Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment.
Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment.
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DOI：
10.1007/s00401-015-1403-6
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发表时间：
2015-04
影响因子：
12.7
通讯作者：
Costello JF
中科院分区：
文献类型：
--
作者：
van Thuijl HF;Mazor T;Johnson BE;Fouse SD;Aihara K;Hong C;Malmström A;Hallbeck M;Heimans JJ;Kloezeman JJ;Stenmark-Askmalm M;Lamfers ML;Saito N;Aburatani H;Mukasa A;Berger MS;Söderkvist P;Taylor BS;Molinaro AM;Wesseling P;Reijneveld JC;Chang SM;Ylstra B;Costello JF
替莫唑胺（TMZ）可提高胶质母细胞瘤（GBM）患者的总生存率，但其在弥漫性低级别胶质瘤（LGG）临床管理中的作用仍有待确定。O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）启动子的DNA超甲基化与TMZ治疗反应的改善相关，而DNA错配修复（MMR）途径的失活与治疗抗性和TMZ诱导的诱变相关。我们先前证明，TMZ治疗LGG诱导RB和AKT-mTOR通路中的驱动突变，这可能导致恶性进展为继发性GBM。为了更好地理解TMZ诱导的突变和恶性进展的机制，我们在34例未经治疗的LGG及其复发的队列中探索了MGMT甲基化和影响MMR基因的遗传改变的演变。与未治疗的初始肿瘤相比，具有TMZ相关超突变的复发患者的MGMT甲基化增加，并且与TMZ治疗的非超突变复发患者相比，总体MGMT甲基化更高。TMZ相关的突变在一个或多个MMR基因中观察到五个六TMZ治疗，高度突变复发。在两种情况下，预先存在的杂合缺失包括MGMT，或MMR基因，其次是TMZ相关的突变在一个感兴趣的基因。这些结果表明，在MMR缺陷的情况下，具有甲基化MGMT的肿瘤细胞在TMZ治疗期间可能经历正选择。
Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ treated, hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.
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影响因子：
6.4
作者：
Grasbon-Frodl, Eva M.;Kreth, Friedrich Wilhelm;Kretzschmar, Hans A.
通讯作者：
Kretzschmar, Hans A.
DOI：
10.1073/pnas.0710052104
发表时间：
2007-12-11
影响因子：
11.1
作者：
Beroukhim, Rameen;Getz, Gad;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
2.2
作者：
Giraldo, A;Gómez, A;Barvo, R
通讯作者：
Barvo, R
影响因子：
5.3
作者：
COSTELLO, JF;FUTSCHER, BW;PIEPER, RO
通讯作者：
PIEPER, RO
影响因子：
48
作者：
Douw, Linda;Klein, Martin;Heimans, Jan J.
通讯作者：
Heimans, Jan J.