Brain tumors are rare and when combined with other nervous system tumors account for ~ 2% of all cancers; however, they are the second most common type of pediatric cancer and the leading cause of childhood cancer-related mortality. The etiology and molecular features of most pediatric brain tumors is poorly understood. Exposure to ionizing radiation and several inherited disorders are the only established risk factors for brain tumors, and these factors contribute to only a small proportion of cases. Thus, it has been suggested that brain tumorigenesis results from complex interactions between genetic and epigenetic variations in concert with exposure to environmental factors.
Despite the extensive research, a small proportion of genetic variants contributing to the genetic architecture of brain tumors are detected. To date, the published genome-wide association studies (GWAS) on adult brain tumors have been largely conducted on pooled histological subtypes of glioma. However, recently it has been shown that of the currently identified variants, eleven single nucleotide polymorphisms (SNPs) were significantly associated with glioblastoma while eighteen SNPs showed significant associations with non-glioblastoma glioma. In addition, the role of genetic variation in pediatric brain tumor etiology is largely unknown. Currently, there are no published GWAS on pediatric brain tumors. Given the importance of identifying validated genetic associations for a better understanding of pediatric brain tumorigenesis, conducting GWAS is necessary and this topic merits further research.
What are the goals of this project?
By conducting the first GWAS on ependymoma, we aim to compare the genetic risk factors and the heritability of risk variants between adult and pediatric ependymoma. In the case of obtaining adequately large sample size, sex-specific and race-specific analyses will also be performed.
What is the impact of this project?
By considering the limited knowledge available on the genetic architecture of pediatric brain tumor subtypes, the proposed histology-specific GWAS will provide essential new knowledge of variants contributing to the genetic architecture of pediatric brain tumors and thus leads to a better understanding of the etiology of brain tumors. The study is supposed to be a large collaborative study including centers in National Institutes of Health, Karolinska Institutet, and Duke University Medical Centre. Therefore, this study, in a unique way, will contribute knowledge that may lead to refined brain tumor prediction and prevention.
Why the CBTN request is important to this project?
An adequately powered study setting is important for the proposed GWAS to identify novel validated germline variants associated with ependymoma. Moreover, a separate set of cases and controls to validate the identified variants is necessary. Given the rarity of pediatric brain tumors, especially when the study is focused on a specific histological subtype, obtaining a large sample size is not easy. Our proposed study is a large collaborative study including more than 1500 ependymoma samples.
However, to obtain an adequate power for performing the GWAS, we are applying for the available specimen and data for ependymoma at CBTN. All the data generated from subjects of the CBTN will be pooled with other available data at Baylor College of Medicine, as well as, the data available from other research centers involved in this study, to achieve an adequately powered GWAS.
The Children's Brain Tumor Network contributed to this project by providing tumor DNA samples and access to the Pediatric Brain Tumor Atlas.
Michael Scheurer, Baylor College of Medicine
Lisa Mirabello, National Institute of Health
Jacqueline Clavel, Université Paris Sud
Medulloblastomas comprise the vast majority of pediatric embryonal tumors and by definition arise in the posterior fossa, where they constitute approximately 40% of all posterior fossa tumors. Other forms of embryonal tumors each make up 2% or less of all childhood brain tumors.The clinica