Cahill Daniel P, Levine Kymberly K, Betensky Rebecca A, Codd Patrick J, Romany Candice A, Reavie Linsey B, Batchelor Tracy T, Futreal P Andrew, Stratton Michael R, Curry William T, Iafrate A John, Louis David N
Molecular Pathology Unit, Neurosurgical Service, Brain Tumor Center, and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Clin Cancer Res. 2007 Apr 1;13(7):2038-45. doi: 10.1158/1078-0432.CCR-06-2149.
Glioblastomas are treated by surgical resection followed by radiotherapy [X-ray therapy (XRT)] and the alkylating chemotherapeutic agent temozolomide. Recently, inactivating mutations in the mismatch repair gene MSH6 were identified in two glioblastomas recurrent post-temozolomide. Because mismatch repair pathway inactivation is a known mediator of alkylator resistance in vitro, these findings suggested that MSH6 inactivation was causally linked to these two recurrences. However, the extent of involvement of MSH6 in glioblastoma is unknown. We sought to determine the overall frequency and clinical relevance of MSH6 alterations in glioblastomas.
The MSH6 gene was sequenced in 54 glioblastomas. MSH6 and O(6)-methylguanine methyltransferase (MGMT) immunohistochemistry was systematically scored in a panel of 46 clinically well-characterized glioblastomas, and the corresponding patient response to treatment evaluated.
MSH6 mutation was not observed in any pretreatment glioblastoma (0 of 40), whereas 3 of 14 recurrent cases had somatic mutations (P = 0.015). MSH6 protein expression was detected in all pretreatment (17 of 17) cases examined but, notably, expression was lost in 7 of 17 (41%) recurrences from matched post-XRT + temozolomide cases (P = 0.016). Loss of MSH6 was not associated with O(6)-methylguanine methyltransferase status. Measurements of in vivo tumor growth using three-dimensional reconstructed magnetic resonance imaging showed that MSH6-negative glioblastomas had a markedly increased rate of growth while under temozolomide treatment (3.17 versus 0.04 cc/mo for MSH6-positive tumors; P = 0.020).
Loss of MSH6 occurs in a subset of post-XRT + temozolomide glioblastoma recurrences and is associated with tumor progression during temozolomide treatment, mirroring the alkylator resistance conferred by MSH6 inactivation in vitro. MSH6 deficiency may therefore contribute to the emergence of recurrent glioblastomas during temozolomide treatment.
胶质母细胞瘤通过手术切除，随后进行放射治疗[X射线治疗（XRT）]和烷化剂化疗药物替莫唑胺进行治疗。最近，在两例替莫唑胺治疗后复发的胶质母细胞瘤中发现错配修复基因MSH6存在失活突变。由于错配修复途径失活是体外烷化剂耐药的已知介导因素，这些发现提示MSH6失活与这两例复发存在因果关系。然而，MSH6在胶质母细胞瘤中的累及程度尚不清楚。我们试图确定胶质母细胞瘤中MSH6改变的总体频率及临床相关性。
对54例胶质母细胞瘤的MSH6基因进行测序。在一组46例临床特征明确的胶质母细胞瘤中，对MSH6和O(6)-甲基鸟嘌呤甲基转移酶（MGMT）进行免疫组化系统评分，并评估相应患者的治疗反应。
在任何未经治疗的胶质母细胞瘤中均未观察到MSH6突变（40例中0例），而14例复发病例中有3例存在体细胞突变（P = 0.015）。在所有检测的未经治疗的病例（17例中的17例）中均检测到MSH6蛋白表达，但值得注意的是，在XRT + 替莫唑胺治疗后匹配的复发病例中，17例中有7例（41%）表达缺失（P = 0.016）。MSH6缺失与O(6)-甲基鸟嘌呤甲基转移酶状态无关。使用三维重建磁共振成像测量体内肿瘤生长情况显示，在替莫唑胺治疗期间，MSH6阴性的胶质母细胞瘤生长速率明显增加（MSH6阳性肿瘤为0.04 cc/月，MSH6阴性肿瘤为3.17 cc/月；P = 0.020）。
MSH6缺失发生在XRT + 替莫唑胺治疗后复发的一部分胶质母细胞瘤中，并且与替莫唑胺治疗期间的肿瘤进展相关，这与体外MSH6失活赋予的烷化剂耐药情况相似。因此，MSH6缺陷可能导致替莫唑胺治疗期间复发性胶质母细胞瘤的出现。
