The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients
The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients
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DOI：
10.1158/1078-0432.ccr-03-0732
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发表时间：
2004-07-01
影响因子：
11.5
通讯作者：
Brown, R
中科院分区：
文献类型：
--
作者：
Gifford, G;Paul, J;Brown, R
异常的表观遗传调控，例如 CpG 岛甲基化和相关的基因转录沉默，与包括癌症在内的多种人类疾病有关。参与细胞凋亡的基因的甲基化，包括 DNA 错配修复 (MMR) 基因 hMLH1，可能发生在化疗药物耐药的肿瘤模型中。然而，患者肿瘤化疗获得性耐药的相关性仍未得到证实。癌症患者（包括卵巢癌患者）的血浆 DNA 通常含有与肿瘤相同的 DNA 变化，并提供了监测 CpG 岛甲基化变化的方法。我们检查了参加 SCOTROC1 III 期临床试验的上皮性卵巢癌患者的血浆 DNA，以检测卡铂/紫杉烷化疗前和复发时 hMLH1 CpG 岛的甲基化情况。 hMLH1 甲基化在复发时增加，25%（138 个中的 34 个）复发样本具有 hMLH1 甲基化，而在匹配的化疗前血浆样本中未检测到。此外，hMLH1 甲基化与复发时血浆 DNA 中微卫星不稳定性的增加显着相关，从而提供了 MMR 通路功能的独立测量。复发时血浆 DNA 中 hMLH1 甲基化的获得预测患者总体生存率较差，与时间、进展和年龄无关（风险比，1.99；95% 置信区间，1.20-3.30；P = 0.007）。这些数据支持卵巢癌患者化疗后获得性 hMLH1 甲基化和伴随的 DNA MMR 丧失的临床相关性。血浆中 DNA 甲基化的变化有可能定义治疗期间的甲基化模式，并确定适合新型表观遗传疗法的患者群体。
Aberrant epigenetic regulation, such as CpG island methylation and associated transcriptional silencing of genes, has been implicated in a variety of human diseases, including cancer. Methylation of genes involved in apoptosis, including the DNA mismatch repair (MMR) gene hMLH1, can occur in tumor models of resistance to chemotherapeutic drugs. However, the relevance for acquired resistance to chemotherapy of patients' tumors remains unsubstantiated. Plasma DNA from cancer patients, including those with ovarian cancer, often contains identical DNA changes as the tumor and provides a means to monitor CpG island methylation changes. We have examined plasma DNA of patients with epithelial ovarian cancer enrolled in the SCOTROC1 Phase III clinical trial for methylation of the hMLH1 CpG island before carboplatin/taxoid chemotherapy and at relapse. Methylation of hMLH1 is increased at relapse, and 25% (34 of 138) of relapse samples have hMLH1 methylation that is not detected in matched prechemotherapy plasma samples. Furthermore, hMLH1 methylation is significantly associated with increased microsatellite instability in plasma DNA at relapse, providing an independent measure of function of the MMR pathway. Acquisition of hMLH1 methylation in plasma DNA at relapse predicts poor overall survival of patients, independent from time to progression and age (hazard ratio, 1.99; 95% confidence interval, 1.20-3.30; P = 0.007). These data support the clinical relevance of acquired hMLH1 methylation and concomitant loss of DNA MMR after chemotherapy of ovarian cancer patients. DNA methylation changes in plasma provide the potential to define patterns of methylation during therapy and identify those patient populations who would be suitable for novel epigenetic therapies.