Pediatric brain tumors: Gene X environment interactions providing new clues?

I n this issue of Pediatric Blood & Cancer, Lupo et al. have provided new thought-provoking clues to factors involved in the development of pediatric medulloblastomas/primitive neuroectodermal tumors (M/PNETs) by examining whether ambient chlorinated solvent exposure increases M/PNET risk in relation to DNA repair and detoxification genotypes. Medulloblastoma is an embryonal tumor of the cerebellum representing the most common malignant pediatric brain tumor affecting approximately 300 children (aged 0–19 years) each year in the United States [1]. PNETs are histologically similar to medulloblastomas occurring in the brain at non-cerebellar sites [2] affecting approximately 200 U.S. children each year. Ten-year survival rates for M/PNETs combined are approximately 60% [1]. Poor survival together with long-term adverse health outcomes for many patients as a result of their treatment [3] underscores the need to understand more about the biology of these malignancies and factors influencing their development. The causes of M/PNETs are mostly unknown being limited to high dose ionizing radiation exposure and a few rare genetic syndromes [2]. Previous studies have reported positive associations between childhood brain tumors and markers of exposure to chlorinated solvents [4–6], which are classified as hazardous air pollutants (HAPs) by the U.S. Environmental Protection Agency. Lupo et al. speculated that the carcinogenic effect of chlorinated solvents on M/PNETs could occur through formation of genotoxic DNA adducts during xenobiotic detoxification reactions followed by failed DNA repair. To gain insight into whether this mechanism may be at play for pediatric M/PNETs, Lupo et al. examined associations between an ecologic measurement of chlorinated solvent exposure and DNA repair and detoxification enzyme genotypes in 98 cases (59 M and 39 PNETs) ascertained from Texas Children’s Hospital and MD Anderson Cancer Center using a case-only analysis. The case-only analysis tests for gene X environment interactions by determining whether the exposure odds is significantly higher in individuals with a certain genotype versus those without that genotype. The authors genotyped 15 xenobiotic detoxification and DNA repair gene variants. A measure of residential exposure to chlorinated solvents at each case’s diagnosis address was obtained from predictions generated by the U.S. EPA’s 1999 ASPEN model that estimates a quantitative exposure level based on ambient levels of chlorinated solvents taking into account several factors including emissions data and meteorological conditions. The authors used unconditional logistic regression to estimate case-only odds ratios (ORs) and 95% confidence intervals (CIs) for the interaction between DNA repair/detoxification genotypes and exposure to four chlorinated solvents (methylene chloride, perchlorethylene, trichloroethylene, and vinyl chloride), controlling for ancestry. The authors reported 11 significant interactions between DNA repair/detoxification genotypes and chlorinated solvent exposure. In the authors’ most stringent analysis that adjusted for multiple comparisons, one of these interactions remained significant. There was a significant interaction between a minor allele of the OGG1 gene (rs293795) in association with living in census tracts with trichloroethylene levels >90th percentile versus <90th percentile (OR 1⁄4 9.24; 95% CI 2.24–38.24). OGG1 is a DNA repair gene that is involved in base excision of DNA adducts which could theoretically be caused by trichloroethylene exposure. The authors concluded from their results that a potential interaction may exist between individual genotypes and chlorinated solvent exposure but acknowledge that their results are exploratory and in need of confirmation. Several limitations of this study merit consideration when evaluating the probable role for the interaction between chlorinated solvent exposure and common variants in OGG1 in M/PNET risk. Major limitations of this and most other childhood cancer etiology studies are the small sample sizes and imprecise exposure estimates as a result of their retrospective assessment through ecological or survey methods. This study included only 98 cases which makes spurious associations a possible explanation for the results. With regard to exposure assessment, the temporal association between the exposure and cancer development in cases was unclear. Exposure to ambient chlorinated solvents was assessed through model predictions at a single time point at the case’s diagnosis address which may not be the etiologically relevant time point if the carcinogenic event(s) occurred earlier at another residence. A particularly vulnerable period for embryonal tumors is thought to be during fetal development and it is unclear whether the in utero period was captured by the case’s diagnosis address. Although the authors give reason to believe that residential mobility was unlikely to impact the results, they could not assess this in their dataset. There is also uncertainty about whether trichloroethylene is the most likely candidate M/PNET