A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer.
Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, USA. haiman@usc.edu
Christopher A
CA
Haiman
Gary K
GK
Chen
Celine M
CM
Vachon
Federico
F
Canzian
Alison
A
Dunning
Robert C
RC
Millikan
Xianshu
X
Wang
Foluso
F
Ademuyiwa
Shahana
S
Ahmed
Christine B
CB
Ambrosone
Laura
L
Baglietto
Rosemary
R
Balleine
Elisa V
EV
Bandera
Matthias W
MW
Beckmann
Christine D
CD
Berg
Leslie
L
Bernstein
Carl
C
Blomqvist
William J
WJ
Blot
Hiltrud
H
Brauch
Julie E
JE
Buring
Lisa A
LA
Carey
Jane E
JE
Carpenter
Jenny
J
Chang-Claude
Stephen J
SJ
Chanock
Daniel I
DI
Chasman
Christine L
CL
Clarke
Angela
A
Cox
Simon S
SS
Cross
Sandra L
SL
Deming
Robert B
RB
Diasio
Athanasios M
AM
Dimopoulos
W Ryan
WR
Driver
Thomas
T
Dünnebier
Lorraine
L
Durcan
Diana
D
Eccles
Christopher K
CK
Edlund
Arif B
AB
Ekici
Peter A
PA
Fasching
Heather S
HS
Feigelson
Dieter
D
Flesch-Janys
Florentia
F
Fostira
Asta
A
Försti
George
G
Fountzilas
Susan M
SM
Gerty
Graham G
GG
Giles
Andrew K
AK
Godwin
Paul
P
Goodfellow
Nikki
N
Graham
Dario
D
Greco
Ute
U
Hamann
Susan E
SE
Hankinson
Arndt
A
Hartmann
Rebecca
R
Hein
Judith
J
Heinz
Andrea
A
Holbrook
Robert N
RN
Hoover
Jennifer J
JJ
Hu
David J
DJ
Hunter
Sue A
SA
Ingles
Astrid
A
Irwanto
Jennifer
J
Ivanovich
Esther M
EM
John
Nicola
N
Johnson
Arja
A
Jukkola-Vuorinen
Rudolf
R
Kaaks
Yon-Dschun
YD
Ko
Laurence N
LN
Kolonel
Irene
I
Konstantopoulou
Veli-Matti
VM
Kosma
Swati
S
Kulkarni
Diether
D
Lambrechts
Adam M
AM
Lee
Loïc Le
LL
Marchand
Timothy
T
Lesnick
Jianjun
J
Liu
Sara
S
Lindstrom
Arto
A
Mannermaa
Sara
S
Margolin
Nicholas G
NG
Martin
Penelope
P
Miron
Grant W
GW
Montgomery
Heli
H
Nevanlinna
Stephan
S
Nickels
Sarah
S
Nyante
Curtis
C
Olswold
Julie
J
Palmer
Harsh
H
Pathak
Dimitrios
D
Pectasides
Charles M
CM
Perou
Julian
J
Peto
Paul D P
PD
Pharoah
Loreall C
LC
Pooler
Michael F
MF
Press
Katri
K
Pylkäs
Timothy R
TR
Rebbeck
Jorge L
JL
Rodriguez-Gil
Lynn
L
Rosenberg
Eric
E
Ross
Thomas
T
Rüdiger
Isabel dos Santos
Idos S
Silva
Elinor
E
Sawyer
Marjanka K
MK
Schmidt
Rüdiger
R
Schulz-Wendtland
Fredrick
F
Schumacher
Gianluca
G
Severi
Xin
X
Sheng
Lisa B
LB
Signorello
Hans-Peter
HP
Sinn
Kristen N
KN
Stevens
Melissa C
MC
Southey
William J
WJ
Tapper
Ian
I
Tomlinson
Frans B L
FB
Hogervorst
Els
E
Wauters
JoEllen
J
Weaver
Hans
H
Wildiers
Robert
R
Winqvist
David
D
Van  Den  Berg
Peggy
P
Wan
Lucy Y
LY
Xia
Drakoulis
D
Yannoukakos
Wei
W
Zheng
Regina G
RG
Ziegler
Afshan
A
Siddiq
Susan L
SL
Slager
Daniel O
DO
Stram
Douglas
D
Easton
Peter
P
Kraft
Brian E
BE
Henderson
Fergus J
FJ
Couch
D001741:Black or African American; D000368:Aged; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics*; D044465:White People
C422445:CLPTM1L protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; C509186:TERT protein, human; D019098:Telomerase