Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Pediatr Blood Cancer. 2010 Dec 1;55(6):1066-71. doi: 10.1002/pbc.22634.
Alkylating agents are commonly used in the treatment of childhood malignant gliomas. Overexpression of O(6)-methylguanine-DNA methyltransferase (MGMT) constitutes an important mechanism for resistance to such agents, and MGMT status has been associated with outcome in several recent trials. Deficiency in mismatch repair (MMR) function has been implicated in preclinical studies as an additional potential mechanism of resistance to methylating agents, such as temozolomide, independent of tumor MGMT status. However, the frequency of this abnormality as a clinical resistance mechanism in childhood malignant gliomas has not been well characterized.
To address this issue, we examined the frequency of microsatellite instability (MSI), a marker of defective MMR, in a series of 68 tumors, derived from newly diagnosed patients treated on the Children's Cancer Group 945 study, and the Children's Oncology Group ACNS0126 and 0423 studies. MSI was assessed using a panel of six microsatellite markers, including BAT-25, BAT-26, CAT-25, D2S123, D5S346, and D17S250. MGMT immunoreactivity was assessed in parallel to allow comparison of the relative incidence of MGMT overexpression and MSI.
Only three tumors had high-level MSI involving three or more markers; the remainder had no MSI at any of the loci examined. These children did not have unusual features in terms of their outcome. In contrast to the infrequency of MSI, 25 tumors (37%) exhibited MGMT overexpression as assessed by immunohistochemistry. None of the tumors with MSI exhibited overexpression of MGMT.
MMR deficiency is an infrequent contributor to initial alkylator resistance in children with malignant gliomas.
烷基化剂常用于治疗儿童恶性脑肿瘤。O(6)-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）的过度表达构成了对这些药物产生耐药性的重要机制，MGMT 状态与几项近期试验的结果相关。在临床前研究中，错配修复（MMR）功能缺陷被认为是对诸如替莫唑胺等烷化剂的另一种潜在耐药机制，这种机制与肿瘤 MGMT 状态无关。然而，这种异常作为儿童恶性脑肿瘤的临床耐药机制的频率尚未得到很好的描述。
为了解决这个问题，我们检查了微卫星不稳定性（MSI）的频率，这是 MMR 缺陷的一个标志物，在一系列 68 个肿瘤中，这些肿瘤来自新诊断的接受儿童癌症组 945 研究、儿童肿瘤组 ACNS0126 和 0423 研究治疗的患者。使用一组 6 个微卫星标记物（BAT-25、BAT-26、CAT-25、D2S123、D5S346 和 D17S250）评估 MSI。平行评估 MGMT 免疫反应性，以比较 MGMT 过度表达和 MSI 的相对发生率。
只有三个肿瘤具有涉及三个或更多标记物的高水平 MSI；其余肿瘤在所有检测的位点均没有 MSI。这些患儿的预后没有不寻常的特征。与 MSI 的罕见性相反，25 个肿瘤（37%）通过免疫组织化学评估表现出 MGMT 过度表达。没有一个具有 MSI 的肿瘤表现出 MGMT 的过度表达。
在患有恶性脑肿瘤的儿童中，MMR 缺陷是初始烷基化剂耐药的罕见原因。
