Classification of Acute Myeloid Leukemia by Cell-Free DNA 5-Hydroxymethylcytosine

Abstract

Epigenetic abnormality is a hallmark of acute myeloid leukemia (AML), and aberrant 5-hydroxymethylcytosine (5hmC) levels are commonly observed in AML patients. As epigenetic subgroups of AML correlate with different clinical outcomes, we investigated whether plasma cell-free DNA (cfDNA) 5hmC could categorize AML patients into subtypes. We profiled the genome-wide landscape of 5hmC in plasma cfDNA from 54 AML patients. Using an unbiased clustering approach, we found that 5hmC levels in genomic regions with a histone mark H3K4me3 classified AML samples into three distinct clusters that were significantly associated with leukemia burden and survival. Cluster 3 showed the highest leukemia burden, the shortest overall survival of patients, and the lowest 5hmC levels in the TET2 promoter. 5hmC levels in the TET2 promoter could represent TET2 activity resulting from mutations in DNA demethylation genes and other factors. The novel genes and key signaling pathways associated with aberrant 5hmC patterns could add to our understanding of DNA hydroxymethylation and highlight the potential therapeutic targets in AML. Our results identify a novel 5hmC-based AML classification system and further underscore cfDNA 5hmC as a highly sensitive marker for AML.

Cell-Free DNA 5-Hydroxymethylcytosine Signatures for Lung Cancer Prognosis

“…CfDNA are degraded DNA fragments released into body fluids from both normal and tumor cells in cancer patients. Several studies, including our own, have shown that cfDNA 5hmC is a highly sensitive marker for the early detection of lung cancer and other cancer types [16][17][18][19][20][21][35][36][37][38][39][40][41][42][43][44]. Our group and others also demonstrated that a cfDNA 5hmC signature is significantly associated with patient prognosis in acute myeloid leukemia and pancreatic cancer [19,44].…”

“…Adjustment of treatment strategies based on prognostic biomarkers has demonstrated improved survival rates in other cancers, such as colon cancer [52]. cfDNA 5hmC markers have demonstrated remarkable versatility across various applications, exhibiting high sensitivity and specificity in pan-cancer detection [16][17][18][19][20][21][35][36][37][38][39][40][41][42][43] and the ability to differentiate cancer types and tissue origins [18,48]. This utility extends to predicting prognosis in various cancers, such as acute myeloid leukemia [19], pancreatic cancer [44], and lung cancer, as demonstrated herein.…”

“…An emerging epigenetic marker in the field of cancer research is 5-hydroxymethylcytosine (5hmC) [16][17][18][19][20][21]. 5hmC is an intermediate product of DNA demethylation, generated through the oxidation of 5-methylcytosine (5mC) by ten-eleven-translocation proteins [22].…”

5-Hydroxymethylcytosine in Cell-Free DNA Predicts Immunotherapy Response in Lung Cancer

“…As 5hmC closely correlates with gene expression [11], it may also serve as a reliable marker for changes in tumor gene expression in response to ICI treatment. Previous studies indicate that cfDNA 5hmC has a high sensitivity for cancer detection and prognosis prediction [30][31][32][33][34][35][36][37][38][39][40][41][42]. We further add to this body of evidence by demonstrating that cfDNA 5hmC can predict the therapeutic response in lung cancer patients receiving ICI therapy.…”

“…Using a highly sensitive nano-hmC-Seal method [29], we and others have demonstrated that 5hmC signatures in plasma cfDNA are highly sensitive for the early detection and prognosis of diverse cancers, including lung cancer [30][31][32][33][34][35][36][37][38][39][40][41][42]. However, the predictive value of cfDNA 5hmC in lung cancer immunotherapy response prediction remains unexplored.…”