Presenting Author:

Jacob Kresovich, Ph.D.

Principal Investigator:

Lifang Hou

Department:

Preventive Medicine

Keywords:

Cancer incidence, DNA methylation, Oxidative stress, PGC1A, PGC1B

Location:

Ryan Family Atrium, Robert H. Lurie Medical Research Center

C108 - Clinical

DNA methylation of mitochondrial biogenesis regulating genes: A possible link between telomeres, mitochondria, and cancer incidence

Background: PGC1A and PGC1B encode transcription factors that regulate mitochondrial biogenesis and have been implicated as a link between telomeric and mitochondrial functions. Telomere dysfunction is associated with impaired mitochondrial biogenesis and increased generation of reactive oxygen species. Loss of PGC1A has been shown to be protective against cancer as mitochondrial function is required for transformation and tumor growth. No studies have examined the prospective relationship between methylation of these genes and cancer incidence. Methods: We studied 491 Normative Aging Study participants with blood drawn 1-4 times from 1999 through 2012. After median 10.2-year follow-up, there were 125 incident cancers. PGC1A and PGC1B methylation was measured at 29 and 27 sites, respectively, using the HumanMethylation450k assay. We used Cox proportional hazards models to examine associations between DNA methylation and cancer incidence measured at baseline and in time-dependent models. We conducted regional methylation analysis to identify spatially-clustered associations. Finally, we examined associations between DNA methylation and mitochondrial 8-OHdG, a marker of oxidative stress. All models adjusted for age, race, smoking status and pack-years, alcohol consumption, blood cell composition, and processing batch. Results: In baseline models, we showed PGC1A promoter methylation was associated with all-cancer incidence (cg04893087, HR: 0.67, p = 0.03). Further, PGC1A gene body methylation was associated at cg1095595 (HR: 0.58, p = 0.01), cg13730600 (HR: 0.60, p = 0.04), cg24716152 (HR: 0.66, p = 0.04), cg07744449 (HR: 1.32, p = 0.01), cg02105087 (HR: 1.32, p = 0.05), and cg05150667 (HR: 1.42, p = 0.03). In regional analyses, the associations with cg07744449, cg02105087 and cg05150667 persisted. In time-dependent models, we identified associations between PGC1A gene body methylation and all-cancer incidence (namely, cg10955995, HR: 0.59, p = 0.01; cg09427718, HR: 0.60, p = 0.01, 0.90; cg03281309, HR: 0.77, p = 0.04) and cg15219393 from the 5’ UTR region of PGC1B (HR: 2.77, p < 0.001). We found PGC1A gene body methylation at three sites (cg07744449, cg02105087 and cg05150667) that were significantly associated with all-cancer incidence in the regional analysis were also inversely associated with mitochondrial 8-OHdG in both baseline and time-dependent analyses. Using the change-of-coefficient method, mitochondrial 8-OHdG mediated between 8-13% of these associations. Conclusion: This is the first study to show site-specific PGC1A and PGC1B methylation is a significant predictor of cancer incidence. We further demonstrated methylation of PGC1A may promote oxidative stress as measured by mitochondrial 8-OHdG, which itself may serve as a potential mechanism to explain our findings. Additional studies examining these associations in larger cohorts with greater racial/ethnic, gender, and socioeconomic diversity are needed to validate these findings.