Abstract LB-368: Mitochondrial DNA and cancer in the normative aging study

Background: Mitochondrial DNA (mtDNA) is a potentially sensitive marker of damage by reactive oxygen species (ROS). Two biomarkers in mtDNA, copy number (mtDNAcn) and 8-OHdG, have therefore been proposed as potential markers of oxidative stress and therefore carcinogenesis. Prospective human studies subjects of mtDNAcn have found inconsistent results, but many suggest that the interval between mtDNAcn measurement and cancer diagnosis affects the association. Moreover, prior studies suggest that the interplay of mtDNAcn and 8-OHdG reflect ongoing oxidative stress related to carcinogenesis, suggesting their potential use in tandem as an early detection biomarker of cancer. Our objective was to examine longitudinal associations between mtDNAcn and 8-OHdG measured in whole blood in relation to both cancer incidence and mortality. Methods: We studied 526 Normative Aging Study participants who had blood drawn 1-4 times from 1999 through 2012 and who were cancer free at first blood draw (median 9.7 years between blood draw and cancer diagnosis/censoring). mtDNAcn and 8-OHdG were measured using quantitative real-time PCR. We used Cox proportional hazards regression models to examine associations between mtDNAcn and mitochondrial 8-OHdG measured at the first blood draw only as well as time-dependent associations across a total of 1043 blood draws and time to all-cancer diagnosis. We ran a second set of models stratified by time between blood draw and diagnosis/censoring, and a third set that explored possible interaction between mtDNAcn and 8-OHdG via inclusion of a product term. All models adjusted for age, BMI, white blood cell count, proportion neutrophils, race, education, smoking status, pack-years of smoking, and alcohol consumption. Results: We found no significant associations between pre-diagnostic mtDNAcn and time to cancer diagnosis or death. When measured at the first blood draw only, 8-OHdG was inversely associated with all-cancer (HR: 0.17; 95% CI: 0.03-0.87) and prostate cancer incidence (HR: 0.05; 95% CI: 0.00-0.97). In the time-dependent models, mitochondrial 8-OHdG was inversely associated with time to all-cancer diagnosis (HR: 0.31; 95% CI: 0.10-1.01) and positively associated with time to all-cancer death (HR: 1.83; 95% CI: 1.13-2.98), while mtDNAcn was positively and independently associated with time to all-cancer death (HR: 1.59; 95% CI: 1.17-2.15; pinteraction = 0.96). In the stratum of 4-6 years between blood draw and diagnosis, 8-OHdG was associated with cancer incidence (HR: 0.01; 95% CI: 0-1.00). Modeling 8-OHdG and mtDNAcn together produced no noteworthy changes in results. Similarly, the test for interaction was non-significant across all models. Conclusion: Pre-diagnostic mtDNAcn does not appear to be significantly associated with cancer, however mitochondrial 8-OHdG may be a significant predictor of cancer several years prior to diagnosis. Mitochondiral markers of oxidative stress may also be significant predictors of cancer mortality, possibly related to metastasis and/or treatment. Additional prospective studies in larger cohorts with greater racial/ethnic, gender, and socioeconomic diversity are needed to validate the utility of 8-OHdG as an early detection biomarker of cancer. Future studies of mitochondrial oxidative stress markers measurable in blood and cancer mortality are warranted. Citation Format: Brian T. Joyce, Tao Gao, Yinan Zheng, Lei Liu, Andrea Baccarelli, Joel Schwartz, Lifang Hou. Mitochondrial DNA and cancer in the normative aging study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-368.