Genes and brain tumors

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.