RESUMEN
Genome-wide association studies (GWASs) underlying case-control design have uncovered hundreds of genetic loci involved in tumorigenesis and provided rich resources for identifying risk factors and biomarkers associated with cancer susceptibility. However, the application of GWAS in determining the genetic architecture of cancer survival remains unestablished. Here, we systematically evaluated genetic effects at the genome-wide level on cancer survival that included overall survival (OS) and cancer-specific survival (CSS), leveraging data deposited in the UK Biobank cohort of a total of 19 628 incident patients across 17 cancer types. Furthermore, we assessed the causal effects of risk factors and circulating biomarkers on cancer prognosis via a Mendelian randomization (MR) analytic framework, which integrated cancer survival GWAS dataset, along with phenome-wide association study (PheWAS) and blood genome-wide gene expression/DNA methylation quantitative trait loci (eQTL/meQTL) datasets. On average, more than 10 traits, 700 genes, and 4,500 CpG sites were prone to cancer prognosis. Finally, we developed a user-friendly online database, SUrvival related cancer Multi-omics database via MEndelian Randomization (SUMMER; http://njmu-edu.cn:3838/SUMMER/), to help users query, browse, and download cancer survival results. In conclusion, SUMMER provides an important resource to assist the research community in understanding the genetic mechanisms of cancer survival.
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Estudio de Asociación del Genoma Completo , Neoplasias , Humanos , Estudio de Asociación del Genoma Completo/métodos , Análisis de la Aleatorización Mendeliana/métodos , Biomarcadores , Factores de Riesgo , Neoplasias/genética , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Early-onset prostate cancer (EOPC, ≤ 55 years) has a unique clinical entity harboring high genetic risk, but the majority of EOPC patients still substantial opportunity to be early-detected thus suffering an unfavorable prognosis. A refined understanding of age-based polygenic risk score (PRS) for prostate cancer (PCa) would be essential for personalized risk stratification. METHODS: We included 167,517 male participants [4882 cases including 205 EOPC and 4677 late-onset PCa (LOPC)] from UK Biobank. A General-, an EOPC- and an LOPC-PRS were derived from age-specific genome-wide association studies. Weighted Cox proportional hazard models were applied to estimate the risk of PCa associated with PRSs. The discriminatory capability of PRSs were validated using time-dependent receiver operating characteristic (ROC) curves with additional 4238 males from PLCO and TCGA. Phenome-wide association studies underlying Mendelian Randomization were conducted to discover EOPC linking phenotypes. RESULTS: The 269-PRS calculated via well-established risk variants was more strongly associated with risk of EOPC [hazard ratio (HR) = 2.35, 95% confidence interval (CI) 1.99-2.78] than LOPC (HR = 1.95, 95% CI 1.89-2.01; I2 = 79%). EOPC-PRS was dramatically related to EOPC risk (HR = 4.70, 95% CI 3.98-5.54) but not to LOPC (HR = 0.98, 95% CI 0.96-1.01), while LOPC-PRS had similar risk estimates for EOPC and LOPC (I2 = 0%). Particularly, EOPC-PRS performed optimal discriminatory capability for EOPC (area under the ROC = 0.613). Among the phenomic factors to PCa deposited in the platform of ProAP (Prostate cancer Age-based PheWAS; https://mulongdu.shinyapps.io/proap ), EOPC was preferentially associated with PCa family history while LOPC was prone to environmental and lifestyles exposures. CONCLUSIONS: This study comprehensively profiled the distinct genetic and phenotypic architecture of EOPC. The EOPC-PRS may optimize risk estimate of PCa in young males, particularly those without family history, thus providing guidance for precision population stratification.
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Puntuación de Riesgo Genético , Neoplasias de la Próstata , Humanos , Masculino , Estudio de Asociación del Genoma Completo , Estudios de Cohortes , Factores de Riesgo , Predisposición Genética a la EnfermedadRESUMEN
OBJECTIVES: We aimed to evaluate the efficacy of anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody therapy by assessing the hyper-enhanced rim phenomenon of hepatocellular carcinoma (HCC) on Sonazoid-contrast-enhanced ultrasound (CEUS) Kupffer phase images. METHODS: This retrospective study included 61 patients with HCC who received anti-PD-1/PD-L1 antibody therapy from August 1, 2020, to January 31, 2022. We compared the progression-free survival (PFS) of patients with hyper-enhanced rim+ and hyper-enhanced rim-nodules and the time to nodule progression (TTnP) of hyper-enhanced rim+ and hyper-enhanced rim- nodules. RESULTS: Thirty-nine patients received postoperative therapy, and 22 patients had unresectable HCC. The mean PFS was 11.8 months (95% confidence interval [CI]: 8.7-14.9) for patients with hyper-enhanced rim+ HCC nodules and 16.5 months (95% CI: 14.9-18.1) for patients with hyper-enhanced rim- HCC nodules in the surgery group (p = 0.017). The mean PFS was 9.2 months (95% CI: 3.6-14.8) for patients with hyper-enhanced rim+ HCC nodules and 17.8 months (95% CI: 14.9-20.6) for patients with hyper-enhanced rim- HCC nodules in the non-surgery group (p = 0.015). For hyper-enhanced rim+ HCC nodules, TTnP for each nodule exceeding the specified threshold was 10.1 months, whereas that for hyper-enhanced rim- HCC nodules was 17.6 months (p = 0 .018). The disease control rate was 42.9% (3/7) for hyper-enhanced rim+ HCC nodules and 85.7% (21/24) for hyper-enhanced rim- HCC nodules (p = 0.013). CONCLUSIONS: The presence of hyper-enhanced rim on the Kupffer phase images obtained via the non-invasive Sonazoid-CEUS is a promising imaging biomarker for predicting unfavorable response with anti-PD-1/PD-L1 therapy in patients with HCC. KEY POINTS: ⢠The mean progression-free survival was 11.8 months for patients with hyper-enhanced rim+ HCC nodules and 16.5 months for patients with hyper-enhanced rim- HCC nodules in the surgery group. ⢠The mean progression-free survival was 9.2 months for patients with hyper-enhanced rim+ HCC nodules and 17.8 months for patients with hyper-enhanced rim- HCC nodules in the non-surgery group. ⢠The disease control rate was 42.9% for hyper-enhanced rim+ HCC nodules and 85.7% for hyper-enhanced rim- HCC nodules (p = 0.013).
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Inhibidores de Puntos de Control Inmunológico , Antígeno B7-H1 , Estudios Retrospectivos , Medios de ContrasteRESUMEN
PIWI-interacting RNAs (piRNAs) are an emerging class of non-coding RNAs involved in tumorigenesis. Expression quantitative trait locus (eQTL) analysis has been demonstrated to help reveal the genetic mechanism of single nucleotide polymorphisms (SNPs) in cancer etiology. However, there are no databases that have been constructed to provide an eQTL analysis between SNPs and piRNA expression. In this study, we collected genotyping and piRNA expression data for 10 997 samples across 33 cancer types from The Cancer Genome Atlas (TCGA). Using linear regression cis-eQTL analysis with adjustment of appropriate covariates, we identified millions of SNP-piRNA pairs in tumor (76 924 831) and normal (24 431 061) tissues. Further, we performed differential expression and survival analyses, and linked the eQTLs to genome-wide association study (GWAS) data to comprehensively decipher the functional roles of identified cis-piRNA eQTLs. Finally, we developed a user-friendly database, piRNA-eQTL (http://njmu-edu.cn:3838/piRNA-eQTL/), to help users query, browse and download corresponding eQTL results. In summary, piRNA-eQTL could serve as an important resource to assist the research community in understanding the roles of genetic variants and piRNAs in the development of cancers.
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Regulación Neoplásica de la Expresión Génica/genética , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , ARN Neoplásico/genética , ARN Interferente Pequeño/biosíntesis , Bases de Datos Genéticas , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Estimación de Kaplan-Meier , Neoplasias/genética , Neoplasias/mortalidad , ARN Interferente Pequeño/genética , Interfaz Usuario-ComputadorRESUMEN
BACKGROUND: The association between vitamin E and cancer risk has been widely investigated by observational studies, but the findings remain inconclusive. Here, we aimed to evaluate the causal effect of circulating vitamin E on the risk of ten common cancers, including bladder, breast, colorectal, esophagus, lung, oral and pharynx, ovarian, pancreatic, prostate, and kidney cancer. METHODS: A Mendelian randomization (MR) analytic framework was applied to data from a cancer-specific genome-wide association study (GWAS) comprising a total of 297,699 cancer cases and 304,736 controls of European ancestry. Three genetic instrumental variables associated with circulating vitamin E were selected. Summary statistic-based methods of inverse variance weighting (IVW) and likelihood-based approach, as well as the individual genotyping-based method of genetic risk score (GRS) were used. Multivariable IVW analysis was further performed to control for potential confounding effects. Furthermore, the UK Biobank cohort was used as external validation, supporting 355,543 European participants (incident cases ranged from 437 for ovarian cancer to 4882 for prostate cancer) for GRS-based estimation of circulating vitamin E, accompanied by a one-sample MR analysis of dietary vitamin E intake underlying the time-to-event analytic framework. RESULTS: Specific to cancer GWAS, we found that circulating vitamin E was significantly associated with increased bladder cancer risk (odds ratios [OR]IVW = 6.23, PIVW = 3.05×10-3) but decreased breast cancer risk (ORIVW = 0.68, PIVW = 8.19×10-3); however, the significance of breast cancer was dampened (Pmultivariable IVW > 0.05) in the subsequent multivariable MR analysis. In the validation stage of the UK Biobank cohort, we did not replicate convincing causal effects of genetically predicted circulating vitamin E concentrations and dietary vitamin E intake on the risk of ten cancers. CONCLUSIONS: This large-scale population study upon data from cancer-specific GWAS and a longitudinal biobank cohort indicates plausible non-causal associations between circulating vitamin E and ten common cancers in the European populations. Further studies regarding ancestral diversity are warranted to validate such causal associations.
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Neoplasias de la Mama , Análisis de la Aleatorización Mendeliana , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Funciones de Verosimilitud , Estudios Longitudinales , Masculino , Polimorfismo de Nucleótido Simple/genética , Vitamina ERESUMEN
SUMMARY: Colorectal cancer is a heterogeneous disease with diverse prognoses between left-sided and right-sided patients; therefore, it is necessary to precisely evaluate the survival probability of side-specific colorectal cancer patients. Here, we collected multi-omics data from The Cancer Genome Atlas program, including gene expression, DNA methylation and microRNA expression. Specificity measure and robust likelihood-based survival analysis were used to identify 6 left-sided and 28 right-sided prognostic biomarkers. Compared to the performance of clinical prognostic models, the addition of these biomarkers could significantly improve the discriminatory ability and calibration in predicting side-specific 5-year survival for colorectal cancer. Additional dataset derived from Gene Expression Omnibus was used to validate the prognostic value of side-specific genes. Finally, we constructed colorectal cancer side-specific molecular database (CoSMeD), a user-friendly interface for estimating side-specific colorectal cancer 5-year survival probability, which can lay the basis for personalized management of left-sided and right-sided colorectal cancer patients. AVAILABILITY AND IMPLEMENTATION: CoSMeD is freely available at https://mulongdu.shinyapps.io/cosmed. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Neoplasias Colorrectales , Metilación de ADN , Humanos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Computadores , Funciones de Verosimilitud , Análisis de Supervivencia , Multiómica , Biomarcadores de Tumor , Bases de Datos FactualesRESUMEN
Choline metabolism alteration is considered as a metabolic hallmark in cancer, reflecting the complex interactions between carcinogenic signaling pathways and cancer metabolism, but little is known about whether genetic variants in the metabolism pathway contribute to the susceptibility of bladder cancer. Herein, a case-control study comprising 580 patients and 1,101 controls was carried out to analyze the association of bladder cancer with genetic variants on candidate genes involved in the choline metabolism pathway using unconditional logistic regression. Gene expression data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were applied for differential gene expression analysis. Cox regression was also applied to estimate the role of candidate genes on bladder cancer prognosis. Our results demonstrated that C allele of rs6810830 in ENPP6 was a significant protective allele of bladder cancer, compared to the T allele [Odds ratio (OR) = 0.74, 95% confidence interval (CI) = 0.64-0.86, P = 7.14 × 10-5 in additive model]. Besides, we also found that the expression of ENPP6 remarkably decreased in bladder tumors compared with normal tissues. Moreover, high expression of ENPP6 was associated with worse overall survival (OS) in bladder cancer patients [hazard ratio (HR) with their 95% CI 1.39 (1.02-1.90), P = 0.039]. In conclusion, our results suggested that SNP rs6810830 (T > C) in ENPP6 might be a potential susceptibility loci for bladder cancer, and these findings provided novel insights into the underlying mechanism of choline metabolism in cancers.
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Neoplasias de la Vejiga Urinaria , Estudios de Casos y Controles , China , Colina , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Cancer is a leading cause of death worldwide, particularly because of its high mortality rate in patients who are diagnosed at late stages. Conventional biomarkers originating from blood are widely used for cancer diagnosis, but their low sensitivity and specificity limit their widespread application in cancer screening among the general population. Currently, emerging studies are exploiting novel, highly-accurate biomarkers in human body fluids that are obtainable through minimally invasive techniques, which is defined as liquid biopsy. Circular RNAs (circRNAs) are a newly discovered class of noncoding RNAs generated mainly by pre-mRNA splicing. Following the rapid development of high-throughput transcriptome analysis techniques, numerous circRNAs have been recognized to exist stably and at high levels in body fluids, including plasma, serum, exosomes, and urine. CircRNA expression patterns exhibit distinctly differences between patients with cancer and healthy controls, suggesting that circRNAs in body fluids potentially represent novel biomarkers for monitoring cancer development and progression. In this study, we summarized the expression of circRNAs in body fluids in a pan-cancer dataset and characterized their clinical applications in liquid biopsy for cancer diagnosis and prognosis. In addition, a user-friendly web interface was developed to visualize each circRNA in fluids ( https://mulongdu.shinyapps.io/circrnas_in_fluids/ ).
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Biomarcadores de Tumor/metabolismo , Líquidos Corporales/metabolismo , Biopsia Líquida , ARN Circular/metabolismo , Bases de Datos Genéticas , Humanos , Modelos BiológicosRESUMEN
BACKGROUND: An angiomyolipoma usually occurs in the kidneys and rarely in the liver. Hepatic epithelioid angiomyolipoma (HEAML), a rare variant of angiomyolipoma, possesses malignant potential and mimics the imaging features of hepatocellular carcinoma. Sonazoid® (perfluorobutane microbubbles), a new contrast agent that facilitates hepatic parenchyma-specific Kupffer phase imaging on contrast-enhanced ultrasonography (CEUS), is useful for the detection and characterization of focal liver lesions. CASE PRESENTATION: A 30-year-old man with HEAML underwent CEUS using Sonazoid®, in which new concepts for ultrasonography-based differentiation between HEAML and hepatocellular carcinoma were applied. CONCLUSIONS: This case report provides clinicians and radiologists with a reference for distinguishing HEAML from hepatocellular carcinoma based on CEUS using Sonazoid®.
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Angiomiolipoma , Medios de Contraste , Adulto , Angiomiolipoma/diagnóstico por imagen , Compuestos Férricos , Humanos , Hierro , Óxidos , UltrasonografíaRESUMEN
Vitamin E is effective for preventing the risk of cancer. However, few studies have elucidated the mechanism of vitamin E in cancer occurrence. Herein, we aimed to identify the genetic variants in vitamin E-related pathway genes associated with colorectal cancer risk. We applied logistic regression models to assess the association between single-nucleotide polymorphisms (SNPs) in vitamin E-related pathway genes and colorectal cancer risk in the Chinese and European population. The false discovery rate (FDR) method was used to correct multiple comparisons. The mRNA and protein expression analysis were evaluated in public database and in-house RNA-Seq data. SCARB1 rs73227586 was identified significantly increased risk of colorectal cancer in the Chinese population (odd ratio (OR) = 1.46, 95% confidence interval (CI) = 1.22-1.75, P = 2.99 × 10-5). This finding was further validated in the European population (OR = 1.11, 95% CI = 1.02-1.20, P = 1.44 × 10-2). Additionally, the mRNA and protein expression of SCARB1 were markedly up-regulated in colorectal tumor tissues. Moreover, rs73227586 T allele could increase the minimum free energy (MFE) and weaken binding ability to transcription factor ELL2. Our findings indicated that SCARB1 may play a carcinogenic role in colorectal cancer. Genetic variants in vitamin E-related pathway genes may concern to be predictors of colorectal cancer risk.
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Neoplasias Colorrectales , Predisposición Genética a la Enfermedad , Estudios de Casos y Controles , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Humanos , Polimorfismo de Nucleótido Simple , Factores de Elongación Transcripcional/genética , Vitamina ERESUMEN
The programmed cell death-1 (PD-1)/cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint pathways serve as targets of immunotherapy for colorectal cancer. However, the associations between genetic variations in these pathways and colorectal cancer risk, prognosis, and immune status remain unclear. The associations between single-nucleotide polymorphisms (SNPs) and colorectal cancer risk and survival were evaluated in a case-control study comprising 1150 cases and 1342 controls along with 287 cases with overall survival information. We found that individuals with the A allele of B7-2 rs2681416 in CTLA-4 immune checkpoint pathway had a significantly increased risk of colorectal cancer [odds ratio (OR) = 1.37, P = 3.17 × 10-4] than those with G allele under the dominant model, which had a predominant site-specific effect in colon cancer (OR = 1.55, P = 3.11 × 10-5). In addition, rs2681416 significantly decreased the overall survival time of patients with colon cancer [hazard ratio (HR) = 1.96, P = 1.10 × 10-2], but not of patients with rectal cancer (P = 0.271). Moreover, rs2681416 had an expression quantitative trait locus effect on the B7-2 flanking gene IQCB1 in colon tissues, which contributed to colon cancer risk by regulating genome organization and influenced the expression of IQCB1 in an allele-specific manner. IQCB1 expression was upregulated in colorectal cancer tissues compared with normal tissues, accounting for various critical carcinogenic states in colon cancer and promoting immune infiltration of Th17 cells in the tumor microenvironment. Our study highlights the important roles of genetic variations in immune checkpoint pathways and provides new insight into potential site-specific independent biomarkers for colorectal cancer susceptibility, prognosis, and tumor immune status.
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Antígeno CTLA-4/genética , Proteínas de Unión a Calmodulina/genética , Neoplasias del Colon/patología , Microambiente Tumoral/inmunología , Adulto , Anciano , Biomarcadores de Tumor , Antígeno CTLA-4/inmunología , Estudios de Casos y Controles , Neoplasias del Colon/genética , Neoplasias del Colon/inmunología , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Pronóstico , Tasa de Supervivencia , Células Th17/inmunología , Regulación hacia Arriba/genéticaRESUMEN
The Hippo signalling pathway plays a crucial role in carcinogenesis. Therefore, we hypothesized that genetic variants in genes related to this pathway are associated with the colorectal cancer risk. A case-control study including 1150 patients and 1342 controls was performed to assess the association of genetic variants of genes involved in the Hippo signalling pathway with the risk of colorectal cancer. The results were corrected for multiple comparisons using the false discovery rate (FDR). We used a regression model to determine the effects of single-nucleotide polymorphisms (SNPs) on the survival of patients with colorectal cancer in The Cancer Genome Atlas (TCGA) datasets. An expression quantitative trait loci (eQTL) analysis was performed using TCGA datasets and the Genotype-Tissue Expression (GTEx) project. Gene Expression Omnibus (GEO) datasets were used to provide additional data on the expression of genes in colorectal cancer. The SCRIB rs13251492 G allele was associated with a significantly decreased risk of colorectal cancer (odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.70-0.89, P = 7.76 × 10-5, P(FDR) = 6.98 × 10-4). Patients with the rs13251492 AG/GG allele experienced a longer recurrence-free survival (RFS) time (hazard ratio (HR) = 0.64, 95% CI = 0.42-0.99, P = 0.049) than patients with the rs13251492 A allele. The eQTL analysis revealed a significant association between rs13251492 and the expression of the SCRIB mRNA in colorectal tumors. Dual-luciferase reporter assays in DLD-1 and HCT116 cells revealed a lower enhancer activity of the rs13251492 G allele than the A allele. In addition, the SCRIB mRNA was expressed at markedly higher levels in colorectal cancer tissues than in normal tissues. Therefore, we identified the SCRIB rs13251492 variant as a novel colorectal cancer susceptibility locus and provided evidence of its functional relevance.
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Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Proteínas de la Membrana/genética , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal/genética , Proteínas Supresoras de Tumor/genética , Estudios de Casos y Controles , China , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Bases de Datos Genéticas , Femenino , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Vía de Señalización Hippo , Humanos , Masculino , Fenotipo , Sitios de Carácter Cuantitativo , Medición de Riesgo , Factores de RiesgoRESUMEN
Gastric cancer (GC) is a heterogeneous tumour with numerous differences of epidemiologic and clinicopathologic features between cardia cancer and non-cardia cancer. However, few studies were performed to construct site-specific GC prognostic models. In this study, we identified site-specific GC transcriptomic prognostic biomarkers using genetic algorithm (GA)-based support vector machine (GA-SVM) and GA-based Cox regression method (GA-Cox) in the Cancer Genome Atlas (TCGA) database. The area under time-dependent receive operating characteristic (ROC) curve (AUC) regarding 5-year survival and concordance index (C-index) was used to evaluate the predictive ability of Cox regression models. Finally, we identified 10 and 13 prognostic biomarkers for cardia cancer and non-cardia cancer, respectively. Compared to traditional models, the addition of these site-specific biomarkers could notably improve the model preference (cardia: AUCtraditional vs AUCcombined = 0.720 vs 0.899, P = 8.75E-08; non-cardia: AUCtraditional vs AUCcombined = 0.798 vs 0.994, P = 7.11E-16). The combined nomograms exhibited superior performance in cardia and non-cardia GC survival prediction (C-indexcardia = 0.816; C-indexnoncardia = 0.812). We also constructed a user-friendly GC site-specific molecular system (GC-SMS, https://njmu-zhanglab.shinyapps.io/gc_sms/), which is freely available for users. In conclusion, we developed site-specific GC prognostic models for predicting cardia cancer and non-cardia cancer survival, providing more support for the individualized therapy of GC patients.
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Algoritmos , Biomarcadores de Tumor/genética , Cardias/patología , Regulación Neoplásica de la Expresión Génica , Nomogramas , Neoplasias Gástricas/patología , Transcriptoma , Cardias/metabolismo , Estudios de Casos y Controles , Biología Computacional , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pronóstico , Curva ROC , Neoplasias Gástricas/genética , Tasa de SupervivenciaRESUMEN
Circular RNAs (circRNAs) are an intriguing class of regulatory RNAs involved in the tumorigenesis of many cancers, including colorectal cancer. Mechanistically, circRNAs sponge microRNAs (miRNAs) with specific miRNA response elements (MREs) and compete for regulatory target genes downstream. However, the genetic effects of MREs on colorectal cancer susceptibility remain unclear. The MREs of colorectal cancer-associated circRNAs (CRC-circRNAs) and corresponding single nucleotide polymorphisms (SNPs) were identified by the transcriptome of cancer cells and the 1000 Genomes Project. The association between candidate SNPs and colorectal cancer risk was evaluated in a Chinese population (1150 cases and 1342 controls) and two European populations (9023 cases and 386,896 controls) using logistic regression analysis. Among the 197 candidate SNPs within MREs of 186 CRC-circRNAs, rs25497 in circTUBB was significantly associated with colorectal cancer risk in a Chinese population after false discovery rate (FDR) correction [odds ratio (OR) = 1.78, 95% confidence interval (CI) = 1.44-2.21, P = 1.42 × 10-7, PFDR = 2.80 × 10-5] and even reached significance in a genome-wide association study (GWAS) under the dominant model (P = 1.28 × 10-8). Similar results were found in the European populations (ORmeta = 1.30, 95% CI = 1.10-1.53). Both stratification and interaction analyses revealed that rs25497 interacting with smoking affected the colorectal cancer risk (Pinteraction = 1.48 × 10-2). Here, we first comprehensively identified genetic variants in MREs of CRC-circRNAs and evaluated their effects on colorectal cancer risk in both Chinese and European populations. These findings provide basis for a comprehensive understanding of colorectal cancer etiology.
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Neoplasias Colorrectales/genética , ARN Circular/genética , Fumar/genética , Anciano , Pueblo Asiatico/genética , Estudios de Casos y Controles , Femenino , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Células HT29 , Humanos , Masculino , MicroARNs , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Elementos de Respuesta , Fumar/efectos adversos , Población Blanca/genéticaRESUMEN
The dysregulation of Ras/Raf/MEK/ERK pathway governs occurrence and progression of cancers. In previous studies, genome-wide association studies (GWAS) have identified multiple gene loci related to gastric cancer. However, a great many genetic loci have been missed due to multiple statistical comparisons of GWAS. In this study, Multi-marker Analysis of GenoMic Annotation (MAGMA) was applied to analyze genes in Ras/Raf/MEK/ERK pathway and their single nucleotide polymorphisms (SNPs) based on Chinese GWAS including 1625 gastric cancer cases and 2100 controls. The SNP effects on gastric cancer susceptibility were calculated on the basis of a logistic regression model. Expression quantitative trait loci (eQTL) analysis was performed based on the genotype-tissue expression (GTEx) project. We identified that three SNPs in MAP2K1, rs4287513, rs76906202 and rs11631448 were markedly associated with gastric cancer risk (rs4287513: OR = 1.30, 95% CI = 1.10-1.54, P = 1.92 × 10-3; rs76906202: OR = 0.87, 95% CI = 0.79-0.96, P = 3.72 × 10-3; rs11631448: OR = 1.21, 95% CI = 1.05-1.39, P = 6.74 × 10-3). All the loci were eQTLs for MAP2K1 in normal gastric samples. Moreover, the low expression of MAP2K1 was significantly associated with poor survival in gastric cancer patients. Thus, MAP2K1 might represent a key gene related to gastric cancer in Ras/Raf/MEK/ERK pathway, whereas SNPs in MAP2K1 confer gastric cancer susceptibility by having biological effects on the MAP2K1 expression.
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MAP Quinasa Quinasa 1/genética , Polimorfismo de Nucleótido Simple , Neoplasias Gástricas/genética , Pueblo Asiatico/genética , Estudios de Casos y Controles , China , Bases de Datos Genéticas , Quinasas MAP Reguladas por Señal Extracelular/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Sitios de Carácter Cuantitativo , Medición de Riesgo , Factores de Riesgo , Transducción de Señal , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/etnologíaRESUMEN
Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk, but whether these SNPs have additive effects on the risk of CRC remains unclear. We performed a systematic analysis of GWAS-identified SNPs using GWAS datasets from China (2,248 patients and 3,173 controls) and Europe (4,461 patients and 4,140 controls). We analyzed 58 independent variants from DNA samples from Chinese populations and found 19 SNPs that were significantly associated with CRC risk. We identified two genetic risk scores (GRSs) based on 58 and 19 SNPs, which were significantly associated with an increased risk of CRC. A decision curve analysis showed higher predictive power for the 58 SNPs. Using all the 58 SNPs to assess 5-year absolute risk (AR), we found that, at a cutoff of 0.4% (two times the median AR) and 0.6% (three times the median AR), approximately 32.76 and 16.45% of Chinese individuals were grouped as high risk for developing CRC, respectively. Risk stratification analysis further indicated that the population in the top 30% risk group accounted for 46.71% of the CRC cases. In addition, the 58 SNPs could explain approximately 1.13% of the phenotypic variance in Chinese populations. Similar findings were found in European populations. Combinations of SNPs identified in GWASs may therefore be useful for identifying individuals at high risk for CRC.
Asunto(s)
Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Adulto , Anciano , Estudios de Casos y Controles , China/epidemiología , Estudios de Cohortes , Neoplasias Colorrectales/epidemiología , Europa (Continente)/epidemiología , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Medición de Riesgo/métodos , Factores de RiesgoRESUMEN
Although gastric cancer (GC) in young adults (≤ 45 years) accounts for fewer than 10% of newly diagnosed cases, the young patients are more likely to have advanced disease at presentation compared with elderly patients. Previous studies have identified that the DNA methylation of genomes are different during aging. Our study aimed to explore the association between DNA methylation and the onset of GC. We applied Illumina HumanMethylation450 BeadChip to examine methylation expression profiles and compared methylation expression patterns in five early onset GC patients and seven elderly patients. Additionally, we evaluated the associations of methylation expression with different clinicopathological characteristics of GC. Our results showed that the pattern of genome-wide methylation expression was significantly different between early onset and elderly GC. The top 10 hypomethylation and hypermethylation CpG sites were selected for further analyses in The Cancer Genome Atlas (TCGA) database. We found that the hypermethylation of cg11037477, located at the promoter of EIF4E, was significantly associated with age at diagnosis and the expression of EIF4E. Besides, GC patients with high level of cg11037477 were more likely to have advance disease with T3/T4 invasion and III/IV stage. The cg11037477 hypermethylation and EIF4E down-expression were significantly related to poor survival of GC patients. Our study provides new insights into the molecular mechanism of early onset patients with GC and suggests that methylation of cg11037477 and expression of EIF4E may act as prognostic markers in GC.
Asunto(s)
Metilación de ADN/genética , Factor 4E Eucariótico de Iniciación/genética , Regiones Promotoras Genéticas/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Adulto , Edad de Inicio , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/mortalidadRESUMEN
Obesity is correlated with increased colorectal cancer (CRC) risk, but few studies have investigated lifetime body mass index (BMI) metrics and CRC risk. In a cohort of 139 229 subjects in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we analysed the effects of life-course BMI trajectories on CRC risk. At 13 years of follow-up, 2031 subjects developed CRC. Compared with subjects who were never overweight/obese, subjects who first exceeded the threshold of 25 kg m-2 at age 20 had a higher CRC risk (HR = 1.28, 95% confidence interval (CI) = 1.11-1.48). A body weight gain of ≥15 kg between 20 and 50 years of age (HR = 1.34, 95% CI = 1.18-1.52) and baseline (HR = 1.24, 95% CI = 1.08-1.43) was significantly associated with increased CRC risk. BMI trajectory analyses revealed that the CRC risk increased gradually over the three BMI trajectories (HR = 1.11-1.27, Ptrend = 0.005) compared with subjects who maintained a normal BMI. Being overweight/obese at the onset of adulthood and BMI trajectories over the lifespan that result in obesity lead to an increased CRC risk.