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[Cancer Research 66, 3987-3991, April 15, 2006]
© 2006 American Association for Cancer Research

Priority Reports

A Hypermutation Phenotype and Somatic MSH6 Mutations in Recurrent Human Malignant Gliomas after Alkylator Chemotherapy

Chris Hunter1, Raffaella Smith1, Daniel P. Cahill2, Philip Stephens1, Claire Stevens1, Jon Teague1, Chris Greenman1, Sarah Edkins1, Graham Bignell1, Helen Davies1, Sarah O'Meara1, Adrian Parker1, Tim Avis1, Syd Barthorpe1, Lisa Brackenbury1, Gemma Buck1, Adam Butler1, Jody Clements1, Jennifer Cole1, Ed Dicks1, Simon Forbes1, Matthew Gorton1, Kristian Gray1, Kelly Halliday1, Rachel Harrison1, Katy Hills1, Jonathon Hinton1, Andy Jenkinson1, David Jones1, Vivienne Kosmidou1, Ross Laman1, Richard Lugg1, Andrew Menzies1, Janet Perry1, Robert Petty1, Keiran Raine1, David Richardson1, Rebecca Shepherd1, Alexandra Small1, Helen Solomon1, Calli Tofts1, Jennifer Varian1, Sofie West1, Sara Widaa1, Andy Yates1, Douglas F. Easton3, Gregory Riggins4, Jennifer E. Roy2, Kymberly K. Levine2, Wolf Mueller2, Tracy T. Batchelor2, David N. Louis2, Michael R. Stratton1,5, P. Andrew Futreal1 and Richard Wooster1

1 Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; 2 Molecular Pathology Unit, Brain Tumor Center, Neurosurgical Service and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; 3 Cancer Research UK Genetic Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom; 4 Johns Hopkins University School of Medicine, Baltimore, Maryland; and 5 Institute of Cancer Research, Sutton, Surrey, United Kingdom

Requests for reprints: P. Andrew Futreal, Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom. Phone: 44-1223-494857; Fax: 44-1223-494809; E-mail: paf{at}sanger.ac.uk.

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. (Cancer Res 2006; 66(8): 3987-91)




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
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Copyright © 2006 by the American Association for Cancer Research.