Advances in the treatment of pediatric medulloblastoma have led to improved survival rates, though treatment-related toxicity leaves children with significant long-term deficits. There is significant variability in the cognitive outcome of medulloblastoma survivors, and it has been suggested that this variability may be attributable to genetic factors. The aim of this study was to explore the contributions of single nucleotide polymorphisms (SNPs) in two genes, peroxisome proliferator activated receptor (PPAR) and glutathione-S-transferase (GST), to changes in general intellectual functioning in medulloblastoma survivors.
Patients (n = 44, meanage = 6.71 years, 61.3% males) were selected on the basis of available tissue samples and neurocognitive measures. Patients received surgical tumor resection, craniospinal radiation, radiation boost to the tumor site, and multiagent chemotherapy. Genotyping analyses were completed using the Illumina Human Omni2.5 BeadChip, and 41 single nucleotide polymorphisms (SNPs) were assessed across both genes. We used a machine learning algorithm to identify polymorphisms that were significantly associated with declines in general intellectual functioning following treatment for medulloblastoma.
We identified age at diagnosis, radiation therapy, chemotherapy, and eight SNPs associated with PPARs as predictors of general intellectual functioning. Of the eight SNPs identified, PPARα (rs6008197), PPARγ (rs13306747), and PPARδ (rs3734254) were most significantly associated with long-term changes in general intellectual functioning in medulloblastoma survivors.
PPAR polymorphisms may predict intellectual outcome changes in children treated for medulloblastoma. Importantly, emerging evidence suggests that PPAR agonists may provide an opportunity to minimize the effects of treatment-related cognitive sequelae in these children.
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Funding for this work was provided by the Garron Family Cancer Center Small Grant Competition at The Hospital for Sick Children in Toronto. We thank Dr. Chao Lu for help with DNA microarray analysis, and Aziz Mezlini for help with our statistical approach.
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Supplementary material 1 Supplementary fig 1. Density plot of VIMP scores for variables with scores less than or equal to zero across all iterations of the prediction RFR model. Due to space considerations axes labels have been omitted. The dashed red line indicates a vimp score of zero. Values to the left of the dashed line indicate negative vimp scores. Supplementary fig 2. Boxplots showing the relationships between intellectual outcome and age at diagnosis, radiation therapy, and chemotherapy. Intellectual outcome was determined as the predicted change in FSIQ scores over time based on RFR model estimates. Older age at diagnosis predicted better intellectual outcome, while reduced craniospinal radiation with a tumor bed boost, as well as the SJMB03 chemotherapy protocol predicted better intellectual outcome. Radiation therapy: S-PF – Standard dose + posterior fossa boost, S-TB – Standard dose + tumor bed boost, R-PF – Reduced dose + posterior fossa boost, R-TB – Reduced dose + tumor bed boost. Chemotherapy protocols: CCCG 9961 (Vincristine, Lomustine, Cisplatin); POG 9631 (Etoposide, Cisplatin, Cyclophosphamide, Vincristine); SJMB03 (Vincristine, Cisplatin, Cyclophosphamide, Amifostine); 99703 (Vincristine, Cisplatin, Cyclophosphamide, Etoposide); ACNS 0331 (Lomustine, Cisplatin, Vincristine, Cyclophosphamide) (TIF 244 KB)
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Oyefiade, A., Erdman, L., Goldenberg, A. et al. PPAR and GST polymorphisms may predict changes in intellectual functioning in medulloblastoma survivors. J Neurooncol 142, 39–48 (2019). https://doi.org/10.1007/s11060-018-03083-x
- Random forest
- Intellectual functioning