Sequence analysis of mutations and translocations across breast cancer subtypes.
Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone. This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy. Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration. Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements. Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1, GATA3 and MAP3K1, we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, we have identified a recurrent MAGI3-AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Shantanu
S
Banerji
Kristian
K
Cibulskis
Claudia
C
Rangel-Escareno
Kristin K
KK
Brown
Scott L
SL
Carter
Abbie M
AM
Frederick
Michael S
MS
Lawrence
Andrey Y
AY
Sivachenko
Carrie
C
Sougnez
Lihua
L
Zou
Maria L
ML
Cortes
Juan C
JC
Fernandez-Lopez
Shouyong
S
Peng
Kristin G
KG
Ardlie
Daniel
D
Auclair
Veronica
V
Bautista-Piña
Fujiko
F
Duke
Joshua
J
Francis
Joonil
J
Jung
Antonio
A
Maffuz-Aziz
Robert C
RC
Onofrio
Melissa
M
Parkin
Nam H
NH
Pho
Valeria
V
Quintanar-Jurado
Alex H
AH
Ramos
Rosa
R
Rebollar-Vega
Sergio
S
Rodriguez-Cuevas
Sandra L
SL
Romero-Cordoba
Steven E
SE
Schumacher
Nicolas
N
Stransky
Kristin M
KM
Thompson
Laura
L
Uribe-Figueroa
Jose
J
Baselga
Rameen
R
Beroukhim
Kornelia
K
Polyak
Dennis C
DC
Sgroi
Andrea L
AL
Richardson
Gerardo
G
Jimenez-Sanchez
Eric S
ES
Lander
Stacey B
SB
Gabriel
Levi A
LA
Garraway
Todd R
TR
Golub
Jorge
J
Melendez-Zajgla
Alex
A
Toker
Gad
G
Getz
Alfredo
A
Hidalgo-Miranda
Matthew
M
Meyerson
D000465:Algorithms; D001943:Breast Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D050658:Core Binding Factor beta Subunit / Q000235:genetics; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D050939:Gene Fusion / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008800:Mexico; D009154:Mutation / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics*; D014744:Vietnam
C493692:CBFB protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; C496469:MAGI3 protein, human; D008565:Membrane Proteins; C493728:RUNX1 protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt