Searching for Blood DNA Methylation Markers of Breast Cancer Risk and Early Detection

Extract

In this issue of the Journal, Xu et al. (1) used prospectively collected blood samples to determine whether epigenome-wide methylation profiles in blood DNA differ between women who subsequently develop breast cancer and those who do not. Potentially, such a profile could predict the risk of developing breast cancer or detect this disease days to several years before it appears clinically. Existing breast cancer risk prediction models have limited discriminatory accuracy for this common disease (2), and improved methods for early detection are also needed (3,4). In this context, the findings of Xu et al. are promising and exemplify the potential value of epigenome-wide association studies (5,6). However, several important considerations temper the initial enthusiasm and highlight challenges for future studies.

In the Sister Study, a cohort of women with a biologic sister with breast cancer, DNA methylation at 27578 CpG sites was compared in blood samples that were stored at study entry from 298 women who developed breast cancer during follow-up and from a random sample of 612 women who remained cancer-free. This study is possibly the first cancer study to use prospectively collected blood and an epigenome-wide assay platform with single nucleotide resolution. Several epigenome-wide association studies have reported methylation profile differences in blood DNA from cancer case subjects and control subjects but relied on blood samples collected after cancer diagnosis and treatment (7). This retrospective design can induce bias if methylation levels are affected by disease progression or treatment.