Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.
Department of Psychology, University of Toronto, Toronto, ON, Canada.
J Neurooncol. 2019 Mar;142(1):39-48. doi: 10.1007/s11060-018-03083-x. Epub 2019 Jan 3.
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, mean = 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.
儿童髓母细胞瘤治疗的进展提高了生存率，但治疗相关的毒性会导致儿童出现严重的长期缺陷。髓母细胞瘤幸存者的认知结果存在显著差异，有人认为这种差异可能归因于遗传因素。本研究旨在探讨过氧化物酶体增殖物激活受体（PPAR）和谷胱甘肽-S-转移酶（GST）两个基因中的单核苷酸多态性（SNP）对髓母细胞瘤幸存者一般智力功能变化的贡献。
根据可用的组织样本和神经认知测量结果，选择了 44 名患者（平均年龄=6.71 岁，61.3%为男性）。患者接受了手术肿瘤切除、颅脊髓放疗、肿瘤部位放疗加量和多药化疗。使用 Illumina Human Omni2.5 BeadChip 完成基因分型分析，评估了两个基因中的 41 个单核苷酸多态性（SNP）。我们使用机器学习算法来识别与髓母细胞瘤治疗后一般智力功能下降显著相关的多态性。
我们确定了诊断时的年龄、放射治疗、化疗以及与 PPAR 相关的 8 个 SNP 是一般智力功能的预测因子。在确定的 8 个 SNP 中，PPARα（rs6008197）、PPARγ（rs13306747）和 PPARδ（rs3734254）与髓母细胞瘤幸存者一般智力功能的长期变化最显著相关。
PPAR 多态性可能预测儿童接受髓母细胞瘤治疗后的智力结果变化。重要的是，新出现的证据表明，PPAR 激动剂可能为减少这些儿童治疗相关认知后遗症提供机会。
