title: 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.
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, 386 Ta-Chung 1st Road, 81362, Kaohsiung, Taiwan.
authors.forename: Kuo-Wang
authors.initials: KW
authors.lastname: Tsai
authors.forename: Guan-Cheng
authors.initials: GC
authors.lastname: Li
authors.forename: Chien-Hsun
authors.initials: CH
authors.lastname: Chen
authors.forename: Ming-Hsin
authors.initials: MH
authors.lastname: Yeh
authors.forename: Jer-Shyung
authors.initials: JS
authors.lastname: Huang
authors.forename: Hui-Hwa
authors.initials: HH
authors.lastname: Tseng
authors.forename: Ting-Ying
authors.initials: TY
authors.lastname: Fu
authors.forename: Huei-Han
authors.initials: HH
authors.lastname: Liou
authors.forename: Hung-Wei
authors.initials: HW
authors.lastname: Pan
authors.forename: Sheng-Feng
authors.initials: SF
authors.lastname: Huang
authors.forename: Chien-Chou
authors.initials: CC
authors.lastname: Chen
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Chang
authors.forename: Luo-Ping
authors.initials: LP
authors.lastname: Ger
authors.forename: Hong-Tai
authors.initials: HT
authors.lastname: Chang
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D006899:Mixed Function Oxygenases; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000172:deficiency; D011980:Receptors, Progesterone / Q000172:deficiency; D012307:Risk Factors; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human