title: A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy.
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.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Hunter
authors.forename: Raffaella
authors.initials: R
authors.lastname: Smith
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Cahill
authors.forename: Philip
authors.initials: P
authors.lastname: Stephens
authors.forename: Claire
authors.initials: C
authors.lastname: Stevens
authors.forename: Jon
authors.initials: J
authors.lastname: Teague
authors.forename: Chris
authors.initials: C
authors.lastname: Greenman
authors.forename: Sarah
authors.initials: S
authors.lastname: Edkins
authors.forename: Graham
authors.initials: G
authors.lastname: Bignell
authors.forename: Helen
authors.initials: H
authors.lastname: Davies
authors.forename: Sarah
authors.initials: S
authors.lastname: O'Meara
authors.forename: Adrian
authors.initials: A
authors.lastname: Parker
authors.forename: Tim
authors.initials: T
authors.lastname: Avis
authors.forename: Syd
authors.initials: S
authors.lastname: Barthorpe
authors.forename: Lisa
authors.initials: L
authors.lastname: Brackenbury
authors.forename: Gemma
authors.initials: G
authors.lastname: Buck
authors.forename: Adam
authors.initials: A
authors.lastname: Butler
authors.forename: Jody
authors.initials: J
authors.lastname: Clements
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cole
authors.forename: Ed
authors.initials: E
authors.lastname: Dicks
authors.forename: Simon
authors.initials: S
authors.lastname: Forbes
authors.forename: Matthew
authors.initials: M
authors.lastname: Gorton
authors.forename: Kristian
authors.initials: K
authors.lastname: Gray
authors.forename: Kelly
authors.initials: K
authors.lastname: Halliday
authors.forename: Rachel
authors.initials: R
authors.lastname: Harrison
authors.forename: Katy
authors.initials: K
authors.lastname: Hills
authors.forename: Jonathon
authors.initials: J
authors.lastname: Hinton
authors.forename: Andy
authors.initials: A
authors.lastname: Jenkinson
authors.forename: David
authors.initials: D
authors.lastname: Jones
authors.forename: Vivienne
authors.initials: V
authors.lastname: Kosmidou
authors.forename: Ross
authors.initials: R
authors.lastname: Laman
authors.forename: Richard
authors.initials: R
authors.lastname: Lugg
authors.forename: Andrew
authors.initials: A
authors.lastname: Menzies
authors.forename: Janet
authors.initials: J
authors.lastname: Perry
authors.forename: Robert
authors.initials: R
authors.lastname: Petty
authors.forename: Keiran
authors.initials: K
authors.lastname: Raine
authors.forename: David
authors.initials: D
authors.lastname: Richardson
authors.forename: Rebecca
authors.initials: R
authors.lastname: Shepherd
authors.forename: Alexandra
authors.initials: A
authors.lastname: Small
authors.forename: Helen
authors.initials: H
authors.lastname: Solomon
authors.forename: Calli
authors.initials: C
authors.lastname: Tofts
authors.forename: Jennifer
authors.initials: J
authors.lastname: Varian
authors.forename: Sofie
authors.initials: S
authors.lastname: West
authors.forename: Sara
authors.initials: S
authors.lastname: Widaa
authors.forename: Andy
authors.initials: A
authors.lastname: Yates
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Gregory
authors.initials: G
authors.lastname: Riggins
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Roy
authors.forename: Kymberly K
authors.initials: KK
authors.lastname: Levine
authors.forename: Wolf
authors.initials: W
authors.lastname: Mueller
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Richard
authors.initials: R
authors.lastname: Wooster
mesh_terms: D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D003606:Dacarbazine; D011494:Protein Kinases; D000077204:Temozolomide