Whole-genome analysis informs breast cancer response to aromatase inhibition.
To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.
Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.
Matthew J
MJ
Ellis
Li
L
Ding
Dong
D
Shen
Jingqin
J
Luo
Vera J
VJ
Suman
John W
JW
Wallis
Brian A
BA
Van Tine
Jeremy
J
Hoog
Reece J
RJ
Goiffon
Theodore C
TC
Goldstein
Sam
S
Ng
Li
L
Lin
Robert
R
Crowder
Jacqueline
J
Snider
Karla
K
Ballman
Jason
J
Weber
Ken
K
Chen
Daniel C
DC
Koboldt
Cyriac
C
Kandoth
William S
WS
Schierding
Joshua F
JF
McMichael
Christopher A
CA
Miller
Charles
C
Lu
Christopher C
CC
Harris
Michael D
MD
McLellan
Michael C
MC
Wendl
Katherine
K
DeSchryver
D Craig
DC
Allred
Laura
L
Esserman
Gary
G
Unzeitig
Julie
J
Margenthaler
G V
GV
Babiera
P Kelly
PK
Marcom
J M
JM
Guenther
Marilyn
M
Leitch
Kelly
K
Hunt
John
J
Olson
Yu
Y
Tao
Christopher A
CA
Maher
Lucinda L
LL
Fulton
Robert S
RS
Fulton
Michelle
M
Harrison
Ben
B
Oberkfell
Feiyu
F
Du
Ryan
R
Demeter
Tammi L
TL
Vickery
Adnan
A
Elhammali
Helen
H
Piwnica-Worms
Sandra
S
McDonald
Mark
M
Watson
David J
DJ
Dooling
David
D
Ota
Li-Wei
LW
Chang
Ron
R
Bose
Timothy J
TJ
Ley
David
D
Piwnica-Worms
Joshua M
JM
Stuart
Richard K
RK
Wilson
Elaine R
ER
Mardis
D000077384:Anastrozole; D000730:Androstadienes / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004260:DNA Repair; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D000077289:Letrozole; D048670:MAP Kinase Kinase 4 / Q000235:genetics; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000378:metabolism; D016896:Treatment Outcome; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use
D000730:Androstadienes; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D000077384:Anastrozole; D000077289:Letrozole; D001141:Aromatase; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; C056516:exemestane