Genes and brain tumors

Although brain tumors are rare and combined with other nervous system tumors account for ~ 2% of all cancers, they are the second most common type of pediatric cancer. The etiology of brain tumors, known as multifactorial traits, is poorly understood. In this thesis we aimed at identifying genetic risk factors for pediatric brain tumors by investigating the association between adult glioma susceptibility loci and risk of pediatric brain tumors. Phacomatoses are a series of rare genetic syndromes that predispose individuals to development of nervous system tumors. The etiology of de novo occurrence of phacomatoses is also largely unknown. It is hypothesized that de novo phacomatoses and nervous system tumors might share common risk factors. Therefore, in this thesis, we also assessed the association between parental age and risk of de novo phacomatoses in offspring. Study I is a systematic review and meta-analysis of published studies investigating the association between germ-line single nucleotide polymorphisms (SNPs) of DNA repair genes and glioma risk. In total, 105 SNPs in 42 DNA repair genes were identified of which 10 SNPs in 7 DNA repair genes were evaluated in at least 4 studies and therefore were included in our meta-analysis. Based on the findings of this study we can conclude that lowpenetrance susceptibility loci for glioma are located on ERCC1, ERCC2 (XPD), and XRCC1 while variations in DNA repair genes MGMT and PARP1might protect against glioma risk. Studies II and III are based on the CEFALO study which is a population-based multicenter case-control study of children and adolescents diagnosed with intracranial central nervous system tumors aged 7-19 years at diagnosis. In total, saliva DNA from 245 cases and 489 controls was included in these two studies. In Study II saliva DNA was genotyped for 29 SNPs identified by genome-wide association studies (GWAS) on adult glioma. The findings of this study indicate that the adult glioma GWAS susceptibility loci at 5p15.33 (TERT), 8q24.21 (CCDC26), 9p21.3 (CDKN2A-CDKN2B), and 20q13.33 (RTEL1) are also associated with pediatric brain tumor risk. In Study III saliva DNA was genotyped for 68 SNPs identified by candidate-gene association studies of adult glioma related to DNA repair, cell cycle, metabolism, and inflammation pathways. In total, 63 SNPs were satisfactorily genotyped. This study provides evidence that of the investigated genetic variations, variants in EGFR, ERCC1, CHAF1A, XRCC1, EME1, ATM, GLTSCR1, and XRCC4, belonging to DNA repair and cell cycle pathways, known to be associated with adult glioma, are also associated with pediatric brain tumors risk. The findings of Studies II and III together indicate that adult and pediatric brain tumors probably have some genetic risk factors in common. Study IV is a nested case-control study within the Swedish population. By using the Patient register, 4625 phacomatosis cases were identified and further classified as familial or nonfamilial. Ten controls per case were randomly selected from the eligible population. Analyses were performed for neurofibromatosis alone and other phacomatoses combined. This study indicates that advanced paternal age increases the risk of de novo occurrence of phacomatoses in offspring with the most pronounced effects on neurofibromatosis. This thesis provides evidence that adult and pediatric brain tumors probably have common genetic risk factors and might share similar etiological pathways. Moreover, this thesis provides evidence of an increased risk of de novo neurofibromatosis by increasing paternal age, suggesting an increasing rate of de novo mutations in the NF1 and NF2 genes in older fathers’ sperm

CCDC26, CDKN2BAS, RTEL1 and TERT Polymorphisms in pediatric brain tumor susceptibility

The role of genetic polymorphisms in pediatric brain tumor (PBT) etiology is poorly understood. In this study, we tested the hypothesis that single nucleotide polymorphisms identified by genome-wide association studies on adult glioma are also associated with PBT ris

CCDC26, CDKN2BAS, RTEL1 and TERT Polymorphisms in pediatric brain tumor susceptibility

The role of genetic polymorphisms in pediatric brain tumor (PBT) etiology is poorly understood. In this study, we tested the hypothesis that single nucleotide polymorphisms identified by genome-wide association studies on adult glioma are also associated with PBT ris

Common genetic variations in cell cycle and DNA repair pathways associated with pediatric brain tumor susceptibility.

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

Psychosocial and health behavioural impacts of COVID-19 pandemic on adults in the USA: protocol for a longitudinal cohort study

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

A Weighted Genetic Risk Score of Adult Glioma Susceptibility Loci Associated with Pediatric Brain Tumor Risk.

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-R$^{2}$ 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

Individual-Level Determinants of Lifestyle Behavioral Changes during COVID-19 Lockdown in the United States: Results of an Online Survey

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 (β = 0.12, 95% CI 0.04 to 0.21). Conversely, women (β = −0.37, 95% CI −0.62 to −0.12), and unemployed individuals (β = −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 (β = 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

CCDC26, CDKN2BAS, RTEL1 and TERT Polymorphisms in pediatric brain tumor susceptibility.

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