Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment.
Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment.
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DOI：
10.1158/1078-0432.ccr-06-2149
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发表时间：
2007-04-01
期刊：
影响因子：
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通讯作者：
Louis DN
中科院分区：
文献类型：
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作者：
Cahill DP;Levine KK;Betensky RA;Codd PJ;Romany CA;Reavie LB;Batchelor TT;Futreal PA;Stratton MR;Curry WT;Iafrate AJ;Louis DN
胶质母细胞瘤通过手术切除，然后放疗（XRT）和烷化剂替莫唑胺（TMZ）治疗。最近，错配修复（MMR）基因MSH 6的失活突变在TMZ后复发的胶质母细胞瘤中被发现。由于MMR途径失活是体外烷化剂抗性的已知介体，这些发现表明MSH 6失活与这两种复发有因果关系。然而，MSH 6在胶质母细胞瘤中的参与程度尚不清楚。我们试图确定胶质母细胞瘤中MSH 6改变的总体频率和临床相关性。对54例胶质母细胞瘤进行了MSH 6基因测序。在一组46例临床特征良好的胶质母细胞瘤中对MSH 6和MGMT免疫组化进行系统评分，并评价相应的患者对治疗的反应。在任何治疗前胶质母细胞瘤中均未观察到MSH 6突变（0/40），而3/14例复发病例具有体细胞突变（p=0.015）。在所有治疗前（17/17）检查病例中检测到MSH 6蛋白表达，但值得注意的是，在匹配的XRT +TMZ后病例中，7/17例复发病例中表达缺失（41%，p=0.016）。MSH 6的缺失与MGMT状态无关。使用3D重建MRI测量体内肿瘤生长表明，在TMZ治疗下，MSH 6阴性胶质母细胞瘤的生长速率显著增加（3.17 cc/月对MSH 6阳性肿瘤的0.04 cc/月，p=0.020）。MSH 6的丢失发生在XRT +TMZ治疗后胶质母细胞瘤复发的亚组中，并且与TMZ治疗期间的肿瘤进展相关，反映了体外MSH 6失活所赋予的烷化剂抗性。因此，MSH 6缺乏可能导致TMZ治疗期间复发性胶质母细胞瘤的出现。
Glioblastomas are treated by surgical resection followed with radiotherapy (XRT) and the alkylating chemotherapeutic agent temozolomide (TMZ). Recently, inactivating mutations in the mismatch repair (MMR) gene MSH6 were identified in two glioblastomas recurrent post-TMZ. Since MMR pathway inactivation is a known mediator of alkylator resistance in vitro, these findings suggested 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 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 pre-treatment glioblastoma (0/40), while 3/14 recurrent cases had somatic mutations (p=0.015). MSH6 protein expression was detected in all pre-treatment (17/17) cases examined but, notably, expression was lost in 7/17 recurrences from matched post-XRT+TMZ cases (41%, p=0.016). Loss of MSH6 was not associated with MGMT status. Measurements of in vivo tumor growth using 3D-reconstructed MRI demonstrated that MSH6-negative glioblastomas had a markedly increased rate of growth while under TMZ treatment (3.17 cc/month vs. 0.04 cc/month for MSH6-positive tumors, p=0.020). Loss of MSH6 occurs in a subset of post-XRT+TMZ glioblastoma recurrences, and is associated with tumor progression during TMZ treatment, mirroring the alkylator resistance conferred by MSH6 inactivation in vitro. MSH6 deficiency may therefore contribute to the emergence of recurrent glioblastomas during TMZ treatment.