Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma.
Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma.
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DOI：
10.1038/srep22477
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发表时间：
2016-03-04
影响因子：
4.6
通讯作者：
Howell VM
中科院分区：
文献类型：
--
作者：
Parker NR;Hudson AL;Khong P;Parkinson JF;Dwight T;Ikin RJ;Zhu Y;Cheng ZJ;Vafaee F;Chen J;Wheeler HR;Howell VM
异质性是胶质母细胞瘤的一个特征，肿瘤内的异质性导致对标准治疗的反应不同和抵抗。DNA修复酶O6-甲基鸟嘌呤DNA甲基转移酶(MGMT)启动子甲基化状态是胶质母细胞瘤最重要的临床生物标志物，可预测治疗反应。然而，它并不总是与反应相关。这可能是由于肿瘤内的异质性，单个活检不太可能代表整个病变。其他DNA修复机制中的异常也可能是原因之一。这项研究调查了多发性胶质母细胞瘤的瘤内异质性，特别关注DNA修复途径。40%的病例发现肿瘤内转录异质性，14%的病例发现MGMT甲基化状态的变异性。除了在转录和表观遗传水平上确定肿瘤内的异质性外，有针对性的下一代测序确定了每个样本1至37个独特的序列变异。然后，硅内工具能够识别碱基切除修复和错配修复途径中可能有助于治疗反应的有害变异。由于这些通路在替莫唑胺的反应中起作用，这些发现可能会混淆患者的治疗，并强调评估多次肿瘤活检的重要性。
Heterogeneity is a hallmark of glioblastoma with intratumoral heterogeneity contributing to variability in responses and resistance to standard treatments. Promoter methylation status of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) is the most important clinical biomarker in glioblastoma, predicting for therapeutic response. However, it does not always correlate with response. This may be due to intratumoral heterogeneity, with a single biopsy unlikely to represent the entire lesion. Aberrations in other DNA repair mechanisms may also contribute. This study investigated intratumoral heterogeneity in multiple glioblastoma tumors with a particular focus on the DNA repair pathways. Transcriptional intratumoral heterogeneity was identified in 40% of cases with variability in MGMT methylation status found in 14% of cases. As well as identifying intratumoral heterogeneity at the transcriptional and epigenetic levels, targeted next generation sequencing identified between 1 and 37 unique sequence variants per specimen. In-silico tools were then able to identify deleterious variants in both the base excision repair and the mismatch repair pathways that may contribute to therapeutic response. As these pathways have roles in temozolomide response, these findings may confound patient management and highlight the importance of assessing multiple tumor biopsies.