A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy.
A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy.
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DOI：
10.1158/0008-5472.can-06-0127
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发表时间：
2006-04-15
期刊：
影响因子：
11.2
通讯作者：
Wooster R
中科院分区：
文献类型：
--
作者：
Hunter C;Smith R;Cahill DP;Stephens P;Stevens C;Teague J;Greenman C;Edkins S;Bignell G;Davies H;O'Meara S;Parker A;Avis T;Barthorpe S;Brackenbury L;Buck G;Butler A;Clements J;Cole J;Dicks E;Forbes S;Gorton M;Gray K;Halliday K;Harrison R;Hills K;Hinton J;Jenkinson A;Jones D;Kosmidou V;Laman R;Lugg R;Menzies A;Perry J;Petty R;Raine K;Richardson D;Shepherd R;Small A;Solomon H;Tofts C;Varian J;West S;Widaa S;Yates A;Easton DF;Riggins G;Roy JE;Levine KK;Mueller W;Batchelor TT;Louis DN;Stratton MR;Futreal PA;Wooster R
恶性胶质瘤预后很差。目前对这些癌症的标准治疗包括在手术切除和放疗后使用烷基化剂替莫唑胺进行延长的辅助治疗。尽管有统计数据表明，这种治疗方案的生存率显著提高，但几乎所有胶质瘤都会复发，并且对这类药物的进一步治疗不敏感。我们在9个胶质瘤中分别测序了对应于518个蛋白激酶结构域的500kb基因组DNA。两例脑胶质瘤经烷基化剂治疗后复发，出现大量体细胞突变。这些病例的突变模式与实验系统中烷基化剂引起的突变模式有很强的相似性。进一步的研究发现，在每个病例中失活的错配修复基因MSH6的体细胞突变。我们提出，MSH6的失活体细胞突变在体内赋予胶质瘤对烷基化剂的抗性，同时在存在缺陷错配修复的情况下，由于持续暴露于烷基化剂，在抗性克隆中释放加速突变。因此，有证据表明，当胶质瘤中的MSH6失活时，烷基化剂从诱导肿瘤细胞死亡转变为促进肿瘤进展。这些观察结果强调了大规模测序在揭示和阐明单个人类癌症中起作用的致突变过程方面的潜力。
Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statistically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents. We sequenced 500 kb of genomic DNA corresponding to the kinase domains of 518 protein kinases in each of nine gliomas. Large numbers of somatic mutations were observed in two gliomas recurrent after alkylating agent treatment. The pattern of mutations in these cases showed strong similarity to that induced by alkylating agents in experimental systems. Further investigation revealed inactivating somatic mutations of the mismatch repair gene MSH6 in each case. We propose that inactivating somatic mutations of MSH6 confer resistance to alkylating agents in gliomas in vivo and concurrently unleash accelerated mutagenesis in resistant clones as a consequence of continued exposure to alkylating agents in the presence of defective mismatch repair. The evidence therefore suggests that when MSH6 is inactivated in gliomas, alkylating agents convert from induction of tumor cell death to promotion of neoplastic progression. These observations highlight the potential of large scale sequencing for revealing and elucidating mutagenic processes operative in individual human cancers.