A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy

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...

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Published in:	Cancer research (Chicago, Ill.) Ill.), 2006-04, Vol.66 (8), p.3987-3991
Main Authors:	HUNTER, Chris, SMITH, Raffaella, O'MEARA, Sarah, PARKER, Adrian, AVIS, Tim, BARTHORPE, Syd, BRACKENBURY, Lisa, BUCK, Gemma, BUTLER, Adam, CLEMENTS, Jody, COLE, Jennifer, DICKS, Ed, CAHILL, Daniel P, FORBES, Simon, GORTON, Matthew, GRAY, Kristian, HALLIDAY, Kelly, HARRISON, Rachel, HILLS, Katy, HINTON, Jonathon, JENKINSON, Andy, JONES, David, KOSMIDOU, Vivienne, STEPHENS, Philip, LAMAN, Ross, LUGG, Richard, MENZIES, Andrew, PERRY, Janet, PETTY, Robert, RAINE, Keiran, RICHARDSON, David, SHEPHERD, Rebecca, SMALL, Alexandra, SOLOMON, Helen, STEVENS, Claire, TOFTS, Calli, VARIAN, Jennifer, WEST, Sofie, WIDAA, Sara, YATES, Andy, EASTON, Douglas F, RIGGINS, Gregory, ROY, Jennifer E, LEVINE, Kymberly K, MUELLER, Wolf, TEAGUE, Jon, BATCHELOR, Tracy T, LOUIS, David N, STRATTON, Michael R, FUTREAL, P. Andrew, WOOSTER, Richard, GREENMAN, Chris, EDKINS, Sarah, BIGNELL, Graham, DAVIES, Helen
Format:	Article
Language:	eng
Subjects:	Aged Antineoplastic agents Antineoplastic Agents, Alkylating - therapeutic use Biological and medical sciences Brain Neoplasms - drug therapy Brain Neoplasms - enzymology Brain Neoplasms - genetics Dacarbazine - analogs & derivatives Dacarbazine - therapeutic use DNA-Binding Proteins - genetics Female Glioma - drug therapy Glioma - enzymology Glioma - genetics Humans Male Medical sciences Middle Aged Mutation Neoplasm Recurrence, Local - enzymology Neoplasm Recurrence, Local - genetics Neurology Pharmacology. Drug treatments Protein Kinases - genetics Temozolomide Tumors Tumors of the nervous system. Phacomatoses
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Summary:	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.
ISSN:	0008-5472 1538-7445