chemical carcinogenesis.The profile of differentially expressed miRNAs was successfully screened, and 4 miRNAs (i.e., miR-31-3p, miR-6736-3p, miR-3065-5p, and miR-3921) appeared to be involved in gastric carcinogenesis. These might serve as promising biomarkers for gastric cancer.


Assuntos
Perfilação da Expressão Gênica , MicroRNAs/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
8.
Yonsei Med J ; 61(9): 750-761, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32882759

RESUMO

PURPOSE: Gastric cancer (GC) is a malignant tumor with a high mortality rate. Drug resistance is a major obstacle to GC therapy. This study aimed to investigate the role and mechanism of exosomal circPRRX1 in doxorubicin resistance in GC. MATERIALS AND METHODS: HGC-27 and AGS cells were exposed to different doses of doxorubicin to construct doxorubicin-resistant cell lines. Levels of circPRRX1, miR-3064-5p, and nonreceptor tyrosine phosphatase 14 (PTPN14) were detected by quantitative real-time PCR or Western blot assay. Then, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, transwell, and Western blot assays were used to explore the function of circPRRX1 in GC cells. Interactions among circPRRX1, miR-3064-5p, and PTPN14 were confirmed by dual-luciferase reporter assay. The in vivo function of circPRRX1 was analyzed in a xenograft tumor model. RESULTS: CircPRRX1 was highly expressed in doxorubicin-resistant GC cell lines. Knockdown of circPRRX1 reversed doxorubicin resistance in doxorubicin-resistant GC cells. Additionally, extracellular circPRRX1 was carried by exosomes to spread doxorubicin resistance. CircPRRX1 silencing reduced doxorubicin resistance by targeting miR-3064-5p or regulating PTPN14. In GC patients, high levels of circPRRX1 in serum exosomes were associated with poor responses to doxorubicin treatment. Moreover, depletion of circPRRX1 reduced doxorubicin resistance in vivo. CONCLUSION: CircPRRX1 strengthened doxorubicin resistance by modulating miR-3064-5p/PTPN14 signaling and might be a therapeutic target for GC patients.


Assuntos
Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio , Humanos , MicroRNAs/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
9.
PLoS One ; 15(8): e0236811, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745141

RESUMO

In this study, we aimed to investigate the molecular biomarkers that are pivotal for the development and progression of gastric cancer (GC). We analyzed clinical specimens using RNA sequencing to identify the target genes. We found that the expression of HOXC6 mRNA was upregulated with the progression of cancer, which was validated by quantitative real time PCR and RNA in-situ hybridization. To compare the protein expression of HOXC6, we evaluated GC and normal gastric tissue samples using western blot analysis and immunohistochemistry. We detected significantly higher levels of HOXC6 in the GC tissues than in the normal controls at both mRNA and protein levels. The expression levels of HOXC6 mRNA in patients with advanced gastric cancer (AGC) were significantly higher than those in patients with early gastric cancer (EGC). Kaplan-Meier curves showed that high expression of HOXC6 mRNA is significantly associated with poor clinical prognosis. Our findings suggest that HOXC6 mRNA may be a novel biomarker and can be potentially valuable in predicting the prognosis of GC patients. Especially, HOXC6 mRNA in-situ hybridization may be a diagnostic tool for predicting prognosis of individual GC patients.


Assuntos
Proteínas de Homeodomínio , Neoplasias Gástricas , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Imuno-Histoquímica , Hibridização In Situ , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/secundário
10.
PLoS Pathog ; 16(8): e1008778, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32841292

RESUMO

EBV-associated gastric cancer (EBVaGC) is characterized by high frequency of DNA methylation. In this study, we investigated how epigenetic alteration of host genome contributes to pathogenesis of EBVaGC through the analysis of transcriptomic and epigenomic datasets from NIH TCGA (The Cancer Genome Atlas) consortium. We identified that immune related genes (IRGs) is a group of host genes preferentially silenced in EBV-positive gastric cancers through DNA hypermethylation. Further functional characterizations of selected IRGs reveal their novel antiviral activity against not only EBV but also KSHV. In particular, we showed that metallothionein-1 (MT1) and homeobox A (HOXA) gene clusters are down-regulated via EBV-driven DNA hypermethylation. Several MT1 isoforms suppress EBV lytic replication and release of progeny virions as well as KSHV lytic reactivation, suggesting functional redundancy of these genes. In addition, single HOXA10 isoform exerts antiviral activity against both EBV and KSHV. We also confirmed the antiviral effect of other dysregulated IRGs, such as IRAK2 and MAL, in scenario of EBV and KSHV lytic reactivation. Collectively, our results demonstrated that epigenetic silencing of IRGs is a viral strategy to escape immune surveillance and promote viral propagation, which is overall beneficial to viral oncogenesis of human gamma-herpesviruses (EBV and KSHV), considering that these IRGs possess antiviral activities against these oncoviruses.


Assuntos
Biomarcadores/metabolismo , Epigênese Genética , Gammaherpesvirinae/isolamento & purificação , Regulação Viral da Expressão Gênica , Infecções por Herpesviridae/complicações , Interações Hospedeiro-Patógeno , Neoplasias Gástricas/genética , Biomarcadores/análise , Metilação de DNA , Gammaherpesvirinae/genética , Células HEK293 , Infecções por Herpesviridae/virologia , Proteínas Homeobox A10/genética , Humanos , Incidência , Metalotioneína/genética , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/virologia , Ativação Viral , Replicação Viral
11.
PLoS One ; 15(7): e0236197, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32701958

RESUMO

Genome-wide association studies of gastric cancer (GC) cases have revealed common gastric cancer susceptibility loci with low effect size. We investigated rare variants with high effect size via whole-exome sequencing (WES) of subjects with familial clustering of gastric cancer. WES of DNAs from the blood of 19 gastric cancer patients and 36 unaffected family members from 14 families with two or more gastric cancer patients were tested. Linkage analysis combined with association tests were performed using Pedigree Variant Annotation, Analysis, and Search Tool (pVAAST) software. Based on the logarithm of odds (LOD) and permutation-based composite likelihood ratio test (CLRT) from pVAAST, MUC4 was identified as a predisposing gene (LOD P-value = 1.9×10-5; permutation-based P-value of CLRT ≤ 9.9×10-9). In a larger cohort consisting of 597 GC patients and 9,759 healthy controls genotyped with SNP array, we discovered common variants in MUC4 regions (rs148735556, rs11717039, and rs547775645) significantly associated with GC supporting the association of MUC4 with gastric cancer. And the MUC4 variants were found in higher frequency in The Cancer Genome Atlas Study (TCGA) germline samples of patients with multiple cancer types. Immunohistochemistry indicated that MUC4 was downregulated in the noncancerous gastric mucosa of subjects with MUC4 germline missense variants, suggesting that loss of the protective function of MUC4 predisposes an individual to gastric cancer. Rare variants in MUC4 can be novel gastric cancer susceptibility loci in Koreans possessing the familial clustering of gastric cancer.


Assuntos
Ligação Genética , Predisposição Genética para Doença , Variação Genética , Mucina-4/genética , Sequenciamento Completo do Exoma , Estudos de Coortes , Família , Feminino , Células Germinativas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mucina-4/química , Linhagem , Reprodutibilidade dos Testes , Estômago/patologia , Neoplasias Gástricas/genética
12.
Gene ; 757: 144937, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32640300

RESUMO

MicroRNAs (miRNAs) are a group of non-coding RNAs that have critical roles in regulation of expression of genes. They can inhibit or decrease expression of target genes mostly via interaction with 3' untranslated region of their targets. Their crucial roles in the regulation of expression of tumor suppressor genes and oncogenes have potentiated them as contributors in tumorigenesis. Moreover, their stability in body fluids has enhanced their potential as cancer biomarkers. In the present review article, we describe the role of miRNAs in the pathogenesis of gastric cancer and advances in application of miRNAs as biomarkers and therapeutic targets in this kind of malignancy.


Assuntos
Biomarcadores Tumorais/genética , MicroRNAs/genética , Neoplasias Gástricas/genética , Animais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , MicroRNAs/sangue , MicroRNAs/metabolismo , Transdução de Sinais , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo
13.
Int J Exp Pathol ; 101(3-4): 96-105, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32608553

RESUMO

Long non-coding RNAs (lncRNAs) have been proven to play important roles in various cancers, including gastric cancer (GC). However, detailed knowledge about lncRNAs in GC is limited. Therefore we carried out an in-depth study of public data and found 83 differently expressed lncRNAs in GC. To further confirm the target genes of these lncRNAs, we constructed a co-expression network between lncRNAs and mRNAs and found three lncRNAs (MBNL1-AS1, HAND2-AS1 and MIR100HG) were at the core of the network. By coalition analysis of clinical information and the three lncRNAs' expression level from The Cancer Genome Atlas (TCGA) and GSE15459 data sets, we found MIR100HG could be a potential prognostic factor. Clinical samples showed patients with higher MIR100HG expression had poorer prognosis, and further experiments demonstrated that MIR100HG was associated with proliferation, migration and invasion of GC cells. Hopefully, MIR100HG might be considered as a novel prognostic factor and biomarker for GC.


Assuntos
Biologia Computacional , Redes Reguladoras de Genes , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia
14.
Drugs Today (Barc) ; 56(7): 469-482, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32648857

RESUMO

Gastric cancer is one of the most common malignant tumors in the world. In China, its morbidity and mortality are second only to lung cancer. Chemotherapy combined with targeted therapy brings survival benefits to patients with advanced gastric cancer. Targets for targeted therapy of gastric cancer include human epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR) and Claudin 18.2 (CLDN 18.2). The main challenge of tumor molecule-targeted drugs is resistance. The main mechanisms of drug resistance include tumor establishment of compensatory signaling pathways, target protein changes, tumor microenvironment changes, tumor heterogeneity and tumor adaptation to targeted drugs. The combined action of multiple drug resistance mechanisms promotes the development of targeted drug resistance. In order to attract the attention of researchers, this paper reviews the mechanisms of drug resistance in gastric cancer-targeted therapy. In addition, the research status of drug resistance in molecule-targeted therapy of gastric cancer is summarized. It is of great clinical significance to explore the drug resistance mechanisms of targeted drugs and reverse drug resistance in gastric cancer. Last, the future development of molecule-targeted therapy is prospected.


Assuntos
Antineoplásicos , Terapia de Alvo Molecular , Neoplasias Gástricas , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Resistência a Medicamentos , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular
15.
DNA Cell Biol ; 39(9): 1532-1544, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32644844

RESUMO

Increasing evidence suggests that aberrant long noncoding (lnc) RNA expression plays a vital role in gastric cancer (GC) initiation and progression. Thus, we aimed to develop a lncRNA-based risk signature and nomogram to predict overall survival (OS) for patients with GC. Our primary cohort was composed of 341 patients with clinical and lncRNA expression data in The Cancer Genome Atlas stomach adenocarcinoma (TCGA STAD), the internal validation cohort was composed of 172 randomly assigned patients, and the external validation cohort was composed of 300 patients from GSE62254 dataset. A risk signature and nomogram were developed for the primary cohort and validated on the validation cohorts. Furthermore, gene set enrichment analysis (GSEA) was used to investigate the pathway enrichment for the risk signature. The expression patterns of several lncRNAs were also investigated in clinical samples from 10 GC patients. We identified and validated a 14-lncRNA signature highly associated with the OS of patients with GC, which performed well on evaluation with C-index, area under the curve, and calibration curves. In addition, univariate and multivariate Cox regression analyses indicated that the lncRNA signature was an independent predictive factor for GC patients. Therefore, a nomogram incorporating lncRNA signature and clinical factors was constructed to predict OS for patients with GC in primary cohort that suggested powerful predictive values for survival in the TCGA cohort and the other two validation cohorts. In addition, GSEA indicated that the identified lncRNAs may regulate the autophagy pathway, affecting tumorigenesis and prognosis of patients with GC. Experimental validation demonstrated that the expression of lncRNAs showed the same trend both in our clinical samples and STAD dataset. These results suggest that both risk signature and nomogram were effective prognostic indicators for patients with GC.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Adenocarcinoma/patologia , Idoso , Autofagia/genética , Biomarcadores Tumorais/metabolismo , Carcinogênese/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/patologia , Análise de Sobrevida , Transcriptoma
16.
Anticancer Res ; 40(6): 3203-3208, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487614

RESUMO

BACKGROUND/AIM: We aimed to evaluate the characteristics of gastric carcinoma with high excision repair cross complementing 1 (ERCC1) expression and the prognostic value of ERCC1 expression. MATERIALS AND METHODS: ERCC1 expression was evaluated by immunohistochemistry in 309 surgically resected gastric carcinoma specimens using a tissue microarray. Cancer-related survival was analysed using competing risk analysis. RESULTS: Compared to ERCC1-low gastric carcinomas, ERCC1-high gastric carcinomas showed less local invasion (p=0.0013), lower N stage (p=0.0302), earlier pTNM stage (p=0.0003), and less frequent recurrence (p=0002). Patients with ERCC1-high gastric carcinoma showed lower cumulative incidence function estimate of cancer-related death [3.37; 95% confidence intervaI (CI)=0.89-8.75] than did those with ERCC1-low gastric carcinoma (17.12; 95% CI=12.24-22.69; p-value by Gray's test=0.0012). Adjusted proportional sub-distribution hazard ratio for cancer-related death in the patients with ERCC1-high tumour was 0.272 (95% CI=0.084-0.878; p=0.0295). CONCLUSION: High ERCC1 expression may be an independent positive prognostic marker for gastric carcinoma.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Endonucleases/biossíntese , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Taxa de Sobrevida , Análise Serial de Tecidos , Adulto Jovem
17.
Medicine (Baltimore) ; 99(23): e20551, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32502020

RESUMO

This study aimed to further understand the role of relative telomere length (RTL) in susceptibility to gastric carcinoma (GC) and investigate the association between genetic polymorphisms in the telomere length related genes and GC risk.RTL was measured using the real-time quantitative polymerase chain reaction from 1000 patients and 1100 healthy controls. Genotyping was performed using the Agena MassARRAY platform. The statistical analysis was performed using the chi-square/ Welch T tests, Mann-Whitney U test, and logistic regression analysis.The association analysis of telomere length and GC showed that the RTL in the case group was shorter than in the controls, and the shorter RTL was associated with an increased risk of GC. The association analysis between telomere length related genes polymorphisms and genetic susceptibility to GC indicated that: In the allele models and genetic models, TERT (rs10069690, rs2242652 and rs2853676) and TN1F1 (rs7708392 and rs10036748) were significantly associated with an increased risk of GC. In addition, the haplotype 'Grs10069690Crs2242652" of TERT and the haplotype 'Grs7708392Trs10036748" of TNIP1 were associated with an increased risk of GCOur results suggested that shorter RTL was associated with an increased risk of GC; The association analysis have identified that the TERT (rs10069690, rs2242652 and rs2853676) and TN1P1 (rs7708392 and rs10036748) were associated with GC risk.


Assuntos
Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Neoplasias Gástricas/genética , Telomerase/genética , Telômero/genética , Estudos de Casos e Controles , China/epidemiologia , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real , Homeostase do Telômero
18.
Virology ; 548: 6-16, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32530809

RESUMO

Gastric carcinoma (GC) is an Epstein-Barr virus (EBV)-associated malignancy characterized by early metastasis. Unlike that of cellular micro(mi)RNAs, the role of viral miRNAs in epithelial-mesenchymal transition (EMT) and metastasis in cancers has not been fully investigated. In this study, we elucidated the involvement of miR-BART11, an EBV-encoded viral miRNA, in the EMT and metastasis of GC cells. EBV-miR-BART11 upregulation can lead to downregulation of forkhead box protein P1 (FOXP1) in both tissues and cell lines of gastric carcinoma. Downregulation of FOXP1 might trigger the secretion of interleukin 1ß (IL-1ß), IL-6, and 1L-10 in cancer cells, resulting in poor survival of GC patients. We found that the observed EMT phenotypes resulted from the EBV-miR-BART11 overexpression-induced FOXP1 downregulation, which impacted the expression of the EMT-transcription factors E-cadherin and snail. We further demonstrated that conditioned medium-derived tumor-associated macrophages (TAMs) promoted phenotypic changes and expression of EMT-related molecules in GC cells. Additionally, EMT changes were significantly promoted in GC cells cultured in conditioned medium from TAMs infected with EBV-miR-BART11-containing lentivirus. On the contrary, GC cells cultured in conditioned medium from TAMs infected with FOXP1-carrying lentivirus showed little or no EMT change. Taken together, our results suggest that EBV-encoded viral miRNA BART11 downregulates the FOXP1 transcription factor, and promotes EMT by directly influencing gastric tumor cells or indirectly affecting the tumor microenvironment, which might, in turn, accelerate cancer invasion and metastasis, thereby affecting the survival and prognosis of patients.


Assuntos
Transição Epitelial-Mesenquimal , Infecções por Vírus Epstein-Barr/fisiopatologia , Fatores de Transcrição Forkhead/metabolismo , Herpesvirus Humano 4/metabolismo , Macrófagos/citologia , MicroRNAs/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias Gástricas/fisiopatologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/virologia , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Herpesvirus Humano 4/genética , Interações Hospedeiro-Patógeno , Humanos , Macrófagos/metabolismo , MicroRNAs/genética , Proteínas Repressoras/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/virologia
19.
Am J Surg Pathol ; 44(9): 1204-1212, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32520759

RESUMO

Hereditary diffuse gastric cancer (HDGC) is a rare autosomal dominant syndrome associated with an increased risk of developing Laurén's diffuse-type gastric carcinoma and lobular breast carcinoma. Although signet-ring cell carcinoma (SRCC) in situ (SRCC-pTis) has been reported as a characteristic lesion in HDGC cases with CDH1 germline mutations (CDH1 pathogenic variant), and a precursor of conventional intramucosal SRCC (SRCC-pT1a), its histopathologic features and specificity have not been sufficiently clarified. Here, we examined gastrectomy samples from 6 Japanese HDGC patients with CDH1 germline mutation, belonging to 4 families, and analyzed SRCC lesions histologically and immunohistochemically. Of the 274 foci found in the 6 samples, SRCC-pT1a accounted for 225 lesions (range: 8 to 107, mean 45.7 lesions per patient), while 46 foci were of SRCC-pTis (range: 1 to 15, mean 7.67 foci per patient). All SRCC-pTis foci were observed in the fundic gland area and on the superficial side of the mucosa. Histologically, tumor cells of SRCC-pTis were found between normal foveolar epithelial cells and the basement membrane, following a typical pagetoid spread pattern. Immunohistochemically, E-cadherin expression was lost in SRCC-pTis (27/28, 96.4%) more frequently than in SRCC-pT1a (95/197, 48.2%; P<0.001). To elucidate the specificity of SRCC-pTis for HDGC, 60 samples (range: 0.12 to 1.49 m, total 28.8 m of mucosal length) from gastric cancer cases were analyzed as controls, in which no SRCC-pTis were identified. Our results indicate that SRCC-pTis is a distinct histologic feature with high specificity for HDGC cases with CDH1 germline mutations.


Assuntos
Carcinoma de Células em Anel de Sinete/patologia , Síndromes Neoplásicas Hereditárias/patologia , Neoplasias Gástricas/patologia , Adulto , Antígenos CD/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Caderinas/genética , Carcinoma de Células em Anel de Sinete/química , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/cirurgia , Análise Mutacional de DNA , Feminino , Gastrectomia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Hereditariedade , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/metabolismo , Síndromes Neoplásicas Hereditárias/cirurgia , Fenótipo , Estudos Retrospectivos , Neoplasias Gástricas/química , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirurgia
20.
Am J Surg Pathol ; 44(8): 1017-1030, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32568823

RESUMO

A robust morphomolecular classification system for gastric carcinoma is required. A 4-tier morphologic classification is proposed, including diffuse, intestinal, tubular, and lymphoid types. A tissue microarray for mismatch repair immunohistochemistry and Epstein-Barr virus (EBV) in situ hybridization were performed in 329 gastric carcinomas. DNA flow cytometry was used to detect aneuploidy in formalin-fixed paraffin-embedded samples. Lymphoid histology was the third most common histologic pattern at our institute and strongly associated with EBV infection and PMS2/MLH1-deficiency (both P<0.001). HER2 overexpression and SATB2 expression more frequently occurred in intestinal histology (both P<0.001). Loss of ARID1A expression was strikingly associated with lymphoid histology (P<0.001) and negative E-cadherin expression was correlated with diffuse histology (P=0.001). Programmed death-ligand 1 expression was most frequently present in lymphoid-type gastric carcinoma than other histologic subtypes and correlated with the molecular features of PMS2/MLH1-deficiency and EBV infection (all P<0.001). Aneuploidy was detected in 53% of gastric carcinomas and was highly correlated with intestinal type and the least with the lymphoid type (P<0.001). Notably, lymphoid-type gastric carcinoma showed the best outcome, whereas tubular type showed the worst survival rate (P<0.001). We integrated aneuploidy with morphologic patterns to propose a morphomolecular classification scheme, which served as a successful and independent prognostic factor in multivariate 5-year disease-free survival analysis (P<0.001). Overall, we describe an integrated morphomolecular classification system for gastric carcinomas to effectively predict patient outcomes. This system is cost-effective and reliable and can help select target therapeutics and facilitate clinical management.


Assuntos
Adenocarcinoma/química , Adenocarcinoma/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias Gástricas/química , Neoplasias Gástricas/genética , Adenocarcinoma/patologia , Adenocarcinoma/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Reparo de Erro de Pareamento de DNA , Intervalo Livre de Doença , Feminino , Herpesvirus Humano 4/genética , Humanos , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/análise , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/análise , Proteína 1 Homóloga a MutL/análise , Estadiamento de Neoplasias , Receptor ErbB-2/análise , Fatores de Risco , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologia , Taiwan , Fatores de Tempo , Fatores de Transcrição/análise , Adulto Jovem
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