Abstract 3676: Race-specific methylation profiles and epigenetic age acceleration differentiates estrogen receptor status breast cancer
Authors: Wu Yanning , Thompson Cheryl L. , Schumacher Fredrick R. 
Published: June 2022

Breast cancer (BrCa) is the second most common cancer among women in the U.S.. Black women with BrCa, on average, have an earlier age of onset, more aggressive subtypes and experience higher mortality compared with White women. Although the underlying causes remain unknown, genetic and lifetime exposures are hypothesized. Here, we utilize blood-based whole-genome methylation arrays to: (1) discover CpG probes related to BrCa receptor status, (2) identify biological pathways driving BrCa subtype disparities, and (3) quantify epigenetic age acceleration differences by race and receptor status.

DNA methylation levels were generated for 95 blood samples from women diagnosed with BrCa using the Illumina EPIC array. After quality control, M-values for 91 samples and 808,329 methylation probes were evaluated using a modified Student t-test. BrCa estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status were collected from health records. Stratified analyses by race adjusting for age were applied. We calculated the association of age acceleration, based on Horvath’s epigenetic clock, by race and receptor status. Statistical significance, corrected for multiple testing, was defined as a p-valueadj &lt;0.05.

Among the 91 BrCa samples, nearly half were Black women (40.7%) and the overall mean age at diagnosis was 56.5 years ±11.3. The majority of BrCa tumors were ER-, 60.4% (N=55), and HER2-, 76.9% (N=70). Overall, two methylation probes significantly differentiated ER+/- BrCa. The most significant methylated gene was FOXK2 (p-valueadj=0.03, logFC=0.63). The race-stratified analysis identified 188,398 probes for ER+/- and five probes for HER2+/- among White women as marginally significant (p&lt;0.05). Two genes (FAM107B, PRKCZ) for ER+/- BrCa and four genes (ZNF430, TTC27, SEC1 and NOS1AP) for HER2+/- BrCa remained statistically significant after correcting for multiple comparisons (p-valueadj &lt; 0.05; |logFC| &gt;1). The mean age acceleration is estimated as 3.7 years greater for Black women compared to White women. Among White women, the mean age acceleration was 1.9 years greater for ER+ than ER- subtypes, and those HER2- were 2.2 years older than HER2+. Similarly, among Black women the mean age acceleration difference for ER- was 3.2 years greater than ER+, and HER2- was 3.8 years older than HER2+.

Our study confirmed (e.g. FOXK2) and identified several novel methylation sites associated with BrCa subtypes. Furthermore, we demonstrated in our study that epigenetic age acceleration of BrCa varies by race, with Black women biologically aging faster than White women. Although this is a limited sample size, stratified analyses revealed biological age differences by race and receptor status. In-depth pathway analyses and measuring additional samples are underway. Lastly, differential methylation profiles for known risk factors of aggressive tumors will be evaluated.

Citation Format: Yanning Wu, Cheryl L. Thompson, Fredrick R. Schumacher. Race-specific methylation profiles and epigenetic age acceleration differentiates estrogen receptor status breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3676.