Authors' Affiliations: Departments of Neurology, Biostatistics, and Pathology, Neuro-Oncology Unit Erasmus MC, Rotterdam; AP-HP, Groupe Hospitalier Pitie Salpêtrière, Service de Neurologie 2 Mazarin and Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), Paris, France; Department of Pathology, UMCU, Utrecht; Department of Pathology, UMCG, Groningen; Department of Neurology, St. Elisabeth Hospital, Tilburg; Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen; Department of Pathology, Free University Medical Center, Amsterdam, the Netherlands; and European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium.
Clin Cancer Res. 2013 Oct 1;19(19):5513-22. doi: 10.1158/1078-0432.CCR-13-1157. Epub 2013 Aug 15.
The long-term follow-up results from the EORTC-26951 trial showed that the addition of procarbazine, CCNU, and vincristine (PCV) after radiotherapy increases survival in anaplastic oligodendrogliomas/oligoastrocytomas (AOD/AOA). However, some patients appeared to benefit more from PCV treatment than others.
We conducted genome-wide methylation profiling of 115 samples included in the EORTC-26951 trial and extracted the CpG island hypermethylated phenotype (CIMP) and MGMT promoter methylation (MGMT-STP27) status.
We first show that methylation profiling can be conducted on archival tissues with a performance that is similar to snap-frozen tissue samples. We then conducted methylation profiling on EORTC-26951 clinical trial samples. Univariate analysis indicated that CIMP+ or MGMT-STP27 methylated tumors had an improved survival compared with CIMP- and/or MGMT-STP27 unmethylated tumors [median overall survival (OS), 1.05 vs. 6.46 years and 1.06 vs. 3.8 years, both P < 0.0001 for CIMP and MGMT-STP27 status, respectively]. Multivariable analysis indicates that CIMP and MGMT-STP27 are significant prognostic factors for survival in presence of age, sex, performance score, and review diagnosis in the model. CIMP+ and MGMT-STP27 methylated tumors showed a clear benefit from adjuvant PCV chemotherapy: the median OS of CIMP+ samples in the RT and RT-PCV arms was 3.27 and 9.51 years, respectively (P = 0.0033); for MGMT-STP27 methylated samples, it was 1.98 and 8.65 years. There was no such benefit for CIMP- or for MGMT-STP27 unmethylated tumors. MGMT-STP27 status remained significant in an interaction test (P = 0.003). Statistical analysis of microarray (SAM) identified 259 novel CpGs associated with treatment response.
MGMT-STP27 may be used to guide treatment decisions in this tumor type.
EORTC-26951 试验的长期随访结果表明，放疗后添加洛莫司汀、卡莫司汀和长春新碱（PCV）可增加间变性少突胶质细胞瘤/少突星形细胞瘤（AOD/AOA）的生存率。然而，一些患者似乎比其他人从 PCV 治疗中获益更多。
我们对 EORTC-26951 试验中包含的 115 个样本进行了全基因组甲基化谱分析，并提取了 CpG 岛高甲基化表型（CIMP）和 MGMT 启动子甲基化（MGMT-STP27）状态。
我们首先表明，甲基化谱分析可以在具有与新鲜冷冻组织样本相似性能的存档组织上进行。然后，我们对 EORTC-26951 临床试验样本进行了甲基化谱分析。单因素分析表明，CIMP+或 MGMT-STP27 甲基化肿瘤的总生存期（OS）优于 CIMP-和/或 MGMT-STP27 未甲基化肿瘤[中位 OS（1.05 比 6.46 年和 1.06 比 3.8 年，CIMP 和 MGMT-STP27 状态的 P<0.0001]。多因素分析表明，CIMP 和 MGMT-STP27 是模型中年龄、性别、表现评分和复查诊断存在时生存的显著预后因素。CIMP+和 MGMT-STP27 甲基化肿瘤从辅助 PCV 化疗中明显获益：CIMP+样本在 RT 和 RT-PCV 臂的中位 OS 分别为 3.27 和 9.51 年（P=0.0033）；对于 MGMT-STP27 甲基化样本，中位 OS 分别为 1.98 和 8.65 年。对于 CIMP-或 MGMT-STP27 未甲基化肿瘤，没有这种获益。MGMT-STP27 状态在交互测试中仍然具有显著意义（P=0.003）。微阵列（SAM）的统计分析确定了 259 个与治疗反应相关的新 CpG。
MGMT-STP27 可用于指导该肿瘤类型的治疗决策。
