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Background: The contribution of genetic and environmental factors to susceptibility to nervous system tumors remains unclear. We performed a quantitative genetic study using a sibling design to estimate the heritability of nervous system tumors, as well as the proportion of the risk of these tumors, which is attributable to environmental factors. Methods: We conducted a population-based cohort study using Swedish National Register data. All individuals born in Sweden during 1950-2010 with available information on both biological parents were included. A Multi-Generation Register was used to identify family clusters, including both full- and half-siblings. Initially, one index person was randomly selected from each cluster containing only full siblings and one sibling was randomly assigned to this index person. Subsequently, within each of the remaining clusters of full- and half-siblings, an index person was randomly selected, and a half-sibling was randomly assigned to this index person. Among the randomly selected siblings, cases of nervous system tumors were identified using the cancer registry. Quantitative genetic models were used to estimate the proportion of the variance in nervous system tumors attributable to additive genetic factors, shared environment, and individual-specific environment. Results: The heritability of nervous system tumors was estimated to be 29% (95% confidence interval (CI) = 19%-39%), while the contribution of the non-shared environment to the variance of nervous system tumors was estimated to be 71% (95% CI = 61%-81%). The shared environmental parameter was estimated as zero in the full model. Conclusion: The variation in susceptibility to nervous system tumors is predominantly attributable to non-shared environmental factors, followed by genetic factors.
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BACKGROUND: Although there is evidence of socioeconomic disparities in survival of children diagnosed with central nervous system (CNS) tumors, the impact of neighborhood socioeconomic deprivation on the survival of these malignancies has not been adequately studied. We investigated the association between area deprivation index (ADI), a measure of neighborhood socioeconomic disadvantage, and pediatric CNS tumor survival. METHODS: Demographic and clinical characteristics, geocoded addresses at diagnosis, and vital status of pediatric CNS tumor cases (n = 5,477) for the period 1995 to 2017 were obtained from the Texas Cancer Registry. ADI scores were computed for census tracts in Texas using the U.S. Census Bureau 2010 geography. Tracts were classified into quartiles as least, third-most, second-most, and most disadvantaged. Children were mapped to quartiles based on residency at diagnosis. The adjusted hazard ratio (HR) and 95% confidence interval (CI) were calculated. RESULTS: The results showed a significantly increased HR for death among children in the most (HR, 1.29; 95% CI, 1.09-1.51), second-most (HR, 1.18; 95% CI, 1.01-1.38), and third-most disadvantaged census tracts (HR, 1.18; 95% CI, 1.02-1.37) compared with children in the least disadvantaged tracts. CONCLUSIONS: Children living in the most disadvantaged neighborhoods experienced a significantly higher risk of mortality, indicating the important role of socioeconomic disparities in the survival of pediatric CNS tumors. IMPACT: The demographic and socioeconomic disparities identified by this study should be considered when planning treatment strategies for these susceptible groups and thus, lead to a better outcome in socioeconomically disadvantaged children diagnosed with CNS tumors.
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Neoplasias del Sistema Nervioso Central/mortalidad , Características del Vecindario/clasificación , Niño , Femenino , Disparidades en el Estado de Salud , Humanos , Masculino , Áreas de Pobreza , Sistema de Registros , Estudios Retrospectivos , Texas/epidemiologíaRESUMEN
Central nervous system (CNS) tumors are the most common solid tumors in children. Findings on the role of maternal and perinatal factors on the susceptibility or outcome of these tumors are inconclusive. Therefore, we investigated the association between these early-life factors, risk, and survival of pediatric CNS tumors, using data from one of the world's largest and most diverse cancer registries. Information on pediatric CNS tumor cases (n = 1950) for the period 1995-2011 was obtained from the Texas Cancer Registry. Birth certificate controls were frequency-matched on birth year at a ratio of 10:1 for the same period. Evaluated maternal and perinatal variables were obtained from birth records. Unconditional logistic regression was used to generate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for etiological factors. Additionally, Cox proportional hazards regression was employed to assess adjusted hazard ratios (HRs) and 95% CIs for survival factors. The results indicated that Hispanic and non-Hispanic black mothers were less likely to have children with CNS tumors compared to non-Hispanic white mothers (OR 0.88 [95% CI 0.78-0.98] P-value = 0.019; OR 0.79 [95% CI 0.67-0.93 P-value = 0.004], respectively). Infants born large for gestational age (OR 1.26 [95% CI 1.07-1.47] P-value = 0.004) and those delivered pre-term (OR 1.19 [95% CI 1.04-1.38] P-value = 0.013) showed an increased risk of CNS tumors. Infants born by vaginal forceps or vacuum delivery had a higher risk of CNS tumors compared to those born by spontaneous vaginal delivery (OR 1.35 [95% CI 1.12-1.62] P-value = 0.002). Additionally, offspring of Hispanic and non-Hispanic black mothers showed a higher risk of death (HR 1.45 [95% CI 1.16-1.80] P-value = 0.001; HR 1.53 [95% CI 1.12-2.09] P-value = 0.008, respectively). Infants born by cesarean had a higher risk of death compared to those delivered vaginally (HR 1.28 [95% CI 1.05-1.57] P-value = 0.016). These findings indicate the important role of maternal and perinatal characteristics in the etiology and survival of these clinically significant malignancies.
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Neoplasias del Sistema Nervioso Central/epidemiología , Nacimiento Prematuro/epidemiología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Adolescente , Adulto , Negro o Afroamericano/estadística & datos numéricos , Peso al Nacer , Estudios de Casos y Controles , Causalidad , Neoplasias del Sistema Nervioso Central/diagnóstico , Cesárea , Niño , Preescolar , Femenino , Estudios de Seguimiento , Edad Gestacional , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Lactante , Recién Nacido , Masculino , Madres/estadística & datos numéricos , Embarazo , Efectos Tardíos de la Exposición Prenatal/diagnóstico , Factores de Riesgo , Análisis de Supervivencia , Población Blanca/estadística & datos numéricos , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Virus mitigation strategies such as adhering to stay-at-home orders, practicing social distancing, and engaging in personal protective behaviors are central to slowing the spread of COVID-19. This population-based cohort study sought to identify sociodemographic characteristics and Health Belief Model factors that are associated with nonadherence to COVID-19 mitigation strategies with the goal of informing public health messaging campaigns. METHODS: An online population-based survey was distributed via social media over an 8-week period from April 13, 2020, to June 8, 2020. RESULTS: Data were derived from 2,222 adults (57% female; 40% racial/ethnic minorities). Univariate analyses revealed that men, younger aged (18-30 years) and unmarried adults, and noncollege educated individuals had lower levels of perceived threat, control, and knowledge about COVID-19 (p ≤ .001). Multivariable linear regression models further revealed that male gender was significantly associated with reporting lower levels of adherence to COVID-19 mitigation strategies (p < .001), and that higher levels of perceived threat, perceived control, and knowledge about how to keep oneself and others safe from COVID-19 were significantly associated with reporting higher levels of adherence to COVID-19 mitigation strategies (p < .01). CONCLUSIONS: Findings suggest that public health appeals that target men, emphasize individual risk, and provide clear, consistent guidance on what individuals can do to decrease their risk for COVID-19 may be effective in motivating increased mitigation adherence.
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COVID-19/prevención & control , Control de Enfermedades Transmisibles , Adhesión a Directriz , Modelo de Creencias sobre la Salud , Adolescente , Adulto , Factores de Edad , Anciano , Escolaridad , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Modelos Lineales , Masculino , Estado Civil , Persona de Mediana Edad , SARS-CoV-2 , Factores Sexuales , Encuestas y Cuestionarios , Estados Unidos , Adulto JovenRESUMEN
This study examined individual-level determinants of self-reported changes in healthy (diet and physical activity) and addictive (alcohol use, smoking, and vaping) lifestyle behaviors during the initial COVID-19 lockdown period in the USA. A national online survey was administered between May and June 2020 that targeted a representative U.S. sample and yielded data from 1276 respondents, including 58% male and 50% racial/ethnic minorities. We used univariate and multivariable linear regression models to examine the associations of sociodemographic, mental health, and behavioral determinants with self-reported changes in lifestyle behaviors. Some study participants reported increases in healthy lifestyle behaviors since the pandemic (i.e., 36% increased healthy eating behaviors, and 33% increased physical activity). However, they also reported increases in addictive lifestyle behaviors including alcohol use (40%), tobacco use (41%), and vaping (46%). With regard to individual-level determinants, individuals who reported adhering to social distancing guidelines were also more likely to report increases in healthy lifestyle behaviors (ß = 0.12, 95% CI 0.04 to 0.21). Conversely, women (ß = -0.37, 95% CI -0.62 to -0.12), and unemployed individuals (ß = -0.33, 95% CI -0.64 to -0.02) were less likely to report increases in healthy lifestyle behaviors. In addition, individuals reporting anxiety were more likely to report increases in addictive behaviors (ß = 0.26, 95% CI 0.09 to 0.43). Taken together, these findings suggest that women and unemployed individuals may benefit from interventions targeting diet and physical activity, and that individuals reporting anxiety may benefit from interventions targeting smoking and alcohol cessation to address lifestyle changes during the pandemic.
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COVID-19 , Control de Enfermedades Transmisibles , Femenino , Humanos , Estilo de Vida , Masculino , SARS-CoV-2 , Encuestas y Cuestionarios , Estados Unidos/epidemiologíaRESUMEN
Brain tumors are the most common solid tumors in children and remain a significant contributor to death by disease in this population. Pediatric brain tumors (PBT) are broadly classified into two major categories: glial and neuronal tumors. Various factors, including tumor histology, tumor location, and demographics, influence the incidence and prognosis of this heterogeneous group of neoplasms. Numerous epidemiologic studies have been conducted to identify genetic and environmental risk factors for these malignancies. Thus far, the only established risk factors for PBTs are exposure to ionizing radiation and some rare genetic syndromes. However, relatively consistent evidence of positive associations for birth defects, markers of fetal growth, advanced parental age, maternal dietary N-nitroso compounds, and exposure to pesticides have been reported. The genetic variants associated with susceptibility to PBTs were predominantly identified by a candidate-gene approach. The identified genetic variants belong to four main pathways, including xenobiotic detoxification, inflammation, DNA repair, and cell-cycle regulation. Conducting large and multi-institutional studies is warranted to systematically detect genetic and environmental risk factors for different histologic subtypes of PBTs. This, in turn, might lead to a better understanding of etiology of PBTs and eventually developing risk prediction models to prevent these clinically significate malignancies.
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Neoplasias Encefálicas/epidemiología , Biomarcadores de Tumor , Niño , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Masculino , Radiación Ionizante , Factores de Riesgo , Factores SexualesRESUMEN
INTRODUCTION: Although social distancing may help contain the spread of COVID-19, the social isolation and loneliness it causes can heighten stress, contribute to unhealthy lifestyle behaviours and have deleterious effects on social relationships. This ongoing longitudinal cohort study aims to (1) characterise the psychological, social and health behavioural impacts of the COVID-19 pandemic over a 12-month period in the USA; (2) determine whether these impacts differ for certain subgroups based on sociodemographics and other individual-level factors; and (3) explore whether there are modifiable factors (eg, coping, social support) that moderate the effects of the pandemic over time. METHODS AND ANALYSIS: Adults (aged ≥18 years) who were fluent in either English or Spanish were recruited via social media and invited to complete an online survey during the 8-week period from 13 April to 8 June 2020 (baseline). Follow-up surveys will be conducted 6 and 12 months after baseline. Data transformations, non-parametric tests or other alternative methods will be used when appropriate. Descriptive statistics and cross-sectional analyses will be performed. Longitudinal associations will be analysed using multilevel modelling with time-variant and time-invariant predictors of change in trajectory over the study period. ETHICS AND DISSEMINATION: Research ethics approval was received from the Baylor College of Medicine Institutional Review Board (H-47505). Overall, this study will provide timely information that can be used to inform public health messaging strategies and guide development of assessment tools and interventions to support vulnerable individuals dealing with the long-term impacts of the COVID-19 pandemic.
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COVID-19 , Control de Enfermedades Transmisibles/métodos , Conductas Relacionadas con la Salud , Salud Mental/tendencias , Funcionamiento Psicosocial , Aislamiento Social/psicología , Adulto , COVID-19/epidemiología , COVID-19/prevención & control , COVID-19/psicología , Estudios de Cohortes , Femenino , Humanos , Estudios Longitudinales , Masculino , Proyectos de Investigación , SARS-CoV-2 , Encuestas y Cuestionarios , Estados Unidos/epidemiologíaRESUMEN
Genetic risk score (GRS) is used to demonstrate the genetic variants contributing to the polygenic architecture of complex diseases. By using a GRS, we have investigated the additive impact of the known adult glioma susceptibility loci on the pediatric brain tumor (PBT) risk and assessed the proportion of PBT heritability attributable to these susceptibility loci. A GRS was generated for PBTs based on the alleles and associated effect sizes derived from a previously published genome-wide association study on adult glioma. The GRS was calculated in CEFALO, a population-based case-control study of brain tumors in children and adolescents including saliva DNA of 245 cases and 489 controls. The unconditional logistic regression model was used to investigate the association between standardized GRS and risk of PBTs. To measure the variance explained by the effect of GRS, Nagelkerke pseudo-R2 was calculated. The GRS for adult brain tumors was associated with an increased risk of PBTs (OR 1.25 [95% CI 1.06-1.49], p = 0.009) and 0.3% of the variance in PBTs could be explained by the effect of GRS on the liability scale. This study provides evidence that heritable risks of PBTs are in-part attributable to some common genetic variants associated with adult glioma.
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Neoplasias Encefálicas/genética , Glioma/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Neoplasias Encefálicas/patología , Niño , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Modelos Logísticos , Masculino , Adulto JovenRESUMEN
Primary brain tumors account for ~1% of new cancer cases and ~2% of cancer deaths in the United States; however, they are the most commonly occurring solid tumors in children. These tumors are very heterogeneous and can be broadly classified into malignant and benign (or non-malignant), and specific histologies vary in frequency by age, sex, and race/ethnicity. Epidemiological studies have explored numerous potential risk factors, and thus far the only validated associations for brain tumors are ionizing radiation (which increases risk in both adults and children) and history of allergies (which decreases risk in adults). Studies of genetic risk factors have identified 32 germline variants associated with increased risk for these tumors in adults (25 in glioma, 2 in meningioma, 3 in pituitary adenoma, and 2 in primary CNS lymphoma), and further studies are currently under way for other histologic subtypes, as well as for various childhood brain tumors. While identifying risk factors for these tumors is difficult due to their rarity, many existing datasets can be leveraged for future discoveries in multi-institutional collaborations. Many institutions are continuing to develop large clinical databases including pre-diagnostic risk factor data, and developments in molecular characterization of tumor subtypes continue to allow for investigation of more refined phenotypes. Key Point 1. Brain tumors are a heterogeneous group of tumors that vary significantly in incidence by age, sex, and race/ethnicity.2. The only well-validated risk factors for brain tumors are ionizing radiation (which increases risk in adults and children) and history of allergies (which decreases risk).3. Genome-wide association studies have identified 32 histology-specific inherited genetic variants associated with increased risk of these tumors.
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Neoplasias Encefálicas/etiología , Neoplasias Encefálicas/patología , Adulto , Niño , Humanos , Factores de RiesgoRESUMEN
PURPOSE: Phacomatoses are genetic syndromes that are associated with increased risk of developing nervous system tumors. Phacomatoses are usually inherited, but many develop de novo, with unknown etiology. In this population-based study, we investigated the effect of parental age on the risk of phacomatoses in offspring. PATIENTS AND METHODS: The study was a population-based nested case-control study. All individuals born and residing in Sweden between January 1960 and December 2010 were eligible for inclusion. Using the Patient Register, 4625 phacomatosis cases were identified and further classified as familial or nonfamilial. Ten matched controls per case were randomly selected from the eligible population. Data were analyzed using conditional logistic regression. Analyses were conducted for neurofibromatosis alone (n=2089) and other phacomatoses combined (n=2536). RESULTS: Compared with offspring of fathers aged 25-29 years, increased risk estimates of nonfamilial neurofibromatosis were found for offspring of fathers aged 35-39 years (odds ratio [OR]=1.43 [95% CI 1.16-1.74]) and ≥40 years (OR =1.74 [95% CI 1.38-2.19]). For other nonfamilial phacomatoses, the risk estimate for offspring of fathers aged ≥40 years was OR =1.23 (95% CI 1.01-1.50). Paternal age was not associated with familial phacomatoses, and no consistent association was observed with maternal age. CONCLUSION: The findings show a consistent increase in risk of de novo occurrence of phacomatoses predisposing to nervous system tumors in offspring with increasing paternal age, most pronounced for neurofibromatosis, while maternal age did not seem to influence the risk. These findings suggest an increasing rate of new mutations in the NF1 and NF2 genes in spermatozoa of older fathers.
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BACKGROUND: Previous studies have evaluated the effect of medical diagnostic radiation on brain tumors. Recent cohort studies have reported an increased risk associated with exposure to head CT scans. METHODS: Information regarding medical conditions, including prenatal and postnatal exposure to medical diagnostic radiation, was obtained from CEFALO, a multicenter case-control study performed in Denmark, Norway, Sweden, and Switzerland through face-to-face interview. Eligible cases of childhood and adolescent brain tumors (CABT) were ages 7 to 19 years, diagnosed between January 1, 2004 and August 31, 2008, and living in the participating countries (n = 352). The cases were matched by age, sex, and region to 646 population-based controls. RESULTS: Prenatal exposure to medical diagnostic radiation and postnatal exposure to X-rays were not associated with CABTs. A higher risk estimate of CABTs, although not statistically significant, was found for exposure to head CT scan (OR, 1.86; 95% confidence interval, 0.82-4.22). The associations with head injury, febrile seizure, fever in the first 12 weeks, and general anesthesia were close to unity. CONCLUSIONS: Prenatal or postnatal medical conditions, including medical diagnostic radiation, were not associated with CABTs. On the basis of small numbers of exposed children, we observed a nonsignificant increased risk for CT scans of the head. IMPACT: We have presented additional evidence, suggesting that exposure to head CT scan may be associated with the occurrence of CABTs. Cancer Epidemiol Biomarkers Prev; 26(1); 110-5. ©2016 AACR.
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Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/etiología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Dosis de Radiación , Exposición a la Radiación/efectos adversos , Adolescente , Neoplasias Encefálicas/fisiopatología , Estudios de Casos y Controles , Niño , Intervalos de Confianza , Dinamarca/epidemiología , Femenino , Humanos , Internacionalidad , Imagen por Resonancia Magnética/efectos adversos , Masculino , Noruega/epidemiología , Oportunidad Relativa , Tomografía de Emisión de Positrones/efectos adversos , Atención Posnatal/métodos , Embarazo , Atención Prenatal/métodos , Suecia/epidemiología , Suiza/epidemiología , Tomografía Computarizada por Rayos X/efectos adversosRESUMEN
Knowledge on the role of genetic polymorphisms in the etiology of pediatric brain tumors (PBTs) is limited. Therefore, we investigated the association between single nucleotide polymorphisms (SNPs), identified by candidate gene-association studies on adult brain tumors, and PBT risk.The study is based on the largest series of PBT cases to date. Saliva DNA from 245 cases and 489 controls, aged 7-19 years at diagnosis/reference date, was genotyped for 68 SNPs. Data were analyzed using unconditional logistic regression.The results showed EGFRrs730437 and EGFRrs11506105 may decrease susceptibility to PBTs, whereas ERCC1rs3212986 may increase risk of these tumors. Moreover, stratified analyses indicated CHAF1Ars243341, CHAF1Ars2992, and XRCC1rs25487 were associated with a decreased risk of astrocytoma subtype. Furthermore, an increased risk of non-astrocytoma subtype associated with EGFRrs9642393, EME1rs12450550, ATMrs170548, and GLTSCRrs1035938 as well as a decreased risk of this subtype associated with XRCC4rs7721416 and XRCC4rs2662242 were detected.This study indicates SNPs in EGFR, ERCC1, CHAF1A, XRCC1, EME1, ATM, GLTSCR1, and XRCC4 may be associated with the risk of PBTs. Therefore, cell cycle and DNA repair pathways variations associated with susceptibility to adult brain tumors also seem to be associated with PBT risk, suggesting pediatric and adult brain tumors might share similar etiological pathways.
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Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/genética , Reparación del ADN , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Adolescente , Estudios de Casos y Controles , Niño , Dinamarca , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Noruega , Análisis de Regresión , Riesgo , Saliva/metabolismo , Suecia , Suiza , Adulto JovenRESUMEN
The role of genetic polymorphisms in pediatric brain tumor (PBT) etiology is poorly understood. We hypothesized that single nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS) on adult glioma would also be associated with PBT risk. The study is based on the Cefalo study, a population-based multicenter case-control study. Saliva DNA from 245 cases and 489 controls, aged 7-19 years at diagnosis/reference date, was extracted and genotyped for 29 SNPs reported by GWAS to be significantly associated with risk of adult glioma. Data were analyzed using unconditional logistic regression. Stratified analyses were performed for two histological subtypes: astrocytoma alone and the other tumor types combined. The results indicated that four SNPs, CDKN2BAS rs4977756 (p = 0.036), rs1412829 (p = 0.037), rs2157719 (p = 0.018) and rs1063192 (p = 0.021), were associated with an increased susceptibility to PBTs, whereas the TERT rs2736100 was associated with a decreased risk (p = 0.018). Moreover, the stratified analyses showed a decreased risk of astrocytoma associated with RTEL1 rs6089953, rs6010620 and rs2297440 (p trend = 0.022, p trend = 0.042, p trend = 0.029, respectively) as well as an increased risk of this subtype associated with RTEL1 rs4809324 (p trend = 0.033). In addition, SNPs rs10464870 and rs891835 in CCDC26 were associated with an increased risk of non-astrocytoma tumor subtypes (p trend = 0.009, p trend = 0.007, respectively). Our findings indicate that SNPs in CDKN2BAS, TERT, RTEL1 and CCDC26 may be associated with the risk of PBTs. Therefore, we suggest that pediatric and adult brain tumors might share common genetic risk factors and similar etiological pathways.
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Neoplasias Encefálicas/genética , ADN Helicasas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Polimorfismo de Nucleótido Simple , Telomerasa/genética , Adolescente , Neoplasias Encefálicas/patología , Estudios de Casos y Controles , Niño , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Glioma/genética , Humanos , Desequilibrio de Ligamiento , ARN Largo no Codificante , Adulto JovenRESUMEN
Aberrant DNA methylation is a feature of human cancer affecting gene expression and tumor phenotype. Here, we quantified promoter methylation of candidate genes and global methylation in 44 small intestinal-neuroendocrine tumors (SI-NETs) from 33 patients by pyrosequencing. Findings were compared with gene expression, patient outcome and known tumor copy number alterations. Promoter methylation was observed for WIF1, RASSF1A, CTNNB1, CXCL14, NKX2-3, P16, LAMA1, and CDH1. By contrast APC, CDH3, HIC1, P14, SMAD2, and SMAD4 only had low levels of methylation. WIF1 methylation was significantly increased (P = 0.001) and WIF1 expression was reduced in SI-NETs vs. normal references (P = 0.003). WIF1, NKX2-3, and CXCL14 expression was reduced in metastases vs. primary tumors (P<0.02). Low expression of RASSF1A and P16 were associated with poor overall survival (P = 0.045 and P = 0.011, respectively). Global methylation determined by pyrosequencing of LINE1 repeats was reduced in tumors vs. normal references, and was associated with loss in chromosome 18. The tumors fell into three clusters with enrichment of WIF1 methylation and LINE1 hypomethylation in Cluster I and RASSF1A and CTNNB1 methylation and loss in 16q in Cluster II. In Cluster III, these alterations were low-abundant and NKX2-3 methylation was low. Similar analyses in the SI-NET cell lines HC45 and CNDT2 showed methylation for CDH1 and WIF1 and/or P16, CXCL14, NKX2-3, LAMA1, and CTNNB1. Treatment with the demethylating agent 5-azacytidine reduced DNA methylation and increased expression of these genes in vitro. In conclusion, promoter methylation of tumor suppressor genes is associated with suppressed gene expression and DNA copy number alterations in SI-NETs, and may be restored in vitro.
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Metilación de ADN , Neoplasias Intestinales/metabolismo , Intestino Delgado/metabolismo , Tumores Neuroendocrinos/metabolismo , Antimetabolitos Antineoplásicos/farmacología , Azacitidina/farmacología , Línea Celular Tumoral , Cromosomas Humanos Par 18 , Análisis por Conglomerados , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Variaciones en el Número de Copia de ADN , Femenino , Genoma Humano , Humanos , Neoplasias Intestinales/mortalidad , Neoplasias Intestinales/patología , Intestino Delgado/efectos de los fármacos , Elementos de Nucleótido Esparcido Largo , Masculino , Metástasis de la Neoplasia , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/patología , Regiones Promotoras Genéticas , ARN Mensajero/metabolismo , Tasa de Supervivencia , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
BACKGROUND: Association studies of germline DNA repair single nucleotide polymorphisms (SNPs) and glioma risk have yielded inconclusive results. We therefore performed a systematic review and meta-analysis of studies investigating this association. METHODS: We identified 27 eligible studies investigating 105 SNPs in 42 DNA repair genes. Of these, 10 SNPs in 7 genes were analyzed in at least 4 studies and were therefore included in our meta-analysis. The meta-analysis was performed for homozygote comparison, heterozygote comparison, and dominant and recessive models by applying a fixed- or random-effects model. The funnel and forest plots were created using RevMan software. RESULTS: We found that SNPs rs3212986 (odds ratio [OR] = 1.35 (1.08-1.68), P = .008), rs13181 (OR = 1.18 (1.06-1.31), P = .002), and rs25487 (OR = 1.12 (1.03-1.22), P = .007) in DNA repair genes ERCC1, ERCC2 (XPD), and XRCC1 may increase the risk of glioma, while polymorphisms rs1136410 (OR = 0.78 (0.68-0.89), P = .0004) and rs12917 (OR = 0.84 (0.73-0.96), P = .01) in PARP1(ADPRT) and MGMT are associated with decreased susceptibility to glioma. No evidence of significant associations between ERCC2 rs1799793, OGG1 rs1052133, XRCC1 rs25489, XRCC1 rs1799782, or XRCC3 rs861539 and risk of glioma was observed. CONCLUSION: This study provides evidence that DNA repair genes ERCC1, ERCC2, and XRCC1 might be low-penetrance glioma-risk genes, while MGMT and PARP1 polymorphisms may confer protection against glioma.