DNA methylation array analyses identified breast cancer‐associated HYAL2 methylation in peripheral blood

Abstract

Breast cancer (BC) is the leading cause of cancer-related mortality in women worldwide. Changes in DNA methylation in peripheral blood could be associated with malignancy at early stage. However, the BC-associated DNA methylation signatures in peripheral blood were largely unknown. Here, we performed a genome-wide methylation screening and identified a BC-associated differentially methylated CpG site cg27091787 in the hyaluronoglucosaminidase 2 gene (HYAL2) (discovery round with 72 BC case and 24 controls: p 5 2.61 3 10 29 adjusted for cell-type proportions). The substantially decreased methylation of cg27091787 in BC cases was confirmed in two validation rounds (first validation round with 338 BC case and 507 controls: p < 0.0001; second validation round with 189 BC case and 189 controls: p < 0.0001). In addition to cg27091787, the decreased methylation of a 650-bp CpG island shore of HYAL2 was also associated with increased risk of BC. Moreover, the expression and methylation of HYAL2 were inversely correlated with a p-value of 0.006. To note, the BC-associated decreased HYAL2 methylation was replicated in the T-cell fraction (p 5 0.034). The cg27091787 methylation level enabled a powerful discrimination of earlystage BC cases (stages 0 and I) from healthy controls [area under curve (AUC) 5 0.89], and was robust for the detection of BC in younger women as well (age < 50, AUC 5 0.87). Our study reveals a strong association between decreased HYAL2 methylation in peripheral blood and BC, and provides a promising blood-based marker for the detection of early BC.Breast cancer (BC) is the most common cancer and the leading cause of cancer-related mortality among women, 1 with 1.7 million new cases and 522,000 deaths in 2012. 2 In the United States, one in eight women will develop BC in her lifetime. 3 Although therapeutic advances have improved the survival rate, most BC patients still suffer from greatly

Blood-based DNA methylation as biomarker for breast cancer: a systematic review

“…After excluding non-eligible articles (see Fig. 1a and Additional file 1: Supplementary materials), 45 articles could be included in this review, including 26 articles used DNA isolated from whole blood [14–21, 24–41], two articles used DNA isolated from both whole blood and plasma [42, 43], six articles used DNA isolated from plasma [44–49], and 11 articles used DNA isolated from serum [50–60] (Table 1). For the studies that used serum or plasma as DNA source, four of them used two centrifugation steps to get serum or plasma [42, 45, 47, 48] and the rest used one centrifugation step or sample processing procedures are not available (Table 1).…”

“…Yang et al [21] showed that reduced methylation levels of the HYAL2 gene were significantly associated with increased BC risk. Specifically, women in the highest quartile of HYAL2 methylation were reported to have a 41.47-fold (cohort I) and a 132.98-fold (cohort II) increased BC risk, compared with women in the lowest quartile (Fig.…”

Breast Cancer Intra-Tumor Heterogeneity: One Tumor, Different Entities

“…Many biomarker genes have been proposed and evaluated; nevertheless, in the absence of a unique biomarker having sufficient specificity and sensitivity, a panel of multiple genes should be used [121][122][123] . Modifications of cancer-related genes could occur at genetic and epigenetic levels, affecting DNA repair.…”

Genomic-Wide Analysis with Microarrays in Human Oncology

“…To validate genome-wide DNA methylation profiles during multistage hepatocarcinogenesis, Ammerpohl et al [105] revealed that the methylation status have changed gradually from normal to cirrhosis and further to HCC using a methylation array. Nagashiro et al [106] established criteria for carcinogenetic risk estimation based on DNA methylation array profiling to compare samples of noncancerous liver tissue obtained from HCC patients with normal liver tissue samples.…”