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

Chris Hunter, Raffaella Smith, Daniel P. Cahill, Philip Stephens, Claire Stevens, Jon Teague, Chris Greenman, Sarah Edkins, Graham Bignell, Helen Davies, Sarah O'Meara, Adrian Parker, Tim Avis, Syd Barthorpe, Lisa Brackenbury, Gemma Buck, Adam Butler, Jody Clements, Jennifer Cole, Ed DicksSimon Forbes, Matthew Gorton, Kristian Gray, Kelly Halliday, Rachel Harrison, Katy Hills, Jonathon Hinton, Andy Jenkinson, David Jones, Vivienne Kosmidou, Ross Laman, Richard Lugg, Andrew Menzies, Janet Perry, Robert Petty, Keiran Raine, David Richardson, Rebecca Shepherd, Alexandra Small, Helen Solomon, Calli Tofts, Jennifer Varian, Sofie West, Sara Widaa, Andy Yates, Douglas F. Easton, Gregory Riggins, Jennifer E. Roy, Kymberly K. Levine, Wolf Mueller, Tracy T. Batchelor, David N. Louis, Michael R. Stratton, P. Andrew Futreal, Richard Wooster

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Abstract

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 languageEnglish (US)
Pages (from-to)3987-3991
Number of pages5
JournalCancer research
Volume66
Issue number8
DOIs
StatePublished - Apr 15 2006

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hunter, C., Smith, R., Cahill, D. P., 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., ... Wooster, R. (2006). A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer research, 66(8), 3987-3991. https://doi.org/10.1158/0008-5472.CAN-06-0127