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BACKGROUND: We characterized age at diagnosis and estimated sex differences for lung cancer and its histological subtypes among individuals who never smoke. METHODS: We analyzed the distribution of age at lung cancer diagnosis in 33,793 individuals across 8 cohort studies and two national registries from East Asia, the United States (US) and the United Kingdom (UK). Student's t-tests were used to assess the study population differences (Δ years) in age at diagnosis comparing females and males who never smoke across subgroups defined by race/ethnicity, geographic location, and histological subtypes. RESULTS: We found that among Chinese individuals diagnosed with lung cancer who never smoke, females were diagnosed with lung cancer younger than males in the Taiwan Cancer Registry (n = 29,832) (Δ years = -2.2 (95% confidence interval (CI):-2.5, -1.9), in Shanghai (n = 1049) (Δ years = -1.6 (95% CI:-2.9, -0.3), and in Sutter Health and Kaiser Permanente Hawai'i in the US (n = 82) (Δ years = -11.3 (95% CI: -17.7, -4.9). While there was a suggestion of similar patterns in African American and non-Hispanic White individuals. the estimated differences were not consistent across studies and were not statistically significant. CONCLUSIONS: We found evidence of sex differences for age at lung cancer diagnosis among individuals who never smoke.
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Etnicidad , Neoplasias Pulmonares , Humanos , Masculino , Femenino , Estados Unidos/epidemiología , Humo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/patología , China , BlancoRESUMEN
AIMS/HYPOTHESIS: An elevated fasting glucose level in non-diabetic individuals is a key predictor of type 2 diabetes. Genome-wide association studies (GWAS) have identified hundreds of SNPs for fasting glucose but most of their functional roles in influencing the trait are unclear. This study aimed to identify the mediation effects of DNA methylation between SNPs identified as significant from GWAS and fasting glucose using Mendelian randomisation (MR) analyses. METHODS: We first performed GWAS analyses for three cohorts (Taiwan Biobank with 18,122 individuals, the Healthy Aging Longitudinal Study in Taiwan with 1989 individuals and the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance with 416 individuals) with individuals of Han Chinese ancestry in Taiwan, followed by a meta-analysis for combining the three GWAS analysis results to identify significant and independent SNPs for fasting glucose. We determined whether these SNPs were methylation quantitative trait loci (meQTLs) by testing their associations with DNA methylation levels at nearby CpG sites using a subsample of 1775 individuals from the Taiwan Biobank. The MR analysis was performed to identify DNA methylation with causal effects on fasting glucose using meQTLs as instrumental variables based on the 1775 individuals. We also used a two-sample MR strategy to perform replication analysis for CpG sites with significant MR effects based on literature data. RESULTS: Our meta-analysis identified 18 significant (p < 5 × 10-8) and independent SNPs for fasting glucose. Interestingly, all 18 SNPs were meQTLs. The MR analysis identified seven CpGs near the G6PC2 gene that mediated the effects of a significant SNP (rs2232326) in the gene on fasting glucose. The MR effects for two CpGs were replicated using summary data based on the European population, using an exonic SNP rs2232328 in G6PC2 as the instrument. CONCLUSIONS/INTERPRETATION: Our analysis results suggest that rs2232326 and rs2232328 in G6PC2 may affect DNA methylation at CpGs near the gene and that the methylation may have downstream effects on fasting glucose. Therefore, SNPs in G6PC2 and CpGs near G6PC2 may reside along the pathway that influences fasting glucose levels. This is the first study to report CpGs near G6PC2, an important gene for regulating insulin secretion, mediating the effects of GWAS-significant SNPs on fasting glucose.
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Glucemia/genética , Islas de CpG/genética , Glucosa-6-Fosfatasa/genética , Estudios de Cohortes , Metilación de ADN , Ayuno/sangre , Estudio de Asociación del Genoma Completo , Genómica/métodos , Humanos , Estudios Longitudinales , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo/genética , Taiwán/epidemiologíaRESUMEN
We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (pâ¯=â¯0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (ORâ¯=â¯1.31, 95% CI: 1.03, 1.66, pâ¯=â¯0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.
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Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/genética , Tuberculosis Pulmonar/genética , Adenocarcinoma del Pulmón/epidemiología , Pueblo Asiatico , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Neoplasias Pulmonares/epidemiología , Análisis de la Aleatorización Mendeliana , No Fumadores/estadística & datos numéricos , Tuberculosis Pulmonar/epidemiologíaRESUMEN
Assuming Cox's regression model, we consider penalized full likelihood approach to conduct variable selection under nested case-control (NCC) sampling. Penalized non-parametric maximum likelihood estimates (PNPMLEs) are characterized by self-consistency equations derived from score functions. A cross-validation method based on profile likelihood is used to choose the tuning parameter within a family of penalty functions. Simulation studies indicate that the numerical performance of (P)NPMLE is better than weighted partial likelihood in estimating the log-relative risk and in identifying the covariates and the model, under NCC sampling. LASSO performs best when cohort size is small; SCAD performs best when cohort size is large and may eventually perform as well as the oracle estimator. Using the SCAD penalty, we establish the consistency, asymptotic normality, and oracle properties of the PNPMLE, as well as the sparsity property of the penalty. We also propose a consistent estimate of the asymptotic variance using observed profile likelihood. Our method is illustrated to analyze the diagnosis of liver cancer among those in a type 2 diabetic mellitus dataset who were treated with thiazolidinediones in Taiwan.
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Funciones de Verosimilitud , Modelos de Riesgos Proporcionales , Muestreo , Algoritmos , Femenino , Humanos , Masculino , Estadísticas no ParamétricasRESUMEN
To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 × 10-8), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1/DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications.
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Adenocarcinoma/genética , Antígenos Nucleares/genética , Butirofilinas/genética , Receptores ErbB/genética , Cadenas beta de HLA-DP/genética , Neoplasias Pulmonares/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genética , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Pueblo Asiatico/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Mutación de Línea Germinal , Humanos , Neoplasias Pulmonares/patología , Masculino , Polimorfismo de Nucleótido Simple , Caracteres Sexuales , Fumar/genética , Población Blanca/genéticaRESUMEN
Recent heritability analyses have indicated that genome-wide association studies (GWAS) have the potential to improve genetic risk prediction for complex diseases based on polygenic risk score (PRS), a simple modelling technique that can be implemented using summary-level data from the discovery samples. We herein propose modifications to improve the performance of PRS. We introduce threshold-dependent winner's-curse adjustments for marginal association coefficients that are used to weight the single-nucleotide polymorphisms (SNPs) in PRS. Further, as a way to incorporate external functional/annotation knowledge that could identify subsets of SNPs highly enriched for associations, we propose variable thresholds for SNPs selection. We applied our methods to GWAS summary-level data of 14 complex diseases. Across all diseases, a simple winner's curse correction uniformly led to enhancement of performance of the models, whereas incorporation of functional SNPs was beneficial only for selected diseases. Compared to the standard PRS algorithm, the proposed methods in combination led to notable gain in efficiency (25-50% increase in the prediction R2) for 5 of 14 diseases. As an example, for GWAS of type 2 diabetes, winner's curse correction improved prediction R2 from 2.29% based on the standard PRS to 3.10% (P = 0.0017) and incorporating functional annotation data further improved R2 to 3.53% (P = 2×10-5). Our simulation studies illustrate why differential treatment of certain categories of functional SNPs, even when shown to be highly enriched for GWAS-heritability, does not lead to proportionate improvement in genetic risk-prediction because of non-uniform linkage disequilibrium structure.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Modelos Genéticos , Herencia Multifactorial/genética , Algoritmos , Simulación por Computador , Humanos , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings.
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Sitios Genéticos , Predisposición Genética a la Enfermedad , Neoplasias Pulmonares/genética , Polimorfismo de Nucleótido Simple , Adulto , Alelos , Pueblo Asiatico , Estudios de Casos y Controles , Cromosomas Humanos Par 12 , Cromosomas Humanos Par 6 , Cromosomas Humanos Par 9 , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Oportunidad Relativa , FumarRESUMEN
Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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Aberraciones Cromosómicas , Genoma Humano , Mosaicismo , Anciano , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/genéticaRESUMEN
BACKGROUND: Phthalic acid esters are ubiquitous and antiandrogenic, and may cause systemic effects in humans, particularly with in utero exposure. Epigenetic modification, such as DNA methylation, has been hypothesized to be an important mechanism that mediates certain biological processes and pathogenic effects of in utero phthalate exposure. OBJECTIVE: The aim of this study was to examine the association between genome-wide DNA methylation at birth and prenatal exposure to phthalate. METHODS: We studied 64 infant-mother pairs included in TMICS (Taiwan Maternal and Infant Cohort Study), a long-term follow-up birth cohort from the general population. DNA methylation levels at more than 450,000 CpG sites were measured in cord blood samples using Illumina Infinium HumanMethylation450 BeadChips. The concentrations of three metabolites of di-(2-ethylhexyl) phthalate (DEHP) were measured using liquid chromatography tandem-mass spectrometry (LC-MS/MS) in urine samples collected from the pregnant women during 28-36 weeks gestation. RESULTS: We identified 25 CpG sites whose methylation levels in cord blood were significantly correlated with prenatal DEHP exposure using a false discovery rate (FDR) of 5% (q-value < 0.05). Via gene-set enrichment analysis (GSEA), we also found that there was significant enrichment of genes involved in the androgen response, estrogen response, and spermatogenesis within those genes showing DNA methylation changes in response to exposure. Specifically, PA2G4, HMGCR, and XRCC6 genes were involved in genes in response to androgen. CONCLUSIONS: Phthalate exposure in utero may cause significant alterations in the DNA methylation in cord blood. These changes in DNA methylation might serve as biomarkers of maternal exposure to phthalate in infancy and potential candidates for studying mechanisms via which phthalate may impact on health in later life. Future investigations are warranted.
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Metilación de ADN , Dietilhexil Ftalato , Disruptores Endocrinos , Ácidos Ftálicos , Efectos Tardíos de la Exposición Prenatal , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Cromatografía Liquida , Estudios de Cohortes , Disruptores Endocrinos/toxicidad , Femenino , Humanos , Hidroximetilglutaril-CoA Reductasas/metabolismo , Recién Nacido , Autoantígeno Ku/metabolismo , Masculino , Exposición Materna , Ácidos Ftálicos/toxicidad , Embarazo , Proteínas de Unión al ARN/metabolismo , Taiwán , Espectrometría de Masas en TándemRESUMEN
RATIONALE: Patients with non-small cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR) are relatively sensitive to EGFR-tyrosine kinase inhibitor (TKI) treatment and have longer progression-free survival (PFS) when treated with EGFR-TKI compared with platinum-based chemotherapy. However, many patients with advanced NSCLC who have mutated EGFR do not respond to first-line EGFR-TKI treatment and still have shorter PFS. OBJECTIVES: The aim of this study was to identify genetic variants associated with PFS among patients with lung adenocarcinoma who were treated with first-line EGFR-TKIs. METHODS: A genome-wide association study on PFS was performed in never-smoking women diagnosed with lung adenocarcinoma and who were treated with first-line EGFR-TKIs (n = 128). Significant single-nucleotide polymorphisms (SNPs) were selected for follow-up association analysis (n = 198) and for replication assay in another independent cohort (n = 153). MEASUREMENTS AND MAIN RESULTS: We identified SNPs at 4q12 associated with PFS at genome-wide significance (P < 10-8) and with an estimated hazard ratio of more than 4. This association was also replicated in a larger but similar cohort and in an independent NSCLC cohort. Follow-up functional analyses showed that these SNPs were associated with the expression of EGFR, which encodes the TKI target, and with a nearby gene neuromedin-U, which encodes a G protein-coupled receptor ligand known to be involved in the progression of NSCLC. Considering these as possible prognostic biomarkers for the treatment of patients with late-stage lung cancer, we found that these SNPs were not associated with EGFR mutation status or with polymorphism of the Bcl2-interacting mediator of cell death gene. CONCLUSIONS: Genetic variants in 4q12 merit further investigation to assess their potential as pharmacogenomic predictors for and to understand the biology underlying its influence on PFS in patients treated with TKI therapy.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Adulto JovenRESUMEN
BACKGROUND: The effect of cardio-metabolic profile on the relationship of body mass index (BMI) with mortality is unclear. The aim of this study was to explore association between BMI and mortality at all ages, taking account of cardio-metabolic disorders. METHODS: We followed 377,929 individuals (≥ 20 years), who registered for health checkups in 1996-2007, until 2008 and found 9490 deaths. From multivariable Cox proportional hazards models we estimated mortality hazard ratios (HR) for those in high blood pressure, hyperglycemia, high waist circumference, dyslipidemia, and different BMIs categories (the underweight [< 18.5 kg/m2], low normal weight [18.5-21.9 kg/m2], normal weight [22-23.9 kg/m2, the referent], overweight [24-26.9 kg/m2], obese1 [27-29.9 kg/m2], and obese2 [≥ 30 kg/m2]). Population attributable risk (PAR) provided estimates of the population mortality burden attributable to high blood pressure, hyperglycemia, high waist circumference, dyslipidemia, and deviant BMIs. RESULTS: Higher blood pressure, hyperglycemia, high waist circumference, and dyslipidemia were significantly predictive of higher mortality for nearly all ages. Compared with the referent BMI, underweight (HR = 1.69, 95% confidence interval = 1.51-1.90) and low normal weight (HR = 1.19, 1.11-1.28) were significant mortality risks, while overweight (HR = 0.82, 0.76-0.89) and obese1 (HR = 0.88, 0.79-0.97) were protective against premature death. The mortality impact of obesity was largely attributable to cardio-metabolic profile and attenuated by age. The population mortality burden with high blood pressure (PAR = 7.29%), hyperglycemia (PAR = 5.15%), high waist circumference (PAR = 4.24%), and dyslipidemia (PAR = 5.66%) was similar to that in the underweight (PAR = 5.50%) or low normal weight (PAR = 6.04%) groups. Findings for non-smokers and by gender were similar. CONCLUSIONS: The effect of BMI on mortality varies with age and is affected by cardio-metabolic status. Compared to any deviant BMI, abnormal cardio-metabolic status has a similar or even greater health impact at both the individual and population levels.
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Índice de Masa Corporal , Enfermedades Cardiovasculares/mortalidad , Enfermedades Metabólicas/mortalidad , Adulto , Distribución por Edad , Anciano , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Distribución por Sexo , Tasa de Supervivencia/tendencias , Taiwán/epidemiología , Adulto JovenRESUMEN
Growth differentiation factor-10 (GDF10), commonly referred as BMP3b, is a member of the transforming growth factor-ß (TGF-ß) superfamily. GDF10/BMP3b has been considered as a tumor suppressor, however, little is known about the molecular mechanism of its roles in tumor suppression in oral cancer. Clinical significance of GDF10 downregulation in oral squamous cell carcinoma (OSCC) was evaluated using three independent cohorts of OSCC patients. The molecular mechanisms of GDF10 in the suppression of cell survival, cell migration/invasion and epithelial-mesenchymal transition (EMT) were investigated by using oral cancer cell lines. The present study shows that GDF10 is downregulated during oral carcinogenesis, and GDF10 expression is also an independent risk factor for overall survival of OSCC patients. Overexpression of GDF10 attenuates cell proliferation, transformation, migration/invasion, and EMT. GDF10-inhibited EMT is mediated by ERK signaling but not by typical TGF-ß signaling. In addition, overexpression of GDF10 promotes DNA damage-induced apoptosis and sensitizes the response to all-trans retinoic acid (ATRA) and camptothecin (CPT). Intriguingly, the expression of GDF10 is induced by type III TGF-ß receptor (TGFBR3) through TGF-ß-SMAD2/3 signaling. Our findings suggest that TGFBR3 is an upstream activator of GDF10 expression and they share the same signaling to inhibit EMT and migration/invasion. These results support that GDF10 acts as a hinge to collaborate with TGFBR3 in the transition of EMT-MET program. Taken together, we illustrated the clinical significance and the molecular mechanisms of tumor-suppressive GDF10 in OSCC.
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Carcinoma de Células Escamosas/patología , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Factor 10 de Diferenciación de Crecimiento/metabolismo , Neoplasias de la Boca/patología , Proteoglicanos/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Factor 10 de Diferenciación de Crecimiento/genética , Humanos , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Pronóstico , Proteoglicanos/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Análisis de SupervivenciaRESUMEN
Coronary heart disease (CHD) is the leading cause of mortality in both developed and developing countries worldwide. Genome-wide association studies (GWAS) have now identified 46 independent susceptibility loci for CHD, however, the biological and disease-relevant mechanisms for these associations remain elusive. The large-scale meta-analysis of GWAS recently identified in Caucasians a CHD-associated locus at chromosome 6q23.2, a region containing the transcription factor TCF21 gene. TCF21 (Capsulin/Pod1/Epicardin) is a member of the basic-helix-loop-helix (bHLH) transcription factor family, and regulates cell fate decisions and differentiation in the developing coronary vasculature. Herein, we characterize a cis-regulatory mechanism by which the lead polymorphism rs12190287 disrupts an atypical activator protein 1 (AP-1) element, as demonstrated by allele-specific transcriptional regulation, transcription factor binding, and chromatin organization, leading to altered TCF21 expression. Further, this element is shown to mediate signaling through platelet-derived growth factor receptor beta (PDGFR-ß) and Wilms tumor 1 (WT1) pathways. A second disease allele identified in East Asians also appears to disrupt an AP-1-like element. Thus, both disease-related growth factor and embryonic signaling pathways may regulate CHD risk through two independent alleles at TCF21.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Enfermedad Coronaria/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Factor de Transcripción AP-1/genética , Alelos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diferenciación Celular/genética , Células Cultivadas , Enfermedad Coronaria/patología , Vasos Coronarios/citología , Vasos Coronarios/crecimiento & desarrollo , Elementos de Facilitación Genéticos , Regulación del Desarrollo de la Expresión Génica , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Miocitos del Músculo Liso/citología , Polimorfismo de Nucleótido Simple , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal , Factor de Transcripción AP-1/metabolismo , Tumor de Wilms/genética , Tumor de Wilms/metabolismoRESUMEN
Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.
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Predisposición Genética a la Enfermedad/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleótido Simple , Telómero/genética , Adulto , Anciano , Pueblo Asiatico/genética , China , Femenino , Predisposición Genética a la Enfermedad/etnología , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Hong Kong , Humanos , Japón , Neoplasias Pulmonares/etnología , Persona de Mediana Edad , Oportunidad Relativa , Estudios Prospectivos , República de Corea , Factores de Riesgo , Singapur , Fumar , Taiwán , Homeostasis del Telómero/genéticaRESUMEN
AIMS: The exact world-wide prevalence of Brugada electrocardiogram (ECG) pattern is still unclear, especially in adults aged 55 years and older. METHODS AND RESULTS: The study was conducted as part of the Healthy Aging Longitudinal Study in Taiwan (HALST). Using a stratified random sampled method, a sample of community-dwelling subjects was recruited from seven community-based regions across Taiwan. All enrolled subjects were follow-up annually and cause of death was documented by citizen death records. A total of 5214 subjects were enrolled (male/female: 2530/2684) with a mean age of 69 ± 8 years. The overall prevalence of Brugada ECG patterns was 3.32%. Four subjects carried spontaneous Type 1 Brugada ECG pattern, 68 carried Type 2, and 101 carried Type 3. Compared with the world-wide average prevalence of Brugada ECG patterns, the prevalence of spontaneous Type 1 Brugada ECG pattern in subjects from the HALST cohort was similar (0.077 vs. 0.07%) and the combined prevalence of Types 2 and 3 Brugada ECG pattern was 10 times higher (3.24 vs. 0.28%) even the mean age of study subjects was significantly higher (69 ± 8 vs. 35 ± 8, P < 0.001). However, all-cause mortality and cardiac mortality rates were not significantly different between subjects with and without Brugada ECG patterns during the 4-year follow-up (log-rank test, P = 0.21, 0.32, respectively). CONCLUSION: The prevalence of Brugada ECG pattern in adults aged 55 years and older in Taiwan was higher than the average world-wide prevalence but was not associated with increased mortality.
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Síndrome de Brugada/diagnóstico , Síndrome de Brugada/mortalidad , Electrocardiografía/estadística & datos numéricos , Distribución por Edad , Anciano , Anciano de 80 o más Años , China/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Pronóstico , Reproducibilidad de los Resultados , Factores de Riesgo , Sensibilidad y Especificidad , Distribución por Sexo , Tasa de Supervivencia , Taiwán/epidemiologíaRESUMEN
SOX2 is a transcription factor essential for self-renewal and pluripotency of embryonic stem cells. Recently, SOX2 was found overexpressed in the majority of the lung squamous cell carcinoma (SQC), in which it acts as a lineage-survival oncogene. However, downstream targets/pathways of SOX2 in lung SQC cells remain to be identified. Here, we show that BMP4 is a downstream target of SOX2 in lung SQC. We found that SOX2-silencing-mediated inhibition of cell growth was accompanied by upregulation of BMP4 mRNA and its protein expression. Meta-analysis with 293 samples and qRT-PCR validation with 73 clinical samples revealed an inversely correlated relationship between levels of SOX2 and BMP4 mRNA, and significantly lower mRNA levels in tumor than in adjacent normal tissues. This was corroborated by immunohistochemistry analysis of 35 lung SQC samples showing lower BMP4 protein expression in tumor tissues. Cell-based experiments including siRNA transfection, growth assay and flow cytometry assay, further combined with a xenograft tumor model in mice, revealed that reactivation of BMP4 signaling could partially account for growth inhibition and cell cycle arrest in lung SQC cells upon silencing SOX2. Finally, chromatin immunoprecipitation analysis and luciferase reporter assay revealed that SOX2 could negatively regulate BMP4 promoter activity, possibly through binding to the promoter located in the first intron region of BMP4. Collectively, our findings suggest that BMP4 could act as a tumor suppressor and its downregulation by elevated SOX2 resulting in enhanced growth of lung SQC cells.
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Proteína Morfogenética Ósea 4/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Pulmonares/metabolismo , Factores de Transcripción SOXB1/metabolismo , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Escamosas/genética , Bases de Datos Genéticas , Regulación hacia Abajo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Humanos , Pulmón/metabolismo , Neoplasias Pulmonares/genética , Ratones , Trasplante de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas , Transducción de SeñalRESUMEN
BACKGROUND & AIMS: Many patients with pancreatic ductal adenocarcinoma (PDAC) develop recurrent or metastatic diseases after surgery, so it is important to identify those most likely to benefit from aggressive therapy. Disruption of tissue microarchitecture is an early step in pancreatic tumorigenesis and a parameter used in pathology grading of glandular tumors. We investigated whether changes in gene expression during pancreatic epithelial morphogenesis were associated with outcomes of patients with PDAC after surgery. METHODS: We generated architectures of human pancreatic duct epithelial cells in a 3-dimensional basement membrane matrix. We identified gene expression profiles of the cells during different stages of tubular morphogenesis (tubulogenesis) and of PANC-1 cells during spheroid formation. Differential expression of genes was confirmed by immunoblot analysis. We compared the gene expression profile associated with pancreatic epithelial tubulogenesis with that of PDAC samples from 27 patients, as well as with their outcomes after surgery. RESULTS: We identified a gene expression profile associated with tubulogenesis that resembled the profile of human pancreatic tissue with differentiated morphology and exocrine function. Patients with PDACs with this profile fared well after surgery. Based on this profile, we established a 6-28 gene tubulogenesis-specific signature that accurately determined the prognosis of independent cohorts of patients with PDAC (total n = 128; accuracy = 81.2%-95.0%). One gene, ASPM, was down-regulated during tubulogenesis but up-regulated in human PDAC cell lines and tumor samples; up-regulation correlated with patient outcomes (Cox regression P = .0028). Bioinformatic, genetic, biochemical, functional, and clinical correlative studies showed that ASPM promotes aggressiveness of PDAC by maintaining Wnt-ß-catenin signaling and stem cell features of PDAC cells. CONCLUSIONS: We identified a gene expression profile associated with pancreatic epithelial tubulogenesis and a tissue architecture-specific signature of PDAC cells that is associated with patient outcomes after surgery.
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Carcinoma Ductal Pancreático/patología , Diferenciación Celular/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/genética , Proteínas del Tejido Nervioso/fisiología , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/patología , Transcriptoma/genética , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/fisiología , Carcinoma Ductal Pancreático/genética , Diferenciación Celular/fisiología , Movimiento Celular/genética , Movimiento Celular/fisiología , Modelos Animales de Enfermedad , Epitelio/patología , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica/fisiología , Xenoinjertos , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas del Tejido Nervioso/genética , Neoplasias Pancreáticas/genética , Pronóstico , Estudios Retrospectivos , Transducción de Señal/genética , Transducción de Señal/fisiología , Transcriptoma/fisiología , Proteínas Wnt/fisiología , beta Catenina/fisiologíaRESUMEN
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with poor prognosis. We aimed to identify a panel of CpG methylation biomarkers for prognosis prediction of ESCC patients. METHODS: Illumina's GoldenGate methylation array, supervised principal components, Kaplan-Meier survival analyses and Cox regression model were conducted on dissected tumor tissues from a training cohort of 40 ESCC patients to identify potential CpG methylation biomarkers. Pyrosequencing quantitative methylation assay were performed to validate prognostic CpG methylation biomarkers in 61 ESCC patients. The correlation between DNA methylation and RNA expression of a validated marker, SOX17, was examined in a validation cohort of 61 ESCC patients. RESULTS: We identified a panel of nine CpG methylation probes located at promoter or exon1 region of eight genes including DDIT3, FES, FLT3, NTRK3, SEPT5, SEPT9, SOX1, and SOX17, for prognosis prediction in ESCC patients. Risk score calculated using the eight-gene panel statistically predicted poor outcome for patients with high risk score. These eight-gene also showed a significantly higher methylation level in tumor tissues than their corresponding normal samples in all patients analyzed. In addition, we also detected an inverse correlation between CpG hypermethylation and the mRNA expression level of SOX17 gene in ESCC patients, indicating that DNA hypermethylation was responsible for decreased expression of SOX17. CONCLUSIONS: This study established a proof-of-concept CpG methylation biomarker panel for ESCC prognosis that can be further validated by multiple cohort studies. Functional characterization of the eight prognostic methylation genes in our biomarker panel could help to dissect the mechanism of ESCC tumorigenesis.
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Carcinoma de Células Escamosas/genética , Islas de CpG/genética , Metilación de ADN/genética , Neoplasias Esofágicas/genética , Proteínas de Neoplasias/biosíntesis , Adulto , Anciano , Biomarcadores de Tumor/genética , Carcinogénesis , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas de Esófago , Femenino , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Pronóstico , Regiones Promotoras GenéticasRESUMEN
Type 2 diabetes (T2D) and hypertension are common comorbidities and, along with hyperlipidemia, serve as risk factors for cardiovascular diseases. This study aimed to evaluate the predictive value of polygenic risk scores (PRSs) on cardiometabolic traits related to T2D, hypertension, and hyperlipidemia and the incidence of these three diseases in Taiwan Biobank samples. Using publicly available, large-scale genome-wide association studies summary statistics, we constructed cross-ethnic PRSs for T2D, hypertension, body mass index, and nine quantitative traits typically used to define the three diseases. A composite PRS (cPRS) for each of the nine traits was constructed by aggregating the significant PRSs of its genetically correlated traits. The associations of each of the nine traits at baseline as well as the change of trait values during a 3- to 6-year follow-up period with its cPRS were evaluated. The predictive performances of cPRSs in predicting future incidences of T2D, hypertension, and hyperlipidemia were assessed. The cPRSs had significant associations with baseline and changes of trait values in 3-6 years and explained a higher proportion of variance for all traits than individual PRSs. Furthermore, models incorporating disease-related cPRSs, along with clinical features and relevant trait measurements achieved area under the curve values of 87.8%, 83.7%, and 75.9% for predicting future T2D, hypertension, and hyperlipidemia in 3-6 years, respectively.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Hiperlipidemias , Hipertensión , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Puntuación de Riesgo Genético , Bancos de Muestras Biológicas , Estudio de Asociación del Genoma Completo , Taiwán/epidemiología , Hipertensión/epidemiología , Enfermedades Cardiovasculares/diagnóstico , Hiperlipidemias/epidemiologíaRESUMEN
Lung cancer in never smokers (LCINS) accounts for up to 25% of all lung cancers and has been associated with exposure to secondhand tobacco smoke and air pollution in observational studies. Here, we evaluate the mutagenic exposures in LCINS by examining deep whole-genome sequencing data from a large international cohort of 871 treatment-naïve LCINS recruited from 28 geographical locations within the Sherlock-Lung study. KRAS mutations were 3.8-fold more common in adenocarcinomas of never smokers from North America and Europe, while a 1.6-fold higher prevalence of EGFR and TP53 mutations was observed in adenocarcinomas from East Asia. Signature SBS40a, with unknown cause, was found in most samples and accounted for the largest proportion of single base substitutions in adenocarcinomas, being enriched in EGFR-mutated cases. Conversely, the aristolochic acid signature SBS22a was almost exclusively observed in patients from Taipei. Even though LCINS exposed to secondhand smoke had an 8.3% higher mutational burden and 5.4% shorter telomeres, passive smoking was not associated with driver mutations in cancer driver genes or the activities of individual mutational signatures. In contrast, patients from regions with high levels of air pollution were more likely to have TP53 mutations while exhibiting shorter telomeres and an increase in most types of somatic mutations, including a 3.9-fold elevation of signature SBS4 (q-value=3.1 × 10-5), previously linked mainly to tobacco smoking, and a 76% increase of clock-like signature SBS5 (q-value=5.0 × 10-5). A positive dose-response effect was observed with air pollution levels, which correlated with both a decrease in telomere length and an elevation in somatic mutations, notably attributed to signatures SBS4 and SBS5. Our results elucidate the diversity of mutational processes shaping the genomic landscape of lung cancer in never smokers.