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

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.

Decreased 5-hydroxymethylcytosine levels correlate with cancer progression and poor survival: a systematic review and meta-analysis

“…Ultimately, ten studies were chosen for the final analysis (Figure 1). The articles included one hepatocellular carcinoma study, one glioblastoma study, one gastric cancer study, one esophageal squamous cell carcinoma study, one prostate cancer study, one ovarian cancer study, one intrahepatic cholangiocarcinoma study, one kidney cancer study, one breast cancer study and one cervical cancer study [11, 12, 14–21]. The characteristics of the included studies are listed in Table 1.…”

Characterization of TET and IDH gene expression in chronic lymphocytic leukemia: comparison with normal B cells and prognostic significance

“…Another study suggested that loss of %5-hmC may be due to simple nuclear exclusion of the oxidases [56]. For breast cancer, reduced %5-hmC was assessed as a biomarker of tumor development [57], and TET1 decreases were linked to poor prognosis [58]. To our knowledge, no other team has performed a prognostic study of TET enzymes in CLL.…”

Potential options for managing LOX+ ER− breast cancer patients

“…The outcomes of treatments aimed at suppressing key signaling pathways are far from satisfying due to the heterogeneity of ER– tumors [13]. At present, much effort is focused on the molecular subtyping of ER– breast cancers [3, 4]. For example, molecular markers such as mTOR and Src are reportedly involved in the development of ER– tumor metastasis [14].…”

“…In addition, the molecular subtypes of ER– tumors are not well defined due to their biological heterogeneity. In recent years, however, a number of potential signaling pathways driving ER– breast cancer have been identified [3, 4]. This makes targeted therapy focusing on a specific molecular subtype a potentially effective strategy for managing ER– breast cancer patients.…”