SOD enzymes, which catalyze the spontaneous dismutation of the superoxide radical to hydrogen peroxide, are present in all parts of the nervous system, including the mitochondrial intermembrane space (SOD1; copper/zinc SOD), the mitochondrial matrix (SOD2; manganese SOD), and the plasma, lymph, and synovial fluid (SOD3; extracellular SOD).4,10
Red-blood-cell activity levels of SOD have been shown to be decreased for most types of intracranial neoplasm.11
The functionality of the SOD3
IVS1+186C>T polymorphism, for which we observed increased risk of meningioma and glioma, has not been characterized. The SOD2 Ala
variant, on the other hand, occurs at a mitochondrial targeting sequence and allows more efficient SOD2 enzyme uptake into the mitochondrial matrix, generating more active SOD2 compared with the Val
We observed increased risk of acoustic neuroma with the SOD2
(C allele) variant, consistent with the known functionality of the polymorphism, as well as previous studies that have observed increased risk of non-Hodgkin lymphoma,13
and bladder cancers20
with the Ala
variant. Other cancer studies, however, have observed no association (lung, breast cancer)21,22
or significantly decreased risk (marginal zone lymphoma)23
with the Ala
allele. In a prospective study of prostate cancer, the SOD2
V16A polymorphism did not have an overall effect, but strongly modified the relationship between prediagnostic serum antioxidant level and risk of prostate cancer.24
We observed no associations with the SOD1
variant and brain tumors, consistent with no association noted with SOD1
variants and prostate cancer.17
The enzyme CAT catalyzes the degradation of hydrogen peroxide into water and molecular oxygen and is found mainly in the peroxisomes but may also appear in plasma. Individuals with the common CC genotype of the CAT
rs1001179 variant have been shown to have significantly higher CAT activity compared with individuals with the T variant, and the high-activity CC CAT genotype has been associated with a significantly reduced risk of breast cancer, especially with high consumption of fruits and vegetables.25,26
We saw some indication of reduced risk of acoustic neuroma with the TT (low-activity) allele, but the lack of statistically significant trend and the unexpected direction of risk suggest that this may be a chance finding.
gene codes for the PON enzyme, which binds to high-density lipoprotein and contributes to the detoxification of organophosphates and lipid-soluble radicals from lipid peroxidation. Serum activity levels of PON1 have been shown to be lower in glioma and meningioma patients than in controls.27
A previous study of childhood brain tumors observed a nonstatistically significant increase in risk with the PON1
–108T allele, which became stronger and statistically significant when restricted to children whose mothers reported chemical treatment of the home for pests during pregnancy or childhood. The same study observed no association with the PON1
While we did not assess the –108T polymorphism and hence cannot compare results for that polymorphism, we detected no association with the Q192R polymorphism.
This study had adequate statistical power to detect moderate to strong main effects (OR
1.5) of common genetic polymorphisms for glioma and meningioma. After controlling for multiple comparisons using the false discovery rate, however, only the association between meningioma and SOD3 rs699473 remained of borderline significance. Strengths include standardized genotyping, high reproducibility of the genotyping results in the quality control samples, and controls in Hardy-Weinberg equilibrium for all but two polymorphisms. Given that deviation from Hardy-Weinberg equilibrium was not extreme (p
< 0.01) for either of these polymorphisms and that we observed no significant associations for the two SNPs in question, this is unlikely to affect our results. Rapid ascertainment of brain tumor cases and blood collection close to the date of diagnosis reduced the possibility that survival bias affected our results. Results of the analyses were very similar after excluding major groups of disease controls, one at a time.
Nevertheless, we underscore the need for replication of our findings given the false-positive reports generated in genetic association studies or the possibility that the notable SNPs are actually in linkage disequilibrium with other causally relevant polymorphisms. While nonparticipation in the blood draw was higher among controls than cases, we believe that this is unlikely to be related to genotype, and thus unlikely to bias our results.
Our findings suggest that SOD3, SOD2, and CAT may be promising candidates for brain tumor susceptibility genes and provide support for a role of the innate immune system in brain tumor etiology. Future research in this area should include more detailed coverage of polymorphisms within the genes implicated in this study, as well as other genes involved in the mediation of oxidative stress response.