| 1. |
- Adel Fahmideh, Maral, et al.
(författare)
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A Weighted Genetic Risk Score of Adult Glioma Susceptibility Loci Associated with Pediatric Brain Tumor Risk.
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 2. |
- Adel Fahmideh, Maral, et al.
(författare)
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Common genetic variations in cell cycle and DNA repair pathways associated with pediatric brain tumor susceptibility
- 2016
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Ingår i: Oncotarget. - Stockholm : Karolinska Institutet, Institute of Environmental Medicine. - 1949-2553.
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Tidskriftsartikel (refereegranskat)abstract
- 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, stratifid 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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| 3. |
- Adel Fahmideh, Maral
(författare)
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Genes and brain tumors
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 4. |
- Adel Fahmideh, Maral, et al.
(författare)
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Parental age and risk of genetic syndromes predisposing to nervous system tumors: nested case-control study.
- 2018
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Ingår i: Clinical epidemiology. - 1179-1349. ; 10, s. 729-738
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Tidskriftsartikel (refereegranskat)abstract
- 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.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).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.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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| 5. |
- Dahlin, Anna M., 1979-, et al.
(författare)
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A genome-wide association study on medulloblastoma
- 2020
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Ingår i: Journal of Neuro-Oncology. - : Springer. - 0167-594X .- 1573-7373. ; 147:2, s. 309-315
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark.Methods: Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2.Results: Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p < 1 × 10–5), but none were statistically significant after adjusting for multiple testing (p < 5 × 10–8). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (ORT = 1.59, pvalidation = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, ORT = 3.76, p = 3.2 × 10–4) and rs79036813 (PTCH1, ORA = 0.42, p = 2.6 × 10–3).Conclusion: The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.
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| 6. |
- Tettamanti, Giorgio, et al.
(författare)
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Prenatal and postnatal medical conditions and the risk of brain tumors in children and adolescents: an international multicenter case-control study.
- 2017
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Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.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 (CABTs) were aged 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.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% CI 0.82-4.22). The associations with head injury, febrile seizure, fever in the first 12 weeks, and general anesthesia were close to unity.Prenatal or postnatal medical conditions, including medical diagnostic radiation, were not associated with CABTs. Based on small numbers of exposed children, we observed a non-significant increased risk for CT scans of the head.We have presented additional evidence suggesting that exposure to head CT scan may be associated with the occurrence of CABTs.
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