There are approximately 2200 children diagnosed with brain tumors each year. As the overall survival of these children has improved from 57–74% in the interval from 1975 to 2002 [1]with 5-year survival reaching 75.5% in the time interval between 2013–2019[2] there is increasing concern over the neurocognitive deficits that accompany treatment for brain tumors. In addition to treatment related risk factors such as radiation dose [3]and surgery [4], several clinical risk factors for neurocognitive deficits have been identified. Some of these include gender [5, 6], younger age at diagnosis [3, 7], and children with hydrocephalus at presentation [8]. More defined biologic markers will make it possible to better predict patients at risk of long-term adverse neurocognitive effects following radiation therapy. This information could allow for better treatment stratification and early cognitive intervention in at-risk individuals.
There has been interest in examining the genetic factors that underlie normal tissue sensitivity to therapy. Numerous groups have examined genetic polymorphisms and radiation toxicity in adults with malignancies of the breast, prostate, head and neck, cervix, endometrium, and lung [9]. One study investigated the potential association between cognitive outcomes and single nucleotide polymorphisms (SNPs) in catechol-o-methyl transferase (COMT), brain-derived neurotrophic factor (BDNF), and dystrobrevin-binding protein 1 (DTNBP). These genes are associated with memory and daily functioning, and all genes are implicated in neurological impairment in adult tumor patients [10]. Other SNPs in the DIO1 gene, associated with control of thyroid hormone metabolism, were found to have a significant prognostic value in adult glioblastoma patients [11]. Most recently, a study found SNP polymorphisms in genes associated with aging, inflammation, dopamine, myelin cell cycle regulation, and DNA repair may be associated with neurocognitive outcomes in adult CNS tumor patients treated with radiation and chemotherapy [12].
There is a paucity of similar studies in children. In pediatric leukemia, certain SNPs, such as UGT2B17, have been correlated with treatment toxicity [13], neurocognitive outcomes [14, 15], and overall mortality. A deletion polymorphism in UGT2B17 is thought to suppress tumor growth, which could contribute to an overall greater prognosis and reduced chance of relapse [16]. Polymorphisms in the ACYP2 [17] and SOD [18] genes have also been associated with differences in cisplatin-induces ototoxicity. These studies focused primarily on SNPs in genes involved in folate metabolism, drug detoxification DNA repair genes [19].
Evidence regarding the use of genetic profiling in the treatment of brain tumor patients is limited. Previous studies have utilized SNP analysis of the primary tumor to help determine treatment response, but there is little data predicting treatment toxicity. SNP analysis of Glutathione S-transferase [GST] has been studied in relation to neurocognitive toxicity. GST is an enzyme that catalyzes glutathione conjugation of alkylating agents, platinum compounds, and free radicals produced by radiation. A SNP analysis of GST in medulloblastoma patients found that the presence of a null genotype was associated with a significant decline in IQ after treatment compared to patients with a no null genotype [20]. Another study found that GTSP1 105 AG/GG genotypes were much more likely to experience radiation induced hearing loss. Furthermore, the G allele in combination with high dose radiation was associated with greater risk of treatment-induced toxicity overall [21].
A study of participants in the Childhood Cancer Survivor Study (CCSS) evaluated GST and other antioxidant enzyme SNPs to determine if they were associated with neuropsychological impairment. On a Brief Symptoms Inventory-18 questionnaire, patients with a GST null genotype reported increased anxiety, depression, and global distress compared to patients with a non-null genotype. But while the CCSS Neurocognitive Questionnaire found poorer functioning in task efficiency and memory by self-report when patients treated for medulloblastoma were compared to sibling controls, there was no difference between genotypes associated with this select set of antioxidant enzymes [22]. A study looking at the association between COMT polymorphisms, coding for an enzyme used in the metabolism related to control of dopamine levels within the prefrontal cortex and working memory in pediatric brain tumor survivors found that patients with the Met/Val polymorphism variant had a greater working memory performance [23].
More recent research has investigated the association between the three most common polymorphisms in Vitamin D located within the Bsm-1, Fok-1, and Taq-1 regions of the receptor in pediatric brain tumors [24]. The vitamin D receptor binds calcitriol which is involved in several cell processes including cell proliferation, apoptosis, tumorigenesis, cell invasion, inflammatory response [25]. This study found that the association between polymorphisms in the Vitamin D receptor and cancer development was insignificant, but no research was done correlating identified polymorphisms in Vitamin D to response to treatment [24]. Additional studies look to identify how SNPs may be used in the diagnostics and prognosis of brain tumors [26], but do not correlate these SNPs to toxicity outcomes.
Finally, a study looked to evaluate p53 Arg72Pro polymorphism as an early detector of tumor progression in pediatric astrocytoma and found that having the Arg/Arg72 variant can be used to predict early tumor growth in partially resected astrocytomas. This study went further to suggest that this polymorphism could be used to inform and predict individual response to therapy [27].
There is mounting evidence of a link between the ability to repair DNA damage and not only the development of cancer, but also the response to therapy [28]. This is important for pediatric brain tumor patients as standard of care therapy involves DNA damaging agents such as radiation and chemotherapy. We hypothesized that somatic genetic variants in DNA repair genes may be associated with lower IQ scores in children treated for brain tumors. We genotyped 46 children who had been treated for a pediatric brain tumor and assessed whether SNP array profiles were associated with differences in IQ scores.