Reduction of global 5-hydroxymethylcytosine is a poor prognostic factor in breast cancer patients, especially for an ER/PR-negative subtype

Breast Cancer Res Treat. 2015 Aug;153(1):219-34. doi: 10.1007/s10549-015-3525-x. Epub 2015 Aug 8.

Abstract

DNA methylation at the 5 position of cytosine (5 mC) is an epigenetic hallmark in cancer. The 5 mC can be converted to 5-hydroxymethylcytosine (5 hmC) through a ten-eleven-translocation (TET). We investigated the impact of 5 mC, 5 hmC, TET1, and TET2 on tumorigenesis and prognosis of breast cancer. Immunohistochemistry was used to assess the levels of 5 mC, 5 hmC, TET1, and TET2 in the corresponding tumor adjacent normal (n = 309), ductal carcinoma in situ (DCIS, n = 120), and invasive ductal carcinoma (IDC, n = 309) tissues for 309 breast ductal carcinoma patients. 5 mC, 5 hmC, TET1-n, and TET2-n were significantly decreased during DCIS and IDC progression. In IDC, the decrease of 5 hmC was correlated with the cytoplasmic mislocalization of TET1 (p < 0.001) as well as poor disease-specific survival (DSS) (adjusted hazard ratio [AHR] 1.95, p = 0.003) and disease-free survival (DFS) (AHR 1.91, p = 0.006). The combined decrease of 5 mC and 5 hmC was correlated with worse DSS (AHR 2.19, p = 0.008) and DFS (AHR 1.99, p = 0.036). Stratification analysis revealed that the low level of 5 mC was associated with poor DSS (AHR 1.89, p = 0.044) and DFS (AHR 2.02, p = 0.035) for the ER/PR-positive subtype. Conversely, the low level of 5 hmC was associated with worse DSS (AHR 2.77, p = 0.002) and DFS (AHR 2.69, p = 0.006) for the ER/PR-negative subtype. The decreases of 5 mC, 5 hmC, TET1-n, and TET2-n were biomarkers of tumor development. The global reduction of 5 hmC was a poor prognostic factor for IDC, especially for ER/PR-negative subtype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / analogs & derivatives
  • Adult
  • Aged
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality*
  • Breast Neoplasms / pathology
  • Cytosine / analogs & derivatives*
  • Cytosine / metabolism
  • DNA Methylation*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dioxygenases
  • Female
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • Middle Aged
  • Mixed Function Oxygenases
  • Neoplasm Grading
  • Neoplasm Staging
  • Prognosis
  • Protein Transport
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Receptors, Estrogen / deficiency
  • Receptors, Progesterone / deficiency
  • Risk Factors
  • Survival Analysis
  • Young Adult

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Receptors, Estrogen
  • Receptors, Progesterone
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Cytosine
  • Mixed Function Oxygenases
  • TET1 protein, human
  • Dioxygenases
  • TET2 protein, human