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BACKGROUND & AIMS: We developed comprehensive models to determine risk of Barrett's esophagus (BE) or esophageal adenocarcinoma (EAC) based on genetic and non-genetic factors. METHODS: We used pooled data from 3288 patients with BE, 2511 patients with EAC, and 2177 individuals without either (controls) from participants in the international Barrett's and EAC consortium as well as the United Kingdom's BE gene study and stomach and esophageal cancer study. We collected data on 23 genetic variants associated with risk for BE or EAC, and constructed a polygenic risk score (PRS) for cases and controls by summing the risk allele counts for the variants weighted by their natural log-transformed effect estimates (odds ratios) extracted from genome-wide association studies. We also collected data on demographic and lifestyle factors (age, sex, smoking, body mass index, use of nonsteroidal anti-inflammatory drugs) and symptoms of gastroesophageal reflux disease (GERD). Risk models with various combinations of non-genetic factors and the PRS were compared for their accuracy in identifying patients with BE or EAC using the area under the receiver operating characteristic curve (AUC) analysis. RESULTS: Individuals in the highest quartile of risk, based on genetic factors (PRS), had a 2-fold higher risk of BE (odds ratio, 2.22; 95% confidence interval, 1.89-2.60) or EAC (odds ratio, 2.46; 95% confidence interval, 2.07-2.92) than individual in the lowest quartile of risk based on PRS. Risk models developed based on only demographic or lifestyle factors or GERD symptoms identified patients with BE or EAC with AUC values ranging from 0.637 to 0.667. Combining data on demographic or lifestyle factors with data on GERD symptoms identified patients with BE with an AUC of 0.793 and patients with EAC with an AUC of 0.745. Including PRSs with these data only minimally increased the AUC values for BE (to 0.799) and EAC (to 0.754). Including the PRSs in the model developed based on non-genetic factors resulted in a net reclassification improvement for BE of 3.0% and for EAC of 5.6%. CONCLUSIONS: We used data from 3 large databases of patients from studies of BE or EAC to develop a risk prediction model based on genetic, clinical, and demographic/lifestyle factors. We identified a PRS that increases discrimination and net reclassification of individuals with vs without BE and EAC. However, the absolute magnitude of improvement is not sufficient to justify its clinical use.
Assuntos
Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Esôfago de Barrett/epidemiologia , Esôfago de Barrett/genética , Técnicas de Apoio para a Decisão , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Adenocarcinoma/diagnóstico , Área Sob a Curva , Austrália/epidemiologia , Esôfago de Barrett/diagnóstico , Estudos de Casos e Controles , Bases de Dados Factuais , Neoplasias Esofágicas/diagnóstico , Europa (Continente)/epidemiologia , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Estilo de Vida , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Herança Multifatorial , América do Norte/epidemiologia , Razão de Chances , Fenótipo , Valor Preditivo dos Testes , Curva ROC , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for esophageal adenocarcinoma (EA) and Barrett's esophagus (BE). However, variants in these loci account for a small fraction of cases of EA and BE. Genetic factors might interact with environmental factors to affect risk of EA and BE. We aimed to identify single nucleotide polymorphisms (SNPs) that may modify the associations of body mass index (BMI), smoking, and gastroesophageal reflux disease (GERD), with risks of EA and BE. METHODS: We collected data on single BMI measurements, smoking status, and symptoms of GERD from 2284 patients with EA, 3104 patients with BE, and 2182 healthy individuals (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium GWAS, the UK Barrett's Esophagus Gene Study, and the UK Stomach and Oesophageal Cancer Study. We analyzed 993,501 SNPs in DNA samples of all study subjects. We used standard case-control logistic regression to test for gene-environment interactions. RESULTS: For EA, rs13429103 at chromosome 2p25.1, near the RNF144A-LOC339788 gene, showed a borderline significant interaction with smoking status (P = 2.18×10-7). Ever smoking was associated with an almost 12-fold increase in risk of EA among individuals with rs13429103-AA genotype (odds ratio=11.82; 95% CI, 4.03-34.67). Three SNPs (rs12465911, rs2341926, rs13396805) at chromosome 2q23.3, near the RND3-RBM43 gene, interacted with GERD symptoms (P = 1.70×10-7, P = 1.83×10-7, and P = 3.58×10-7, respectively) to affect risk of EA. For BE, rs491603 at chromosome 1p34.3, near the EIF2C3 gene, and rs11631094 at chromosome 15q14, at the SLC12A6 gene, interacted with BMI (P = 4.44×10-7) and pack-years of smoking history (P = 2.82×10-7), respectively. CONCLUSION: The associations of BMI, smoking, and GERD symptoms with risks of EA and BE appear to vary with SNPs at chromosomes 1, 2, and 15. Validation of these suggestive interactions is warranted.
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Adenocarcinoma/epidemiologia , Esôfago de Barrett/complicações , Esôfago de Barrett/epidemiologia , Exposição Ambiental , Neoplasias Esofágicas/epidemiologia , Predisposição Genética para Doença , Adenocarcinoma/etiologia , Idoso , Neoplasias Esofágicas/etiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco , Reino Unido/epidemiologiaRESUMO
OBJECTIVE: Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett's oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA. DESIGN: We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-κB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. RESULTS: We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10-5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk. CONCLUSIONS: This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1 influence disease susceptibility.
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Adenocarcinoma/genética , Esôfago de Barrett/genética , Neoplasias Esofágicas/genética , Mutação em Linhagem Germinativa , Glutationa Transferase/genética , Idoso , Citocinas/metabolismo , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA/metabolismo , Humanos , Inflamação/genética , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Estresse Oxidativo , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Prostaglandina-Endoperóxido Sintases/metabolismo , Fatores de Risco , Transdução de Sinais/genéticaRESUMO
BACKGROUND: Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs. METHODS: Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined. RESULTS: Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006). CONCLUSIONS: The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.
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Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Metástase Neoplásica/patologia , HumanosRESUMO
The strong male predominance in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic-epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene-based approach: versatile gene-based test association study. This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body-mass index, waist-to-hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p = 0.002) and in males (p = 0.003), but not in females separately (p = 0.3). This association was found in tobacco smokers (p = 0.003) and in BE patients without reflux (p = 0.004), but not in nonsmokers (p = 0.2) or those with reflux (p = 0.036). SNPs within JMJD1C were associated with risk of EAC in females (p = 0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed.
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Adenocarcinoma/genética , Esôfago de Barrett/genética , Neoplasias Esofágicas/genética , Predisposição Genética para Doença , Histona Desmetilases com o Domínio Jumonji/genética , Oxirredutases N-Desmetilantes/genética , Polimorfismo de Nucleotídeo Único , Esteroide 17-alfa-Hidroxilase/genética , Adenocarcinoma/etiologia , Adulto , Idoso , Esôfago de Barrett/etiologia , Neoplasias Esofágicas/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RiscoRESUMO
Incidence of esophageal adenocarcinoma (EA) in Western countries has increased markedly in recent decades. Although several risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), including reflux, Caucasian race, male gender, obesity, and smoking, less is known about the role of inherited genetic variation. Frequent somatic mutations in the tumor suppressor genes CDKN2A and TP53 were recently reported in EA tumors, while somatic alterations at 9p (CDKN2A) and 17p (TP53) have been implicated as predictors of progression from BE to EA. Motivated by these findings, we used data from a genome-wide association study of 2515 EA cases and 3207 controls to analyze 37 germline single nucleotide polymorphisms at the CDKN2A and TP53 loci. Three CDKN2A polymorphisms were nominally associated (P < 0.05) with reduced risk of EA: rs2518720 C>T [intronic, odds ratio 0.90, P = 0.0121, q = 0.3059], rs3088440 G>A (3'UTR, odds ratio 0.84, P = 0.0186, q = 0.3059), and rs4074785 C>T (intronic, odds ratio 0.85, P = 0.0248, q = 0.3059). None of the TP53 single nucleotide polymorphisms reached nominal significance. Two of the CDKN2A variants identified were also associated with reduced risk of progression from BE to EA, when assessed in a prospective cohort of 408 BE patients: rs2518720 (hazard ratio 0.57, P = 0.0095, q = 0.0285) and rs3088440 (hazard ratio 0.34, P = 0.0368, q = 0.0552). In vitro functional studies of rs3088440, a single nucleotide polymorphism located in the seed sequence of a predicted miR-663b binding site, suggested a mechanism whereby the G>A substitution may attenuate miR-663b-mediated repression of the CDKN2A transcript. This study provides the first evidence that germline variation at the CDKN2A locus may influence EA susceptibility.
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Adenocarcinoma/genética , Esôfago de Barrett/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Esofágicas/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Proteína Supressora de Tumor p53/genética , Adenocarcinoma/patologia , Idoso , Esôfago de Barrett/patologia , Estudos de Casos e Controles , Progressão da Doença , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Fatores de RiscoRESUMO
BACKGROUND & AIMS: Risks for some cancers increase with height. We investigated the relationship between height and risk of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE). METHODS: We analyzed epidemiologic and genome-wide genomic data from individuals of European ancestry in the Barrett's and Esophageal Adenocarcinoma Consortium, from 999 cases of EAC, 2061 cases of BE, and 2168 population controls. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for associations between height and risks of EAC and BE. We performed a Mendelian randomization analysis to estimate an unconfounded effect of height on EAC and BE using a genetic risk score derived from 243 genetic variants associated with height as an instrumental variable. RESULTS: Height was associated inversely with EAC (per 10-cm increase in height: OR, 0.70; 95% CI, 0.62-0.79 for men and OR, 0.57; 95% CI 0.40-0.80 for women) and BE (per 10-cm increase in height: OR, 0.69; 95% CI, 0.62-0.77 for men and OR, 0.61; 95% CI, 0.48-0.77 for women). The risk estimates were consistent across strata of age, education level, smoking, gastroesophageal reflux symptoms, body mass index, and weight. Mendelian randomization analysis yielded results quantitatively similar to those from the conventional epidemiologic analysis. CONCLUSIONS: Height is associated inversely with risks of EAC and BE. Results from the Mendelian randomization study showed that the inverse association observed did not result from confounding factors. Mechanistic studies of the effect of height on EAC and BE are warranted; height could have utility in clinical risk stratification.
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Adenocarcinoma/epidemiologia , Estatura , Neoplasias Esofágicas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Esôfago de Barrett/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
he colonization of the liver by colorectal cancer (CRC) cells is a complicated process which includes many stages, until macrometastases occur. The entrapment of malignant cells within the hepatic sinusoids and their interactions with resident non-parenchymal cells are considered very important for the whole metastatic sequence. In the sinusoids, cell connection and signalling is mediated by multiple cell adhesion molecules, such as the selectins. The three members of the selectin family, E-, P- and L-selectin, in conjunction with sialylated Lewis ligands and CD44 variants, regulate colorectal cell communication and adhesion with platelets, leucocytes, sinusoidal endothelial cells and stellate cells. Their role in CRC liver metastases has been investigated in animal models and human tissue, in vivo and in vitro, in static and shear flow conditions, and their key-function in several molecular pathways has been displayed. Therefore, trials have already commenced aiming to exploit selectins and their ligands in the treatment of benign and malignant diseases. Multiple pharmacological agents have been developed that are being tested for potential therapeutic applications.
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Neoplasias Colorretais , Ligantes , Neoplasias Hepáticas , Isoformas de Proteínas/metabolismo , Selectinas/metabolismo , Configuração de Carboidratos , Sequência de Carboidratos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Hexanos/química , Hexanos/metabolismo , Humanos , Antígenos CD15/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Manose/análogos & derivados , Manose/química , Manose/metabolismo , Dados de Sequência Molecular , Estrutura Molecular , Isoformas de Proteínas/genética , Selectinas/genética , Antígeno Sialil Lewis XRESUMO
OBJECTIVES: It is important to identify factors responsible for the development of Barrett's oesophagus (BO). The effect of proton pump inhibitors (PPIs) on oesophageal clearance of both acid and alkaline reflux in these patients is uncertain and studies comparing BO patients and healthy controls (HCs) have not been performed earlier. METHODS: Two groups of patients were studied: 18 HCs and 12 BO patients. Oesophageal motility, acid reflux and duodenogastro-oesophageal reflux (DGOR) were measured using a three-pressure transducer catheter with an antimony pH tip, connected to a sodium ion selective electrode. All patients were studied both on and off PPIs. RESULTS: Without PPI therapy, BO patients had significantly more upright and supine acid reflux and upright DGOR compared with HCs. During acid reflux, HC demonstrated more peristalsis than BO [HC, % peristalsis=64 (9), BO=53 (8), P<0.01], but this was not seen during DGOR. [HC, % peristalsis=68 (14), BO=56 (11)]. In Barrett's patients, DGOR was significantly reduced with PPIs [off PPI, % upright DGOR=61 (17), on PPIs=19 (15), P<0.01], and no oesophageal motility differences were seen compared with results without PPIs. CONCLUSION: HCs demonstrate better oesophageal motility compared with BO patients to prevent acid and alkaline reflux. When acid reflux occurred, HCs had better coordinated motility to remove it. This increased coordination did not occur during DGOR, suggesting different stimulation mechanisms. PPI reduced DGOR in BO patients, without any change in oesophageal motility.
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Esôfago de Barrett/complicações , Refluxo Gastroesofágico/etiologia , Refluxo Gastroesofágico/prevenção & controle , Inibidores da Bomba de Prótons/uso terapêutico , Adulto , Esôfago de Barrett/tratamento farmacológico , Esôfago de Barrett/fisiopatologia , Refluxo Duodenogástrico/etiologia , Refluxo Duodenogástrico/fisiopatologia , Refluxo Duodenogástrico/prevenção & controle , Monitoramento do pH Esofágico , Esôfago/fisiopatologia , Feminino , Refluxo Gastroesofágico/fisiopatologia , Humanos , Masculino , Manometria/métodos , Pessoa de Meia-Idade , Peristaltismo/efeitos dos fármacos , Postura , Adulto JovemRESUMO
Identifying the heterogeneous biomechanical property of human gallbladder (GB) walls from non-invasive measurements can have clinical significance in patient-specific modeling and acalculous biliary pain diagnosis. In this article, a pointwise method was proposed to measure the heterogeneity of ten samples of human GB during refilling. Three different points, two on the equator of GB body 90° apart and one on the apex of GB fundus, were chosen to represent the typical regions of interest. The stretches at these points were estimated from ultrasound images of the GB during the bile emptying phase based on an analytical model. The model was validated against the experimental data of a lamb GB. The material parameters at the different points were determined inversely by making use of a structure-based anisotropic constitutive model. This anisotropic model yielded much better accuracy when compared to a number of phenomenologically-based constitutive laws, as demonstrated by its significantly reduced least-square errors in stress curve fitting. The results confirmed that the human GB wall material was heterogeneous, particularly toward the apex region. Our study also suggested that non-uniform wall thickness of the GB was important in determining the material parameters, in particular, on the parameters associated with the properties of the matrix and the longitudinal fibers-the difference could be as large as 20-30% compared to that of the uniform thickness model.
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Incidence of esophageal adenocarcinoma (EA) has increased substantially in recent decades. Multiple risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), such as reflux, European ancestry, male sex, obesity, and tobacco smoking, and several germline genetic variants were recently associated with disease risk. Using data from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), small non-coding RNAs implicated in post-transcriptional gene regulation, and deregulated in many cancers, including EA. Polymorphisms in three classes of genes were examined for association with risk of EA or BE: miRNA biogenesis genes (157 SNPs, 21 genes); miRNA gene loci (234 SNPs, 210 genes); and miRNA-targeted mRNAs (177 SNPs, 158 genes). Nominal associations (P<0.05) of 29 SNPs with EA risk, and 25 SNPs with BE risk, were observed. None remained significant after correction for multiple comparisons (FDR q>0.50), and we did not find evidence for interactions between variants analyzed and two risk factors for EA/BE (smoking and obesity). This analysis provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE. While common genetic variants within components of the miRNA biogenesis core pathway appear unlikely to modulate susceptibility to EA or BE, further studies may be warranted to examine potential associations between unassessed variants in miRNA genes and targets with disease risk.
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Adenocarcinoma/diagnóstico , Esôfago de Barrett/diagnóstico , Neoplasias Esofágicas/diagnóstico , Esôfago/metabolismo , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Adenocarcinoma/etnologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Esôfago de Barrett/etnologia , Esôfago de Barrett/genética , Esôfago de Barrett/patologia , Estudos de Casos e Controles , Neoplasias Esofágicas/etnologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Esôfago/patologia , Feminino , Refluxo Gastroesofágico/genética , Refluxo Gastroesofágico/patologia , Regulação da Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/patologia , Fatores de Risco , Fatores Sexuais , Fumar/genética , Fumar/patologia , População BrancaRESUMO
BACKGROUND: Important risk factors for esophageal adenocarcinoma and its precursor, Barrett's esophagus, include gastroesophageal reflux disease, obesity, and cigarette smoking. Recently, genome-wide association studies have identified seven germline single-nucleotide polymorphisms (SNP) that are associated with risk of Barrett's esophagus and esophageal adenocarcinoma. Whether these genetic susceptibility loci modify previously identified exposure-disease associations is unclear. METHODS: We analyzed exposure and genotype data from the BEACON Consortium discovery phase GWAS, which included 1,516 esophageal adenocarcinoma case patients, 2,416 Barrett's esophagus case patients, and 2,187 control participants. We examined the seven newly identified susceptibility SNPs for interactions with body mass index, smoking status, and report of weekly heartburn or reflux. Logistic regression models were used to estimate ORs for these risk factors stratified by SNP genotype, separately for Barrett's esophagus and esophageal adenocarcinoma. RESULTS: The odds ratio for Barrett's esophagus associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of rs2687201 (nominal P = 0.0005, FDR = 0.042). ORs (95% CIs) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of rs2687201 were 6.17 (4.91-7.56), 3.56 (2.85-4.44), and 3.97 (2.47-6.37), respectively. No statistically significant interactions were observed for smoking status and body mass index. CONCLUSION: Reflux symptoms are more strongly associated with Barrett's esophagus risk among persons homozygous for the major allele of rs2687201, which lies approximately 75 kb downstream of the transcription factor gene FOXP1. IMPACT: The novel gene-exposure interaction discovered in this study provides new insights into the etiology of esophageal adenocarcinoma.
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Esôfago de Barrett/genética , Fatores de Transcrição Forkhead/genética , Refluxo Gastroesofágico/genética , Predisposição Genética para Doença/genética , Proteínas Repressoras/genética , Adenocarcinoma/etiologia , Adenocarcinoma/genética , Esôfago de Barrett/etiologia , Estudos de Casos e Controles , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/genética , Feminino , Fatores de Transcrição Forkhead/fisiologia , Refluxo Gastroesofágico/complicações , Loci Gênicos/genética , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla , Homozigoto , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Proteínas Repressoras/fisiologia , Fatores de RiscoRESUMO
BACKGROUND: Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus. METHODS: We examined the associations between risks of EA and Barrett's esophagus and 387 SNPs that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 Barrett's esophagus) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn. RESULTS: After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or Barrett's esophagus. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed. CONCLUSIONS: Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or Barrett's esophagus. IMPACT: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and Barrett's esophagus.
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Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Esôfago de Barrett/genética , Pleiotropia Genética/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
BACKGROUND: The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett's oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute. METHODS: This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR), oxytocin protein (OXT), and cyclic ADP ribose hydrolase glycoprotein (CD38)), were analysed using a gene-based approach, versatile gene-based test association study (VEGAS). RESULTS: Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058) and an increased risk of OAC and BO combined in males (p = 0.0023). Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035) and in males (p = 0.0012). We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only. CONCLUSION: Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed.
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Adenocarcinoma/genética , Esôfago de Barrett/genética , Neoplasias Esofágicas/genética , Receptor alfa de Estrogênio/genética , Polimorfismo de Nucleotídeo Único , Receptores de Ocitocina/genética , ADP-Ribosil Ciclase 1/genética , Adenocarcinoma/epidemiologia , Aromatase/genética , Esôfago de Barrett/epidemiologia , Neoplasias Esofágicas/epidemiologia , Receptor beta de Estrogênio/genética , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Humanos , Masculino , Glicoproteínas de Membrana/genética , Ocitocina/genética , Fatores SexuaisRESUMO
BACKGROUND: Increases in urokinase-like plasminogen activator (uPA) activity are reported to be amongst the earliest events occurring in remnant liver following partial hepatectomy in rats, and have been proposed as a key component of the regenerative response. Remodelling of the extracellular matrix, conversion of single chain hepatocyte growth factor to the active two-chain form and a possible activation of a mitogenic signalling pathway have all been ascribed to the increased uPA activity. The present study aimed to determine whether similar early increases in uPA activity could be detected in the remnant liver following resection of metastatic tumours in surgical patients. RESULTS: Eighteen patients undergoing partial hepatectomy for the removal of hepatic metastases secondary to primary colonic tumours were studied. Increased plasminogen activator activity was found in the final liver samples for the group of patients in whom the resection size was at least 50%. For smaller resections, the increased activity was not observed. The increased activity did not correlate with the age of the patient or with the time between the start of resection and the end of the operation. There was, however, a negative correlation between plasminogen activator activity and the time for which blood supply to the liver was clamped. CONCLUSIONS: Our findings are in accordance with those from experimental animal models and show, for the first time, that rapid increases in plasminogen activator activity can occur following similarly large liver resection in humans. Thus, increases in plasminogen activator activity are an early event in the remnant liver following major liver resection in man. Our observations provide support for the contention that increases in plasminogen activators play a key role in the initiation of hepatic regeneration in man.
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OBJECTIVE: The metaplastic change of Barrett's oesophagus is linked to both acid and duodenal reflux together with impaired motility. Proton pump inhibitors (PPI) reduce acid reflux, but no treatment is available that reduces duodenogastro-oesophageal reflux (DGOR). The aim of this study was to investigate whether adding a prokinetic to PPI treatment could improve oesophageal motility and subsequently reduce reflux. METHODS: Two groups of patients with Barrett's oesophagus on PPI therapy (prokinetic, n = 12; placebo, n = 11) were investigated. At visit 1, ambulatory oesophageal manometry was performed, and peristaltic and simultaneous wave percentage and characteristics were measured. DGOR and pH measurements were also performed. After treatment with either the prokinetic cisapride or placebo, all investigations were repeated (visit 2). Analysis of covariance and Spearman's correlation coefficients of changes from visit 1 to visit 2 were used to compare data. RESULTS: There was no significant difference between the two groups with respect to DGOR, DGOR characteristics, or the percentage of peristalsis and simultaneous waves and their characteristics. There was no correlation between DGOR and motility changes. Although no significant differences existed between acid reflux in the two groups, five patients with high supine acid reflux showed a significant reduction after treatment with cisapride. CONCLUSIONS: Addition of cisapride to PPI treatment does not appear to improve oesophageal motility or reduce DGOR in patients with Barrett's oesophagus.
Assuntos
Esôfago de Barrett/tratamento farmacológico , Cisaprida/uso terapêutico , Refluxo Duodenogástrico/tratamento farmacológico , Refluxo Gastroesofágico/tratamento farmacológico , Inibidores da Bomba de Prótons , Adulto , Idoso , Antiulcerosos/uso terapêutico , Esôfago de Barrett/etiologia , Método Duplo-Cego , Quimioterapia Combinada , Refluxo Duodenogástrico/complicações , Feminino , Refluxo Gastroesofágico/complicações , Fármacos Gastrointestinais/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Peristaltismo/efeitos dos fármacosRESUMO
Colorectal cancer hepatic metastases represent the final stage of a multi-step biological process. This process starts with a series of mutations in colonic epithelial cells, continues with their detachment from the large intestine, dissemination through the blood and/or lymphatic circulation, attachment to the hepatic sinusoids and interactions with the sinusoidal cells, such as sinusoidal endothelial cells, Kupffer cells, stellate cells and pit cells. The metastatic sequence terminates with colorectal cancer cell invasion, adaptation and colonisation of the hepatic parenchyma. All these events, termed the colorectal cancer invasion-metastasis cascade, include multiple molecular pathways, intercellular interactions and expression of a plethora of chemokines and growth factors, and adhesion molecules, such as the selectins, the integrins or the cadherins, as well as enzymes including matrix metalloproteinases. This review aims to present recent advances that provide insights into these cell-biological events and emphasizes those that may be amenable to therapeutic targeting.
Assuntos
Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Apoptose , Caderinas/metabolismo , Moléculas de Adesão Celular/metabolismo , Células Estreladas do Fígado/citologia , Humanos , Células de Kupffer/patologia , Fígado/patologia , Metaloproteinases da Matriz/metabolismo , Mutação , Invasividade Neoplásica , Metástase Neoplásica , Neovascularização Patológica , Resultado do TratamentoRESUMO
BACKGROUND: Data from observational studies suggest that body mass index (BMI) is causally related to esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE). However, the relationships may be affected by bias and confounding. METHODS: We used data from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study: 999 patients with EAC, 2061 patients with BE, and 2169 population controls. We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of BMI on risk of EAC and BE. This was performed using a genetic risk score, derived from 29 genetic variants shown to be associated with BMI, as an instrument for lifetime BMI. A higher score indicates propensity to obesity. All tests were two-sided. RESULTS: The genetic risk score was not associated with potential confounders, including gastroesophageal reflux symptoms and smoking. In the instrumental variable analyses (IV), EAC risk increased by 16% (IV-odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.01 to 1.33) and BE risk increased by 12% (IV-OR = 1.12, 95% CI = 1.00 to 1.25) per 1kg/m(2) increase in BMI. BMI was statistically significantly associated with EAC and BE in conventional epidemiologic analyses. CONCLUSIONS: People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses.
Assuntos
Adenocarcinoma/genética , Esôfago de Barrett/genética , Índice de Massa Corporal , Neoplasias Esofágicas/genética , Análise da Randomização Mendeliana , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Lesões Pré-Cancerosas/genética , Adenocarcinoma/epidemiologia , Adulto , Idoso , Esôfago de Barrett/complicações , Esôfago de Barrett/epidemiologia , Neoplasias Esofágicas/epidemiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/epidemiologia , Lesões Pré-Cancerosas/epidemiologia , Valor Preditivo dos Testes , Medição de Risco , Fatores de RiscoRESUMO
The liver is host to many metastatic cancers, particularly colorectal cancer, for which the last 2 decades have seen major advances in diagnosis and treatment. The liver is a vital organ, and the extent of its involvement with metastatic disease is a major determinant of survival. Metastatic cells arriving in the liver via the bloodstream encounter the microenvironment of the hepatic sinusoid. The interactions of the tumor cells with hepatic sinusoidal and extrasinusoidal cells (endothelial, Kupffer, stellate, and inflammatory cells) determine their fate. The sinusoidal cells can have a dual role, sometimes fatal to the tumor cells but also facilitatory to their survival and growth. Adhesion molecules participate in these interactions and may affect their outcome. Bone marrow-derived cells and chemokines also play a part in the early battle for survival of the metastases. Once the tumor cells have arrested and survived the initial onslaught, tumors can grow within the liver in 3 distinct patterns, reflecting differing host responses, mechanisms of vascularization, and proteolytic activity. This review aims to present current knowledge of the interactions between the host liver cells and the invading metastases that has implications for the clinical course of the disease and the response to treatment.
Assuntos
Neoplasias Hepáticas/secundário , Microambiente Tumoral , HumanosRESUMO
BACKGROUND: Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA. METHODS: We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h(2)g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used. RESULTS: We estimated a statistically significant genetic variance explained for BE (h(2)g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10(-9)) and for EA (h(2)g = 25 %; SE = 5%; one-sided P = 2 × 10(-7)). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10(-6)), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD. CONCLUSIONS: We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.