Abstract P2-09-02: Evidence of accelerated epigenetic aging of breast tissues in patients with breast cancer compared to women without cancer
Authors: Hofstatter Erin , Levine Morgan , Liu Zuyun , O'Meara Tess , Dalela Disha , Pusztai Lajos 
Published: March 2020

Background: Age is the largest risk factor for breast cancer development. Faster biological aging, particularly in breast tissue, may predispose women to higher risk of developing breast cancer. Recently, a set of promising biomarkers of aging, called “epigenetic clocks” (also referred to as “epigenetic age”) have been developed to estimate aging rates in tissues and cells. Using one of the original epigenetic clocks based on DNA methylation patterns, we previously demonstrated that normal breast tissue from luminal breast cancer patients exhibited accelerated aging compared to patients without breast cancer. Here we test whether incorporation of nearly a dozen epigenetic clocks, each capturing slightly different biological aging phenomena, can consistently distinguish normal breast tissue from cancer patients versus healthy controls. We also examined concordance between epigenetic age assessment from paired breast tissue and peripheral blood mononuclear cells.

Methods: We examined 282 specimens including DNA from 94 normal breast tissues (41 from patients with breast cancer, and 53 from non-cancer controls) and 188 blood samples (97 from breast cancer, and 91 from controls). DNA methylation was assessed via the Illumina HumanMethylation450k and HumanMethylationEPIC BeadChip for both tissue and blood samples, and 11 epigenetic clocks were calculated following published methods. Associations of these clocks with breast cancer were examined using logistic regression models and Receiver Operating Characteristics (ROC) curves to determine predictive power in distinguishing samples from cancer patients versus healthy controls.

Results: After accounting for chronological age, we observed increases in most epigenetic clocks for cancer patients compared to normal samples from controls, which indicates accelerated epigenetic aging (e.g., Zhang clock in tissue, 0.55 vs. -0.42; in blood, 0.10 vs. -0.20, all P&lt;0.05). When including age, Zhang clock showed the best predictive power of breast cancer in tissues (Area Under The Curve [AUC] =0.79, 95% Confidence Interval [CI]: 0.69, 0.87) and including all clocks further improved the predictive power (AUC=0.89, 95% CI: 0.83, 0.95). However, all clocks exhibited moderate predictive powers in blood (all AUC&lt;0.7), even when combining them together (AUC=0.70, 95% CI: 0.62, 0.77). In 80 participants with both tissue and blood samples, we observed highest concordance for Hannum clock (bicor=0.43) and lowest concordance for Zhang clock (bicor =-0.19).

Conclusions: Epigenetic aging-based biomarkers distinguish non-tumor breast tissues of patients with breast cancer from breast tissues of healthy controls. These findings raise the possibility that epigenetic markers assessed on needle biopsies of the breast might identify individuals at risk for developing breast cancer.

Citation Format: Erin Hofstatter, Morgan Levine, Zuyun Liu, Tess O'Meara, Disha Dalela, Lajos Pusztai. Evidence of accelerated epigenetic aging of breast tissues in patients with breast cancer compared to women without cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-09-02.