Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA.
Department of Medicine, The University of Chicago, Chicago, IL, USA.
Sci Rep. 2022 Jul 20;12(1):12410. doi: 10.1038/s41598-022-16685-3.
Aberrant changes in 5-hydroxymethylcytosine (5hmC) are a unique epigenetic feature in many cancers including acute myeloid leukemia (AML). However, genome-wide analysis of 5hmC in plasma cell-free DNA (cfDNA) remains unexploited in AML patients. We used a highly sensitive and robust nano-5hmC-Seal technology and profiled genome-wide 5hmC distribution in 239 plasma cfDNA samples from 103 AML patients and 81 non-cancer controls. We developed a 5hmC diagnostic model that precisely differentiates AML patients from controls with high sensitivity and specificity. We also developed a 5hmC prognostic model that accurately predicts prognosis in AML patients. High weighted prognostic scores (wp-scores) in AML patients were significantly associated with adverse overall survival (OS) in both training (P = 3.31e-05) and validation (P = 0.000464) sets. The wp-score was also significantly associated with genetic risk stratification and displayed dynamic changes with varied disease burden. Moreover, we found that high wp-scores in a single gene, BMS1 and GEMIN5 predicted OS in AML patients in both the training set (P = 0.023 and 0.031, respectively) and validation set (P = 9.66e-05 and 0.011, respectively). Lastly, our study demonstrated the genome-wide landscape of DNA hydroxymethylation in AML and revealed critical genes and pathways related to AML diagnosis and prognosis. Our data reveal plasma cfDNA 5hmC signatures as sensitive and accurate markers for AML diagnosis and prognosis. Plasma cfDNA 5hmC analysis will be an effective and minimally invasive tool for AML management.
5-羟甲基胞嘧啶（5hmC）的异常改变是包括急性髓系白血病（AML）在内的许多癌症的独特表观遗传特征。然而，在 AML 患者中，血浆无细胞游离 DNA（cfDNA）的全基因组 5hmC 分析仍未得到充分利用。我们使用了一种高度敏感和稳健的纳米 5hmC-Seal 技术，对 103 名 AML 患者和 81 名非癌症对照的 239 个血浆 cfDNA 样本进行了全基因组 5hmC 分布分析。我们开发了一种 5hmC 诊断模型，该模型具有高灵敏度和特异性，能够精确地区分 AML 患者和对照组。我们还开发了一种 5hmC 预后模型，能够准确预测 AML 患者的预后。在 AML 患者中，加权预后评分（wp-scores）较高与训练集（P=3.31e-05）和验证集（P=0.000464）中的不良总生存期（OS）显著相关。wp-score 还与遗传风险分层显著相关，并随着疾病负担的变化而发生动态变化。此外，我们发现单个基因 BMS1 和 GEMIN5 中的高 wp-score 可预测 AML 患者的 OS，在训练集和验证集中的 P 值分别为 0.023 和 0.031（P=9.66e-05 和 0.011，分别）。最后，我们的研究展示了 AML 中 DNA 羟甲基化的全基因组图谱，并揭示了与 AML 诊断和预后相关的关键基因和途径。我们的数据显示，cfDNA 5hmC 特征可作为 AML 诊断和预后的敏感且准确的标志物。cfDNA 5hmC 分析将成为 AML 管理的有效和微创工具。
