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

Int J Cancer. 2015 Apr 15;136(8):1845-55. doi: 10.1002/ijc.29205. Epub 2014 Sep 24.


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 = 2.61 × 10(-9) 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 = 0.034). The cg27091787 methylation level enabled a powerful discrimination of early-stage BC cases (stages 0 and I) from healthy controls [area under curve (AUC) = 0.89], and was robust for the detection of BC in younger women as well (age < 50, AUC = 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.

Keywords: HYAL2; breast cancer; early detection; marker; methylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / genetics
  • Breast Neoplasms / blood
  • Breast Neoplasms / diagnosis*
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Cell Adhesion Molecules / blood
  • Cell Adhesion Molecules / genetics*
  • CpG Islands / genetics
  • DNA Methylation / genetics*
  • Early Detection of Cancer / methods
  • Female
  • GPI-Linked Proteins / blood
  • GPI-Linked Proteins / genetics
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Hyaluronoglucosaminidase / blood
  • Hyaluronoglucosaminidase / genetics*
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis / methods
  • Young Adult


  • Biomarkers, Tumor
  • Cell Adhesion Molecules
  • GPI-Linked Proteins
  • Hyal2 protein, human
  • Hyaluronoglucosaminidase