Germline Variation in Superoxide Dismutase-2 (SOD2) and Survival Outcomes after Radiation Therapy for Prostate Cancer: Results from a Test and Validation Set Analysis

Abstract

Background: Genetic variants in antioxidant pathways may decrease the efficacy of radiation therapy (RT) by suppressing the generation of reactive oxygen species (ROS). We studied the association between single nucleotide polymorphisms (SNPs) in the antioxidant gene superoxide dismutase-2 (SOD2) and cancer-specific outcomes after RT. Methods: Among 816 prostate cancer patients who received radiation as primary therapy from the Physicians’ Health Study and the Health Professionals Follow-up Study, we evaluated the association of 7 tagging SNPs in SOD2 with lethal prostate cancer (death from prostate cancer or distant metastasis among living patients). We sought to validate findings in a separate cohort of 612 prostate cancer patients treated with RT with a higher proportion of intermediate and high-risk Gleason scores at the Dana-Farber Cancer Institute. Genetic effects were analyzed using a co-dominant model, using the genotype homozygous for the major allele as baseline. Results: Among patients who underwent RT in the test cohort, there was a significant association between three of the seven SOD2 SNPs and lethal prostate cancer: rs6917589 (overall p-value =0.006), rs2758331 (p=0.04) and the functional valine to alanine polymorphism in rs4880 (p=0.04). These SNPs were not associated with outcome among men who had undergone prostatectomy. The associations were not replicated in the validation cohort. Conclusion: Germline genetic variation in the SOD2 gene may be a predictive biomarker of response to radiation therapy for prostate cancer but is not consistently associated with outcome after radiation therapy across prostate cancer cohorts with different clinical characteristics.