Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer.
Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer.
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DOI：
10.1158/1078-0432.ccr-17-1958
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发表时间：
2018-03-15
期刊：
影响因子：
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通讯作者：
Dinulescu DM
中科院分区：
文献类型：
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作者：
Tucker DW;Getchell CR;McCarthy ET;Ohman AW;Sasamoto N;Xu S;Ko JY;Gupta M;Shafrir A;Medina JE;Lee JJ;MacDonald LA;Malik A;Hasselblatt KT;Li W;Zhang H;Kaplan SJ;Murphy GF;Hirsch MS;Liu JF;Matulonis UA;Terry KL;Lian CG;Dinulescu DM
以铂为基础的癌症治疗的一个主要挑战是对化疗耐药肿瘤的临床处理，这些肿瘤在表观遗传调节水平上的发病机制基本上未知。我们评估了使用5-羟甲基胞嘧啶(5-HMC)水平的全球丢失作为一种新的诊断和预后表观遗传学标记物来更好地评估高级别浆液性肿瘤(HGSOC)的铂类化疗反应和临床结果的可能性。HGSOC是卵巢癌中最常见和最致命的亚型。此外，我们确定了一条有针对性的途径，从遗传学和药理学上逆转这些表观遗传变化。这项研究表明，5-HMC水平降低是HGSOC恶性和肿瘤进展的表观遗传学标志。此外，在新诊断为HGSOC的患者中，全球5-HMC丢失与以铂为基础的化疗反应降低、复发时间较短以及总体存活率较低有关。有趣的是，挽救5-HMC的丢失在体外和体内恢复了对铂类化疗的敏感性，减少了使用癌症干细胞标记物的肿瘤细胞的百分比，并在铂耐药疾病的侵袭性动物模型中提高了总存活率。因此，未来的临床试验应该包括对患者5-HMC水平的全球分析，这些临床试验使用表观遗传佐剂预处理来提高5-HMC水平，并改善当前化疗的疗效。找出预后的表观遗传学标志物，改变化疗方案，在低5-HMC水平的肿瘤中加入DNMTi预处理，对新诊断的HGSOC疾病具有重要的临床意义。
A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy in vitro and in vivo, decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease. Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease.