Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA.
Cancer Res. 2022 Nov 2;82(21):3888-3902. doi: 10.1158/0008-5472.CAN-22-1123.
Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease.
In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.
分析 DNA 甲基化是了解疾病进展的一种有价值的工具，并且越来越多地被用于创建诊断和预后的临床生物标志物。虽然胞嘧啶转化为 5-甲基胞嘧啶（5mC）通常会导致转录抑制，但进一步转化为 5-羟甲基胞嘧啶（5hmC）与转录激活有关。在这里，我们首次在良性、局限性和晚期前列腺癌的临床样本中进行了全基因组 5hmC 与 DNA、5mC 和转录组测序的整合研究。5hmC 被证明可以标记癌症驱动基因和下游靶基因的激活。此外，5hmC 测序揭示了整个疾病过程中细胞状态的深刻改变，其特征是增殖增加、致癌信号转导、去分化和向神经内分泌和胃肠道谱系的谱系可塑性。最后，对转移性疾病患者的循环游离 DNA 进行 5hmC 测序被证明是一种有用的预后生物标志物，能够利用 TOP2A 和 EZH2 这两个基因识别前列腺癌的侵袭性亚型，而这些基因以前只能通过实体瘤活检的转录组分析来检测。总的来说，这些发现表明 5hmC 标记了前列腺癌中的表观基因组激活，并确定了前列腺癌进展的特征，具有作为侵袭性疾病生物标志物的潜力。
在前列腺癌中，5-羟甲基胞嘧啶描绘了癌基因的激活和特定阶段的细胞状态，可以在液体活检中进行分析，以检测癌症表型。见 Wu 和 Attard 发表的相关文章，第 3880 页。
Zotero 插件
