Abstract 146: DNA methylation age of paired tumor-normal breast tissue in Chinese women with breast cancer
Authors: Koka Hela , Zhu Bin , Tse Shelly Lap Ah , Wang Difei , Kiely Maeve , Guida Jennifer Lyn , Lee Priscilla , Wang Feng , Wu Cherry , Tsang Koon Ho , Chan Wing-cheong , Law Sze Hong , Karlins Eric , Zhu Bin , Hutchinson Amy , Hicks Belynda , Yang Xiaohong R. 
Published: September 2020

Background: Epigenetic age, captured by DNA methylation changes, is thought to be more informative with respect to disease risk and progression, than chronological age. A few studies have associated epigenetic age acceleration (EAA), the difference between DNA methylation age (DNAm age) and chronological age, with BC risk and subtypes. However, most of these studies were conducted in Western populations. In this study, we examined EAA in an Asian population, in which BC incidence rate is lower and age at BC onset is younger compared to most Western populations.

Methods: We performed genome-wide DNA methylation profiling of 97 tumor and 89 paired distant normal tissue samples collected from BC patients in Hong Kong (HK) using an Illumina MethylationEPIC array. Two independent datasets were used to compare results: The Cancer Genome Atlas (TCGA, n=525 tumor and n=88 adjacent normal) and healthy women from the Komen tissue bank (n=59). DNAm age was calculated using Horvath's model based on 353 CpGs. The significance of EAA was tested using a simple linear regression model. We also used a multivariate regression model to test for equality of slopes (EAA rates) among different BC subtypes or datasets, considering interaction terms between age and subtype/dataset.

Results: The average age at BC diagnosis was 58 years old (range: 33-81) and the distribution of the molecular subtype based on PAM50 was 43.0%, 29.1%, and 27.9% for luminal A, luminal B, and HER2-enriched/basal tumors, respectively. As expected, DNAm age showed a stronger correlation with chronological age in normal tissue (r=0.78, p&lt;.0001) than in tumor tissue (r=0.27, p=0.0075). The average EAAs in normal and tumor samples were 9.43 and 6.02 years, respectively. Among different BC subtypes, EAA in normal tissue did not vary by subtypes. However, in tumor samples, luminal patients showed positive EAA (average 10/13 years in luminal A/B, respectively), while HER2-enriched/basal patients showed a negative EAA (average -8 years), although the rate of EAA did not vary significantly by subtype. Analyses on TCGA data produced consistent results. When comparing the rate of DNAm acceleration in normal tissue of HK, TCGA, and Komen, HK patients had a significantly different rate (βHK=0.46) compared to TCGA (βTCGA=0.65, p=0.001) and Komen (βKomen=0.80, p&lt;.0001).

Conclusion: Consistent with previous studies, we found that EAA in tumor samples varied across tumor subtypes. We also found that HK BC patients' epigenetic age accelerated at a different rate compared to predominantly white TCGA and Komen women, suggesting a potential racial biological difference. Large studies in other Asian populations are warranted to confirm our findings, which may provide biological insight into racial heterogeneity of BC, especially with regard to age at onset.

Citation Format: Hela Koka, Bin Zhu, Shelly Lap Ah Tse, Difei Wang, Maeve Kiely, Jennifer Lyn Guida, Priscilla Lee, Feng Wang, Cherry Wu, Koon Ho Tsang, Wing-cheong Chan, Sze Hong Law, Eric Karlins, Bin Zhu, Amy Hutchinson, Belynda Hicks, Xiaohong R. Yang. DNA methylation age of paired tumor-normal breast tissue in Chinese women with breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 146.