RESUMEN
The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets.
Asunto(s)
Carcinogénesis/genética , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Regulación Neoplásica de la Expresión Génica , Adulto , Anciano , Anciano de 80 o más Años , Animales , Proteínas Portadoras/genética , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Variaciones en el Número de Copia de ADN , Carcinoma de Células Escamosas de Esófago , Exoma , Proteína de Dominio de Muerte Asociada a Fas/genética , Femenino , Perfilación de la Expresión Génica , Estudios de Asociación Genética , Humanos , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos BALB C , MicroARNs/genética , Persona de Mediana Edad , Mutación , Proteínas del Tejido Nervioso/genética , Pronóstico , Selección Genética , Transactivadores/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This review aims to systematically summarize the epidemiological studies on nasopharyngeal carcinoma (NPC) conducted over the past half century, covering descriptive epidemiological studies and reports on non-viral risk factors. Multiple lines of epidemiologic evidence for established risk factors are systematically presented in comprehensive tables. The potential interactions among environmental factors and genetic components, and also the impacts of parallel sequencing technology on the aetiology of NPC are discussed. Finally, we propose a modified model for the pathogenesis of nasopharyngeal carcinoma based on the current knowledge.
Asunto(s)
Ambiente , Modelos Biológicos , Neoplasias Nasofaríngeas/etiología , Carcinoma , Dieta/efectos adversos , Contaminantes Ambientales/envenenamiento , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad/genética , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/epidemiología , Neoplasias Nasofaríngeas/genética , Factores de Riesgo , Fumar/efectos adversosRESUMEN
Over the years, many studies have attempted to establish a link between tobacco smoking and an increased risk of nasopharyngeal carcinoma (NPC), but their results have been inconsistent. To clarify this link, we first conducted a comprehensive meta-analysis to integrate the findings of epidemiologic studies from the last half-century. The methodology used for this study followed the checklist proposed by the Meta-analysis of Observational Studies in Epidemiology (MOOSE) Group. Pooled risk estimates were generated using a random-effects model. Twenty-eight case-control studies and 4 cohort studies involving a total of 10,274 NPC cases and 415,266 comparison subjects were included. A substantial effect of smoking on the risk of NPC was identified in this study. The results showed that ever smokers had a 60% greater risk of developing the disease than never smokers (95% confidence interval: 1.38, 1.87); this was a robust dose-dependent association. More importantly, stronger associations were observed in low-risk populations and among persons with the predominant histological type of differentiated NPC than in high-risk populations and persons with an undifferentiated type; the odds ratios were 1.76 and 2.20, respectively, versus 1.29 and 1.27. In this comprehensive meta-analysis, well-established statistical evidence was provided about the role of tobacco smoking in the etiology of NPC.
Asunto(s)
Monitoreo del Ambiente/estadística & datos numéricos , Neoplasias Nasofaríngeas/epidemiología , Fumar/epidemiología , Carcinoma , Estudios de Casos y Controles , Causalidad , Estudios de Cohortes , Comorbilidad , Intervalos de Confianza , Exposición a Riesgos Ambientales/análisis , Femenino , Humanos , Masculino , Carcinoma Nasofaríngeo , Oportunidad Relativa , Factores de RiesgoRESUMEN
Epstein-Barr virus (EBV) infection is a major risk factor for nasopharyngeal carcinoma (NPC). Despite high prevalence of infection among the general population worldwide, only a small proportion of infected individuals presents with seropositivity for EBV-specific IgA antibodies. This seropositive subgroup of EBV carriers has an elevated cumulative risk for NPC during their lifetime. Previous studies reported that the host homologous recombination repair (HRR) system participates in EBV lytic replication, suggesting a potential mechanism to influence EBV reactivation status and thus seropositivity. To investigate whether genetic variants of HRR genes are associated with the serostatus in a healthy population, we investigated the association between seropositivity for anti-VCA-IgA and 156 tagging SNPs in 35 genes connected with HRR in an observational study among 755 healthy Cantonese speakers in southern China. Six variant alleles of MDC1, RAD54L, TP53BP1, RPA1, LIG3 and RFC1 exhibited associations with seropositivity (p(trend) from 0.0085 to 0.00027). Our study provides evidence that genetic variation within the HRR might affect an individual's propensity for EBV seropositive status of anti-VCA IgA antibody.
Asunto(s)
Anticuerpos Antivirales/análisis , Reparación del ADN/genética , Herpesvirus Humano 4/inmunología , Polimorfismo de Nucleótido Simple , Adulto , Cápside/inmunología , Femenino , Genotipo , Humanos , Inmunoglobulina A/análisis , Masculino , Persona de Mediana Edad , Recombinación GenéticaRESUMEN
Serum antibodies to Epstein-Barr virus (EBV) antigens can be used to predict the risk of nasopharyngeal carcinoma (NPC). To investigate whether EBV seropositivity rates were higher among healthy family members from multiplex and sporadic families with NPC (i.e., families with multiple or single cases) compared to the general population, a study was conducted on 2,665 unaffected individuals from 140 multiplex and 413 sporadic families. The titers of the IgA antibody to the EBV capsid antigen (VCA-IgA) were compared to those of 904 controls from the general population. The VCA-IgA titer was correlated among sibling pairs to a high significance in both family types (P < 0.0001 and P = 0.0005 for the multiplex and the sporadic families, respectively); parent-offspring pairs also showed significant correlation (P < 0.0001 and P = 0.0002, respectively); and spouse pairs were correlated, but at lower significance levels (P = 0.0790 and P = 0.0040, respectively). When compared to the controls, among first-degree relatives in the multiplex families, the age- and gender-adjusted odds ratio (OR) was 2.06 (95% confidence interval 1.56-2.71), 3.55 (2.24-5.64), and 2.25 (1.57-3.23) for siblings, parents, and children, respectively. In the sporadic families, the adjusted OR was 1.55 (1.21-2.00) and 2.08 (1.51-2.86) for siblings and parents, respectively. The adjusted P-value of spouses lost significance in the multiplex families, but remained significant in the sporadic families (P = 0.0146). In conclusion, EBV seropositivity rates were elevated among unaffected family members in both multiplex and sporadic families with NPC.
Asunto(s)
Anticuerpos Antivirales/sangre , Antígenos Virales/inmunología , Proteínas de la Cápside/inmunología , Infecciones por Virus de Epstein-Barr/epidemiología , Herpesvirus Humano 4/inmunología , Neoplasias Nasofaríngeas/epidemiología , Adulto , Anciano , Biomarcadores/sangre , Carcinoma , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/virología , Familia , Femenino , Humanos , Inmunoglobulina A/sangre , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/virologíaRESUMEN
BACKGROUND: Nasopharyngeal carcinoma (NPC) is rare in most parts of the world but is a common malignancy in southern China, especially in Guangdong. Dietary habit is regarded as an important modifier of NPC risk in several endemic areas and may partially explain the geographic distribution of NPC incidence. In China, rapid economic development during the past few decades has changed the predominant lifestyle and dietary habits of the Chinese considerably, requiring a reassessment of diet and its potential influence on NPC risk in this NPC-endemic area. METHODS: To evaluate the association between dietary factors and NPC risk in Guangdong, China, a large-scale, hospital-based case-control study was conducted. 1387 eligible cases and 1459 frequency matched controls were recruited. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated using a logistic regression model, adjusting for age, sex, education, dialect, and habitation household type. RESULTS: Observations made include the following: 1) consumption of canton-style salted fish, preserved vegetables and preserved/cured meat were significantly associated with increased risk of NPC, with enhanced odds ratios (OR) of 2.45 (95% CI: 2.03-2.94), 3.17(95% CI: 2.68-3.77) and 2.09 (95% CI: 1.22-3.60) respectively in the highest intake frequency stratum during childhood; 2) consumption of fresh fruit was associated with reduced risk with a dose-dependent relationship (p = 0.001); and 3) consumption of Canton-style herbal tea and herbal slow-cooked soup was associated with decreased risk, with ORs of 0.84 (95% CI: 0.68-1.03) and 0.58 (95% CI: 0.47-0.72) respectively in the highest intake frequency stratum. In multivariate analyses, these associations remained significant. CONCLUSIONS: It can be inferred that previously established dietary risk factors in the Cantonese population are still stable and have contributed to the incidence of NPC.
Asunto(s)
Dieta , Neoplasias Nasofaríngeas/etiología , Adulto , Estudios de Casos y Controles , China/epidemiología , Conducta Alimentaria , Femenino , Frutas , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/epidemiología , Factores de Riesgo , Tasa de Supervivencia , VerdurasRESUMEN
Nasopharyngeal carcinoma (NPC) is rare in most parts of the world but is more prevalent in Southern China, especially in Guangdong. The cytochrome P450 2E1 (CYP2E1) has been recognized as one of the critically important enzymes involved in oxidizing carcinogens and is probably to be associated with NPC carcinogenesis. To systematically investigate the association between genetic variants in CYP2E1 and NPC risk in Cantonese, two independent studies, a family-based association study and a case-control study, were conducted using the haplotype-tagging single-nucleotide polymorphism approach. A total of 2499 individuals from 546 nuclear families were initially genotyped for the family-based association study. Single-nucleotide polymorphisms (SNPs) rs9418990, rs915908, rs8192780, rs1536826, rs3827688 and one haplotype h2 (CGTGTTAA) were revealed to be significantly associated with the NPC phenotype (P = 0.045-0.003 and P = 0.003, respectively). To follow up the initial study, a case-control study including 755 cases and 755 controls was conducted. Similar results were observed in the case-control study in individuals <46 years of age and had a history of cigarette smoking, with odds ratios (ORs) of specific genotypes ranging from 1.88 to 2.99 corresponding to SNP rs9418990, rs3813865, rs915906, rs2249695, rs8192780, rs1536826, rs3827688 and of haplotypes h2 with OR = 1.65 (P = 0.026), h5 (CCCGTTAA) with OR = 2.58 (P = 0.007). The values of false-positive report probability were <0.015 for six SNPs, suggesting that the reported associations are less probably to be false. This study provides robust evidence for associations between genetic variants of CYP2E1 and NPC risk.
Asunto(s)
Carcinoma/genética , Citocromo P-450 CYP2E1/genética , Neoplasias Nasofaríngeas/genética , Polimorfismo Genético , Adulto , Anciano , Antígenos Virales/genética , Estudios de Casos y Controles , China , Reacciones Falso Positivas , Femenino , Variación Genética , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , RiesgoRESUMEN
BACKGROUND: Radiation-induced brain injury is a nonnegligible issue in the management of cancer patients treated by partial or whole brain irradiation. In particular, temporal lobe injury (TLI), a deleterious late complication in nasopharyngeal carcinoma, greatly affects the long-term life quality of these patients. Although genome-wide association studies (GWASs) have successfully identified single nucleotide polymorphisms (SNPs) associated with radiation toxicity, genetic variants contributing to the radiation-induced brain injury have not yet been assessed. METHODS: We recruited and performed follow-up for a prospective observational cohort, Genetic Architecture of Radiotherapy Toxicity and Prognosis, using magnetic resonance imaging for TLI diagnosis. We conducted genome-wide association analysis in 1082 patients and validated the top associations in two independent cohorts of 1119 and 741 patients, respectively. All statistical tests were two-sided. RESULTS: We identified a promoter variant rs17111237 (A > G, minor allele frequency [MAF] = 0.14) in CEP128 associated with TLI risk (hazard ratio = 1.45, 95% confidence interval = 1.26 to 1.66, Pcombined=3.18 × 10-7) which is in moderate linkage disequilibrium (LD) with rs162171 (MAF = 0.18, R2 = 0.69), the top signal in CEP128 (hazard ratio = 1.46, 95% confidence interval = 1.29-1.66, Pcombined= 6.17 × 10-9). Combining the clinical variables with the top SNP, we divided the patients into different subgroups with varying risk with 5-year TLI-free rates ranging from 33.7% to 95.5%. CEP128, a key component of mother centriole, tightly interacts with multiple radiation-resistant genes and plays an important role in maintaining the functional cilia, which otherwise will lead to a malfunction of the neural network. We found that A > G alteration at rs17111237 impaired the promoter activity of CEP128 and knockdown of CEP128 decreased the clonogenic cell survival of U87 cells under radiation. Noteworthy, 12.7% (27/212) of the GWAS-based associated genes (P < .001) were enriched in the neurogenesis pathway. CONCLUSIONS: This three-stage study is the first GWAS of radiation-induced brain injury that implicates the genetic susceptibility gene CEP128 involved in TLI development and provides the novel insight into the underlying mechanisms of radiation-induced brain injury.
Asunto(s)
Lesiones Encefálicas/genética , Traumatismos por Radiación/genética , Lóbulo Temporal/efectos de la radiación , Adulto , Lesiones Encefálicas/etiología , Lesiones Encefálicas/patología , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/radioterapia , Regiones Promotoras Genéticas , Traumatismos por Radiación/etiología , Traumatismos por Radiación/patología , Lóbulo Temporal/patologíaRESUMEN
PURPOSE: The aim of the present study was to analyze the expression of Centromere protein H (CENP-H), one of the fundamental components of the human active kinetochore, in nasopharyngeal carcinoma (NPC) and to correlate it with clinicopathologic data, including patient survival. EXPERIMENTAL DESIGN: Using reverse transcription-PCR and Western blot, we detected the expression of CENP-H in normal nasopharyngeal epithelial cells, immortalized nasopharyngeal epithelial cell lines, and NPC cell lines. Using immunohistochemistry, we analyzed CENP-H protein expression in 160 clinicopathologically characterized NPC cases. Statistical analyses were applied to test for prognostic and diagnostic associations. RESULTS: Reverse transcription-PCR and Western blot showed that the expression level of CENP-H was higher in NPC cell lines and in immortalized nasopharyngeal epithelial cells than in the normal nasopharyngeal epithelial cell line at both transcriptional and translational levels. By immunohistochemical analysis, we found that 76 of 160 (47.5%) paraffin-embedded archival NPC biopsies showed high expression of CENP-H. Statistical analysis showed that there was a significant difference of CENP-H expression in patients categorized according to clinical stage (P = 0.024) and T classification (P = 0.027). Patients with higher CENP-H expression had shorter overall survival time, whereas patients with lower CENP-H expression had better survival. A prognostic value of CENP-H was also found of the subgroup of N(0)-N(1) tumor classification. Multivariate analysis showed that CENP-H expression was an independent prognostic indicator for patient's survival. CONCLUSIONS: Our results suggest that CENP-H protein is a valuable marker of NPC progression. High CENP-H expression is associated with poor overall survival in NPC patients.
Asunto(s)
Carcinoma/diagnóstico , Carcinoma/metabolismo , Proteínas Cromosómicas no Histona/biosíntesis , Regulación Neoplásica de la Expresión Génica , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/metabolismo , Adulto , Carcinoma/patología , China , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/patología , Pronóstico , Factores de Tiempo , Resultado del TratamientoRESUMEN
Nasopharyngeal carcinoma is a common malignancy in Southeast Asian countries, and genetic background is a well-known component of the complexity underlying its tumorigenic process. We have mapped a nasopharyngeal carcinoma susceptibility locus to chromosome 4p15.1-q12 in a previous linkage study on nasopharyngeal carcinoma pedigrees. In this study provided in this communication, we screened all the genes in this region, with a focus on exons, promoters, and the exon-intron boundary to identify nasopharyngeal carcinoma-associated mutations or functional variants. Importantly, we found a novel gene (LOC344967) with a single nucleotide polymorphism -32G/A in the promoter region. This gene is a member of the acyl CoA thioesterase family that plays an important role in fatty acid metabolism and is involved in the progression of various types of tumors. The -32A variant was found cosegregated with the disease phenotype in the nasopharyngeal carcinoma pedigrees that we previously used for the linkage study. Moreover, this -32A variant creates an activator protein (AP-1)-binding site in the transcriptional regulatory region of LOC344967, which significantly enhanced the binding of AP-1 to the promoter region and the transcription activity of the promoter in vivo. Furthermore, the expression of LOC344967 was significantly up-regulated at both mRNA and protein levels in nasopharyngeal carcinoma cells sharing the -32G/A genotype compared with nasopharyngeal carcinoma cells with the -32G/G genotype. Collectively, these results provide evidence that the -32A variant is a functional sequence change and may be related to nasopharyngeal carcinoma susceptibility in the families studied.
Asunto(s)
Carcinoma/genética , Carcinoma/patología , Predisposición Genética a la Enfermedad , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Factores de Transcripción/genética , Exones , Humanos , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Factores de Transcripción/fisiología , Transcripción GenéticaRESUMEN
Preoperative lymph node (LN) status is important for the treatment of bladder cancer (BCa). Here, we report a genomic-clinicopathologic nomogram for preoperatively predicting LN metastasis in BCa. In the discovery stage, 325 BCa patients from TCGA were involved and LN-status-related mRNAs were selected. In the training stage, multivariate logistic regression analysis was used to developed a genomic-clinicopathologic nomogram for preoperative LN metastasis prediction in the training set (SYSMH set, n=178). In the validation stage, we validated the nomogram using two independent sample sets (SYSUCC set, n=142; RJH set, n=104) with respect to its discrimination, calibration and clinical usefulness. As results, we identified five LN-status-related mRNAs, including ADRA1D, COL10A1, DKK2, HIST2H3D and MMP11. Then, a genomic classifier was developed to classify patients into high- and low-risk groups in the training set. Furthermore, a nomogram incorporating the five-mRNA-based classifier, image-based LN status, transurethral resection (TUR) T stage, and TUR lymphovascular invasion (LVI) was constructed in the training set, which performed well in the training and validation sets. Decision curve analysis demonstrated the clinical value of our nomogram. Thus, our genomic-clinicopathologic nomogram shows favorable discriminatory ability and may aid in clinical decision-making, especially for cN-patients.
Asunto(s)
Genómica , Proteínas de Neoplasias , ARN Mensajero , ARN Neoplásico , Neoplasias de la Vejiga Urinaria , Anciano , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Valor Predictivo de las Pruebas , Cuidados Preoperatorios , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Bcl-3 as an oncoprotein is overexpressed in nasopharyngeal carcinoma (NPC). Nedd4 binding protein 2 (N4BP2), which is located in the NPC susceptibility locus, is a Bcl-3 binding protein. This study is aimed to explore the association between N4BP2 genetic polymorphism and the risk of NPC. METHODS: We performed a hospital-based case-control study, including 531 sporadic NPC and 480 cancer-free control subjects from southern China. PCR-sequencing was carried out on Exons, promoter region and nearby introns of the N4BP2 gene. The expression pattern of N4BP2 and Bcl-3 was also analyzed. RESULTS: We observed a statistically significant difference in haplotype blocks ATTA and GTTG between cases and controls. In addition, three novel SNPs were identified, two of which were in exons (loc123-e3l-snp2, position 39868005, A/G, Met171Val; RS17511668-SNP2, position 39926432, G/A, Glu118Lys), and one was in the intron6 (RS794001-SNP1, position 39944127, T/G). Moreover, N4BP2 was at higher levels in a majority of tumor tissues examined, relative to paired normal tissues. CONCLUSION: These data suggest that haplotype blocks ATTA and GTTG of N4BP2 is correlation with the risk of sporadic nasopharyngeal carcinoma in the Southern Chinese population and N4BP2 has a potential role in the development of NPC.
Asunto(s)
Pueblo Asiatico/genética , Proteínas Portadoras/genética , Predisposición Genética a la Enfermedad , Haplotipos , Neoplasias Nasofaríngeas/epidemiología , Neoplasias Nasofaríngeas/genética , Adulto , Proteínas del Linfoma 3 de Células B , Proteínas Portadoras/metabolismo , Estudios de Casos y Controles , Línea Celular Tumoral , China/epidemiología , Enzimas Reparadoras del ADN , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Frecuencia de los Genes , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Nasopharyngeal carcinoma is endemic in Southern China, displays a strong relationship with genetic susceptibility and associates with Epstein-Barr virus infection. Toll-like receptor 3 (TLR3) plays an important role in the antivirus response. Therefore, we examined the association between TLR3 gene polymorphisms and NPC susceptibility. METHODS: We performed a case-control study of 434 NPC cases and 512 healthy controls matched on age, sex and residence. Both cases and controls are of Cantonese origin from Southern China. Genetic variants in TLR3 were determined by polymerase chain reaction (PCR)-based DNA direct sequencing and four SNPs were genotyped in all samples. RESULTS: Our results showed that allele C for SNP 829A/C increased NPC risk significantly ((p = 0.0068, OR = 1.49, 95%CI:1.10-2.00). When adjusted for age, gender and VCA-IgA antibody titers, the NPC risk was reduced significantly among individuals who carried the haplotype "ATCT" compared to those who carried the most common haplotype "ACCT" (p = 0.0054, OR = 0.028; 95% CI (0.002-0.341). CONCLUSION: The TLR3 polymorphisms may be relevant to NPC susceptibility in the Cantonese population, although the reduction in NPC risk is modest and the biological mechanism of the observed association merits further investigation.
Asunto(s)
Pueblo Asiatico/genética , Neoplasias Nasofaríngeas/etnología , Neoplasias Nasofaríngeas/genética , Receptor Toll-Like 3/genética , Adulto , Estudios de Casos y Controles , China/epidemiología , Enfermedades Endémicas , Femenino , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Medición de RiesgoRESUMEN
Esophageal squamous cell carcinoma (ESCC), one of the most aggressive cancers, is characterized by heterogeneous genetic and epigenetic changes. Recently, A-to-I RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), was found to be aberrantly regulated during tumorigenesis. We previously reported that ADAR2 was downregulated in ESCC but its role was unclear. Thus, we report here that overexpression of ADAR2 can induce apoptosis in ESCC cell lines and inhibit tumor growth in vitro and in vivo. ADAR2 knockdown inhibited apoptosis in ADAR2 highly expressing tumor cells. RNA-seq assay showed that ADAR2, not ADAR1 or active-site-mutated ADAR2, could edit insulin-like growth factor binding protein 7 (IGFBP7) mRNA in ESCC. IGFBP7 knockdown or ADAR2 catalytic activity destruction abolished the pro-apoptotic function of ADAR2. Mechanistically, RNA editing may stabilize IGFBP7 protein by changing the protease recognition site of matriptase and this is essential for IGFBP7 to induce apoptosis. Western blotting revealed that ADAR2 overexpression could induce IGFBP7-dependent inhibition of Akt signaling. Thus, our data indicate that ADAR2 suppresses tumor growth and induces apoptosis by editing and stabilizing IGFBP7 in ESCC, and this may represent a novel therapeutic target for treating ESCC.
Asunto(s)
Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismo , Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/patología , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Animales , Apoptosis , Sitios de Unión , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Proliferación Celular , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/química , Ratones , Trasplante de Neoplasias , Estabilidad Proteica , Edición de ARN , Transducción de SeñalRESUMEN
Nasopharyngeal carcinoma (NPC) is a common malignancy in southern China and Southeast Asia. Genetic susceptibility is a major factor in determining the individual risk of NPC in these areas. To test the association between NPC and variants in Toll-like receptor 10 (TLR10), we conducted a hospital-based case-control study in a Cantonese-speaking population in Guangdong province. Seven single nucleotide polymorphisms in TLR10, selected with a tagging algorithm, were genotyped. When assessing each unique haplotype compared with the most common haplotype, "GAGTGAA," with the expectation-maximization algorithm in Haplo.stats, the risk of developing NPC was significantly elevated among men who carried the haplotype "GCGTGGC" (P = 0.005). After adjusting for age, gender, and VCA-IgA antibody titers, this association was more significant (P = 0.0007). To further assess the overall differences of haplotype frequency profiles between cases and healthy controls, the global score test, considering all haplotypes and adjusting for age, gender, and VCA-IgA antibody titers, gave a haplo score of 27.52 with P = 0.002. The haplotype specific odds ratio was 2.66 (confidence interval, 1.34-3.82) for GCGTGGC. We concluded that in this Cantonese population-based study, haplotype GCGTGGC with frequency of 11.4% in TLR10 was found to be associated with NPC and this association was statistically significant after adjusting for age, gender, and VCA-IgA antibody titers. It is possible that this is not a causal haplotype for NPC; rather, it is in strong linkage disequilibrium with a causal single nucleotide polymorphism in close proximity.
Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias Nasofaríngeas/genética , Receptor Toll-Like 10/genética , Adulto , Algoritmos , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , China/epidemiología , Variación Genética , Genotipo , Haplotipos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/epidemiología , Polimorfismo de Nucleótido SimpleRESUMEN
Gastric carcinoma is one of the most common malignancies in Asia. Although the allelic deletion of 7q has been reportedly associated with primary gastric carcinoma tumorigenesis, no predisposing genes in this region have been identified so far. Here, we report the results of genotype and loss of heterozygosity (LOH) analysis on 7q in this tumor. A panel of nine microsatellite markers distributed over the whole chromosome 7q was used for genotyping primary gastric carcinomas. Of 72 primary tumors LOH of D7S486 occurred in 24.0% (12/50) of cases. Fine mapping with 12 additional markers flanking D7S486 resulted in LOH of 30.36% (17/56) and defined one minimal deleted region in primary gastric carcinomas, a 90-kilobase region bounded by D7S2543 and D7S486 at 7q31.2. The allelic deletion correlates statistically with clinicopathologic variables. Our data suggest a possible link between putative tumor suppressor genes and gastric carcinoma in the 7q31 region.
Asunto(s)
Cromosomas Humanos Par 7/genética , Genes Supresores de Tumor , Pérdida de Heterocigocidad/genética , Neoplasias Gástricas/genética , Adulto , Anciano , Deleción Cromosómica , Femenino , Humanos , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Mapeo Físico de CromosomaRESUMEN
Nasopharyngeal carcinoma (NPC) is characterized by a high prevalence in Southern China, especially among Cantonese individuals of the Guangdong Province. Epidemiological studies have suggested that frequent exposure to high levels of nitrosamine from preserved foods such as salted fish could be a risk factor for NPC. Cytochrome P450 encompasses a family of enzymes that metabolize carcinogens and CYP2A13, a member of this family, is expressed predominantly in the respiratory tract with the highest levels in the nasal mucosa. In an effort to test whether a correlation exists between CYP2A13 genetic polymorphism and the risk of developing NPC, we sequenced all nine exons and the exon-intron junctions of the CYP2A13 gene in 45 NPC patients. We identified a total of 21 single nucleotide polymorphism (SNPs), including 7 novel SNPs. The most frequent functional variant allele was 74A-1757G-3375T-7233G with a haplotype frequency of 7.8% in the 45 NPC cases. In addition, a stop codon mutation was detected in one case. We then selected the 3 most frequent SNPs and one stop codon mutation to expand our study to a case-control analysis within the Cantonese population. A novel haplotype consisting 8 SNPs in introns, and four additional novel SNPs were identified; but no correlation between CYP2A13 genetic polymorphism and individual susceptibility to NPC was observed.
RESUMEN
Autism spectrum disorders (ASD) comprise a number of underlying sub-types with various symptoms and presumably different genetic causes. One important difference between these sub-phenotypes is IQ. Some forms of ASD such as Asperger's have relatively intact intelligence while the majority does not. In this study, we explored the role of genetic factors that might account for this difference. Using a case-control study based on IQ status in 1657 ASD probands, we analyzed both common and rare variants provided by the Autism Genome Project (AGP) consortium via dbGaP (database of Genotypes and Phenotypes). We identified a set of genes, among them HLA-DRB1 and KIAA0319L, which are strongly associated with IQ within a population of ASD patients.
RESUMEN
To date, the only established model for assessing risk for nasopharyngeal carcinoma (NPC) relies on the sero-status of the Epstein-Barr virus (EBV). By contrast, the risk assessment models proposed here include environmental risk factors, family history of NPC, and information on genetic variants. The models were developed using epidemiological and genetic data from a large case-control study, which included 1,387 subjects with NPC and 1,459 controls of Cantonese origin. The predictive accuracy of the models were then assessed by calculating the area under the receiver-operating characteristic curves (AUC). To compare the discriminatory improvement of models with and without genetic information, we estimated the net reclassification improvement (NRI) and integrated discrimination index (IDI). Well-established environmental risk factors for NPC include consumption of salted fish and preserved vegetables and cigarette smoking (in pack years). The environmental model alone shows modest discriminatory ability (AUCâ=â0.68; 95% CI: 0.66, 0.70), which is only slightly increased by the addition of data on family history of NPC (AUCâ=â0.70; 95% CI: 0.68, 0.72). With the addition of data on genetic variants, however, our model's discriminatory ability rises to 0.74 (95% CI: 0.72, 0.76). The improvements in NRI and IDI also suggest the potential usefulness of considering genetic variants when screening for NPC in endemic areas. If these findings are confirmed in larger cohort and population-based case-control studies, use of the new models to analyse data from NPC-endemic areas could well lead to earlier detection of NPC.
Asunto(s)
Neoplasias Nasofaríngeas/epidemiología , Neoplasias Nasofaríngeas/genética , Anciano , Carcinoma , Estudios de Casos y Controles , China/epidemiología , Simulación por Computador , Femenino , Humanos , Masculino , Modelos Biológicos , Modelos Genéticos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patología , Nasofaringe/metabolismo , Nasofaringe/patología , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is a squamous cell cancer endemic in Southern China and Southeast Asia. It has been shown that inflammatory and immune responses during EBV infection contribute to the development of NPC. The complement receptor 2 (CR2) gene plays central roles during inflammatory and immune responses and, therefore, is a good candidate susceptibility gene for NPC. We performed PCR-based sequencing to identify multiple single-nucleotide polymorphisms (SNPs) within the exon regions of the CR2 gene in a Cantonese population. Two SNPs were screened in 528 NPC patients and 408 normal individuals to perform a case-control study matched according to age, gender and residence. Furthermore, we cloned the entire 5'-UTR and entire CR2 promoter into a luciferase report system and compared the luciferase activities between the different allelic constructs. A SNP in the 5'-UTR of CR2 (24 T/C, rs3813946) showed a significant association (P<0.01) with NPC in the Cantonese population studied. The subjects were categorized into 2 age groups: group 1, age ≤45 years and group 2, age >45 years. In group 1, the allelic frequencies of 24 T/C in the patients were significantly different from those of the controls (P=0.0034). The odds ratio (OR=1.81) also indicated a higher risk of NPC in individuals who carried the minor allele C. All constructs exerted allelic differences on luciferase activities, but only the susceptible allele +24C construct showed increased activity. Our findings implicate CR2 as a susceptibility gene for NPC and suggest that enhanced CR2 expression may be involved in the oncogenesis and development of NPC.