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 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.
Hunter
Chris
C
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Smith
Raffaella
R
Cahill
Daniel P
DP
Stephens
Philip
P
Stevens
Claire
C
Teague
Jon
J
Greenman
Chris
C
Edkins
Sarah
S
Bignell
Graham
G
Davies
Helen
H
O'Meara
Sarah
S
Parker
Adrian
A
Avis
Tim
T
Barthorpe
Syd
S
Brackenbury
Lisa
L
Buck
Gemma
G
Butler
Adam
A
Clements
Jody
J
Cole
Jennifer
J
Dicks
Ed
E
Forbes
Simon
S
Gorton
Matthew
M
Gray
Kristian
K
Halliday
Kelly
K
Harrison
Rachel
R
Hills
Katy
K
Hinton
Jonathon
J
Jenkinson
Andy
A
Jones
David
D
Kosmidou
Vivienne
V
Laman
Ross
R
Lugg
Richard
R
Menzies
Andrew
A
Perry
Janet
J
Petty
Robert
R
Raine
Keiran
K
Richardson
David
D
Shepherd
Rebecca
R
Small
Alexandra
A
Solomon
Helen
H
Tofts
Calli
C
Varian
Jennifer
J
West
Sofie
S
Widaa
Sara
S
Yates
Andy
A
Easton
Douglas F
DF
Riggins
Gregory
G
Roy
Jennifer E
JE
Levine
Kymberly K
KK
Mueller
Wolf
W
Batchelor
Tracy T
TT
Louis
David N
DN
Stratton
Michael R
MR
Futreal
P Andrew
PA
Wooster
Richard
R
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
D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D003606:Dacarbazine; D011494:Protein Kinases; D000077204:Temozolomide