Abstract
Previous work has shown that DNA methylation in peripheral blood may be associated with malignancy; however, these studies have mainly been conducted within Caucasian populations. Here, we investigated the association between blood-based methylation of S100 calcium-binding protein P gene (S100P) and hyaluronoglucosaminidase 2 gene (HYAL2) and breast cancer (BC) via mass spectrometry in two independent case-control studies of the Chinese population with a total of 351 BC cases and 427 cancer-free female controls. In Study I, in which subjects had an average of 45 years, hypomethylation of S100P showed a protective effect for women ≤45 years (six out of nine CpG sites, p < 0.05) but not for women >45 years. In contrast, hypomethylation of HAYL2 was not correlated with BC in women ≤45 years but was a risk factor for women >45 years (three out of four CpG sites, p < 0.05). We proposed an age-dependent correlation between BC and methylation of S100P and HYAL2 and performed further validation in Study II with older subjects (average age = 52.5 years), where hypomethylation of both S100P and HYAL2 was a risk factor for BC (p < 0.05 for 10 CpG sites) as reported in Caucasians who develop BC around 55 years old. Together with the observation that Chinese cancer-free females having variant basal methylation levels comparing to Caucasians, we assumed that blood-based methylation might be modified by ethnic background, hormone status, and lifestyle. Here, we highlighted that the epigenetic biomarkers warrant validations when its application in variant ethnic groups is considered.
Highlights
As the most common cancer among women, breast cancer (BC) resulted in 2.1 million new cases and 626,679 deaths in 2018 according to the estimation of WHO (Bray et al, 2018)
The current study showed an association between increased methylation of S100 calcium-binding protein P gene (S100P) and BC (S100P_CpG_2.3, S100P_CpG_4, S100P_CpG_9, and S100P_CpG_10.11.12; all p ≤ 0.05; Figure 1A), which is contrary to the previous report in Caucasians that BC was associated with decreased methylation of S100P (Yang et al, 2017)
We reported the bloodbased hypomethylation of S100P and hyaluronoglucosaminidase 2 gene (HYAL2) as a risk factor for BC in the Caucasian population (Yang et al, 2015, 2017)
Summary
As the most common cancer among women, breast cancer (BC) resulted in 2.1 million new cases and 626,679 deaths in 2018 according to the estimation of WHO (Bray et al, 2018). Age, and family history are the major risk factors for BC (Benson et al, 2009). Even combining those three major factors with other known factors, such as lifestyle, exposure to hormones, and medical and reproductive factors, the predictive model for BC has an accuracy of just 58– 59% (Decarli et al, 2006). Genome-wide association studies have identified multiple variants with low-penetrance risk to BC, but a model of 10 single-nucleotide polymorphisms (SNPs) still only reached a predictive accuracy of 59.7% (Wacholder et al, 2010). There is still a lack of biomarkers for the evaluation of BC risk, especially for the early detection of BC
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