The landscape of cancer genes and mutational processes in breast cancer.
All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
Philip J
PJ
Stephens
Patrick S
PS
Tarpey
Helen
H
Davies
Peter
P
Van Loo
Chris
C
Greenman
David C
DC
Wedge
Serena
S
Nik-Zainal
Sancha
S
Martin
Ignacio
I
Varela
Graham R
GR
Bignell
Lucy R
LR
Yates
Elli
E
Papaemmanuil
David
D
Beare
Adam
A
Butler
Angela
A
Cheverton
John
J
Gamble
Jonathan
J
Hinton
Mingming
M
Jia
Alagu
A
Jayakumar
David
D
Jones
Calli
C
Latimer
King Wai
KW
Lau
Stuart
S
McLaren
David J
DJ
McBride
Andrew
A
Menzies
Laura
L
Mudie
Keiran
K
Raine
Roland
R
Rad
Michael Spencer
MS
Chapman
Jon
J
Teague
Douglas
D
Easton
Anita
A
Langerød
Ming Ta Michael
MT
Lee
Chen-Yang
CY
Shen
Benita Tan Kiat
BT
Tee
Bernice Wong
BW
Huimin
Annegien
A
Broeks
Ana Cristina
AC
Vargas
Gulisa
G
Turashvili
John
J
Martens
Aquila
A
Fatima
Penelope
P
Miron
Suet-Feung
SF
Chin
Gilles
G
Thomas
Sandrine
S
Boyault
Odette
O
Mariani
Sunil R
SR
Lakhani
Marc
M
van de Vijver
Laura
L
van 't Veer
John
J
Foekens
Christine
C
Desmedt
Christos
C
Sotiriou
Andrew
A
Tutt
Carlos
C
Caldas
Jorge S
JS
Reis-Filho
Samuel A J R
SA
Aparicio
Anne Vincent
AV
Salomon
Anne-Lise
AL
Børresen-Dale
Andrea L
AL
Richardson
Peter J
PJ
Campbell
P Andrew
PA
Futreal
Michael R
MR
Stratton
D000367:Age Factors; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003596:Cytosine / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016296:Mutagenesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009857:Oncogenes / Q000235:genetics*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics
D003596:Cytosine; D048031:JNK Mitogen-Activated Protein Kinases