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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.

Original publication

DOI

10.1158/0008-5472.can-06-0127

Type

Journal

Cancer research

Publication Date

04/2006

Volume

66

Pages

3987 - 3991

Addresses

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.

Keywords

Humans, Glioma, Brain Neoplasms, Neoplasm Recurrence, Local, Dacarbazine, Protein Kinases, DNA-Binding Proteins, Antineoplastic Agents, Alkylating, Mutation, Aged, Middle Aged, Female, Male