Abstract 4251: DNA methylation of mitochondrial biogenesis regulating genes: A possible link between telomeres, mitochondria, and cancer incidence
Authors: Kresovich Jacob K. , Gao Tao , Joyce Brian T. , Vokonas Pantel , Schwartz Joel , Baccarelli Andrea A. , Hou Lifang 
Published: July 2017

Background: PGC1A and PGC1B encode transcriptional 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. Animal studies have also shown that loss of PGC1A protects against cancer as mitochondrial function is required for transformation and tumor growth. No human studies have examined the role of these genes in relation to cancer incidence. Our objective was to examine associations between PGC1A and PGC1B methylation in relation to cancer incidence.

Methods: We studied 491 Normative Aging Study participants who had blood drawn 1-4 times from 1999 through 2012. After median 10.2-year follow-up, there were 125 incident cancers including 36 prostate. PGC1A and PGC1B methylation was measured at 30 and 27 sites, respectively, using the HumanMethylation450k assay. We used Cox proportional hazards models to examine associations between CpG methylation and cancer incidence measured at first blood draw as well as in time-dependent associations. All models adjusted for age, race, smoking status and pack-years, alcohol consumption, blood cell composition, and processing batch.

Results: In single-site adjusted time-dependent models, we identified 13 instances of 11 individual loci (10 from PGC1A and 1 from PGC1B) significantly associated with all-cancer and prostate cancer incidence. In multi-site adjusted models, we showed cg0677257 from the 3’ UTR of PGC1A was inversely associated with first-visit (HR: 0.41; 95% CI: 0.21, 0.79) and time-dependent all-cancer incidence (HR: 0.42; 95% CI: 0.22, 0.81). Similarly, we showed cg0942771 and cg03281309 from the gene body of PGC1A were inversely associated with time-dependent all-cancer incidence (HR: 0.51; 95% CI: 0.30, 0.88; HR: 0.74; 95% CI: 0.56, 0.98, respectively). Finally, we found that cg1521939 from the 5’ UTR region of PGC1B was positively associated with time-dependent all-cancer incidence (HR: 3.27; 95% CI: 1.55, 6.90).

Conclusion: This is the first study in humans to show site-specific PGC1A and PGC1B methylation is a significant predictor of cancer incidence. These findings point to a possible interplay between telomere and mitochondrial dysfunction, and epigenetics in carcinogenesis. Additional studies should also examine these associations in larger cohorts with greater racial/ethnic, gender, and socioeconomic diversity to validate these findings.

Citation Format: Jacob K. Kresovich, Tao Gao, Brian T. Joyce, Pantel Vokonas, Joel Schwartz, Andrea A. Baccarelli, Lifang Hou. DNA methylation of mitochondrial biogenesis regulating genes: A possible link between telomeres, mitochondria, and cancer incidence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4251. doi:10.1158/1538-7445.AM2017-4251