Signatures of mutational processes in human cancer.
All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Ludmil B
LB
Alexandrov
Serena
S
Nik-Zainal
David C
DC
Wedge
Samuel A J R
SA
Aparicio
Sam
S
Behjati
Andrew V
AV
Biankin
Graham R
GR
Bignell
Niccolò
N
Bolli
Ake
A
Borg
Anne-Lise
AL
Børresen-Dale
Sandrine
S
Boyault
Birgit
B
Burkhardt
Adam P
AP
Butler
Carlos
C
Caldas
Helen R
HR
Davies
Christine
C
Desmedt
Roland
R
Eils
Jórunn Erla
JE
Eyfjörd
John A
JA
Foekens
Mel
M
Greaves
Fumie
F
Hosoda
Barbara
B
Hutter
Tomislav
T
Ilicic
Sandrine
S
Imbeaud
Marcin
M
Imielinski
Marcin
M
Imielinsk
Natalie
N
Jäger
David T W
DT
Jones
David
D
Jones
Stian
S
Knappskog
Marcel
M
Kool
Sunil R
SR
Lakhani
Carlos
C
López-Otín
Sancha
S
Martin
Nikhil C
NC
Munshi
Hiromi
H
Nakamura
Paul A
PA
Northcott
Marina
M
Pajic
Elli
E
Papaemmanuil
Angelo
A
Paradiso
John V
JV
Pearson
Xose S
XS
Puente
Keiran
K
Raine
Manasa
M
Ramakrishna
Andrea L
AL
Richardson
Julia
J
Richter
Philip
P
Rosenstiel
Matthias
M
Schlesner
Ton N
TN
Schumacher
Paul N
PN
Span
Jon W
JW
Teague
Yasushi
Y
Totoki
Andrew N J
AN
Tutt
Rafael
R
Valdés-Mas
Marit M
MM
van Buuren
Laura
L
van 't Veer
Anne
A
Vincent-Salomon
Nicola
N
Waddell
Lucy R
LR
Yates
Jessica
J
Zucman-Rossi
P Andrew
PA
Futreal
Ultan
U
McDermott
Peter
P
Lichter
Matthew
M
Meyerson
Sean M
SM
Grimmond
Reiner
R
Siebert
Elías
E
Campo
Tatsuhiro
T
Shibata
Stefan M
SM
Pfister
Peter J
PJ
Campbell
Michael R
MR
Stratton
D000375:Aging / Q000235:genetics; D000465:Algorithms; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D003564:Cytidine Deaminase / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D006801:Humans; D008957:Models, Genetic; D016296:Mutagenesis / Q000235:genetics*; D016254:Mutagenesis, Insertional / Q000235:genetics; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009928:Organ Specificity; D015203:Reproducibility of Results; D017384:Sequence Deletion / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
D009153:Mutagens; D004247:DNA; D003564:Cytidine Deaminase