Genetic variation in apoptosis gene predicts neurocognitive impairment in children with medulloblastoma

Purpose: Medulloblastoma is the most common malignant brain tumor in children. As survival rates have risen, the importance of permanent side effects of therapy has grown. Neurocognitive impairment is one of the most prominent chronic toxicities of treatment. Age and craniospinal radiation (CSI) dose are established risk factors, however this adverse outcome cannot be predicted. We hypothesized that host genetic polymorphisms in pathways involved in the inflammatory response to radiation would be associated with neurocognitive impairment in children with medulloblastoma. Experimental Design: This study included 40 children with medulloblastoma/primitive neuroectodermal tumor (PNET) seen at Texas Children\u27s Cancer Center or MD Anderson Cancer Center, who had been treated with CSI and had received a neuropsychological evaluation at least 9 months post-CSI. Subjects who had an intelligence-quotient score (full-scale, verbal, or performance) at or below 77.5 were deemed impaired. Genotyping of single nucleotide polymorphisms (SNPs) was performed using an Illumina HumanOmni1-Quad BeadChip. Only SNPs in relevant inflammation pathways were assessed. Odds ratios were estimated using unconditional logistic regression with adjustments for age group, CSI dose group, and a measure of population stratification. Results: There were 19 children with neurocognitive impairment and 21 were unimpaired. In univariate analyses, these groups did not differ by demographic, disease, or therapy characteristics. No individual SNPs were associated with neurocognitive impairment in children with medulloblastoma/PNET. However, an apoptosis gene, Caspase-2 and Receptor Interacting Protein Kinase-1 Domain Containing Adaptor with Death Domain (CRADD ), haplotype (rs11107146, rs2304439, and rs12582133) was associated with the outcome in univariate and multivariable models. Subjects with an AGA haplotype were more than 7 times more likely to be impaired than those with a GAG haplotype (OR 7.8, 95%CI 1.1-53.9). Conclusions: We have discovered a new association between CRADD and neurocognitive impairment in medulloblastoma/PNET. In the future, medulloblastoma patients with the at-risk genotypes may be considered for enrollment on clinical trials using reduced craniospinal radiation doses and/or novel anti-apoptotic strategies