Deoxyribonucleic Acid 5-Hydroxymethylation in Cell-Free Deoxyribonucleic Acid, a Novel Cancer Biomarker in the Era of Precision Medicine

Abstract

Aberrant methylation has been regarded as a hallmark of cancer. 5-hydroxymethylcytosine (5hmC) is recently identified as the ten-eleven translocase (ten-eleven translocase)-mediated oxidized form of 5-methylcytosine, which plays a substantial role in DNA demethylation. Cell-free DNA has been introduced as a promising tool in the liquid biopsy of cancer. There are increasing evidence indicating that 5hmC in cell-free DNA play an active role during carcinogenesis. However, it remains unclear whether 5hmC could surpass classical markers in cancer detection, treatment, and prognosis. Here, we systematically reviewed the recent advances in the clinic and basic research of DNA 5-hydroxymethylation in cancer, especially in cell-free DNA. We further discuss the mechanisms underlying aberrant 5hmC patterns and carcinogenesis. Synergistically, 5-hydroxymethylation may act as a promising biomarker, unleashing great potential in early cancer detection, prognosis, and therapeutic strategies in precision oncology.

Ovarian Cancer Diagnosis and Prognosis Based on Cell-Free DNA Methylation

“… 15 , 34 By catalyzing the conversion of 5-methyl cytosine into its derivatives like 5-hydroxymethyl cytosine (5hmC), 5-carboxyl cytosine (5caC), and 5-formyl cytosine (5fC), TET family proteins alter the recognition of DNMT at the conversion site, facilitating the process of demethylation. 35 …”

Epigenetic reprogramming in cancer: From diagnosis to treatment

“…Similarly, other tumors, as breast, prostate and colorectal used cfDNA methylation to differentiate malignant and normal lesions, and prognosis stratification ( Zhang et al, 2021c ; Wu Q. et al, 2021 ; Chen et al, 2022a ; Rodriguez-Casanova et al, 2022 ). Besides target ctDNA methylation, cell-free genome-wide 5hmC has been recently used for cancer diagnosis and prognosis stratification ( Song et al, 2017 ; Xu et al, 2021 ; Shao et al, 2022 ). Despite the advances and promising use of cfDNA methylation in clinical oncology, there are some technical limitations that need to be addressed for use in clinical practice as a standard diagnostic tool ( Heidrich et al, 2021 ; Lone et al, 2022 ).…”

Cell-free DNA 5-hydroxymethylcytosine is highly sensitive for MRD assessment in acute myeloid leukemia

“…5-hydroxymethylcytosine (5hmC) is an emerging DNA marker in cancer and the first intermediate product in the oxidation of 5-methylcytosine (5mC) by ten-eleven-translocation proteins [ 5 , 6 ]. It is significantly correlated with gene expression and 5hmC levels change early and dynamically in cancer [ 5 , 6 ].…”

“…5-hydroxymethylcytosine (5hmC) is an emerging DNA marker in cancer and the first intermediate product in the oxidation of 5-methylcytosine (5mC) by ten-eleven-translocation proteins [ 5 , 6 ]. It is significantly correlated with gene expression and 5hmC levels change early and dynamically in cancer [ 5 , 6 ]. Specifically, a global decrease in 5hmC occurs in AML and many other malignancies and correlates with somatic mutations or abnormal expression in DNA-methylation-related genes in AML patients [ 5 – 7 ].…”

“…A high level of 5hmC is associated with adverse OS in AML [ 7 ]. Using a highly sensitive nano-hmC-Seal method, we and others have demonstrated that plasma cell-free DNA (cfDNA) 5hmC is highly sensitive for the detection and prognosis of AML and other malignancies [ 5 , 6 , 8 , 9 ]. Thus, we hypothesized that cfDNA 5hmC could act as a highly sensitive marker of MRD in AML.…”