A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.
Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P(trend) = 2.3 × 10⁻⁹ to P(trend) = 3.9 × 10⁻⁷), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P(trend) = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P(trend) = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (P(trend) = 1 × 10⁻⁷) to P(trend) = 8 × 10⁻⁵; rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P(trend) = 1.1 × 10⁻⁷
Antoniou
Antonis C
AC
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Wang
Xianshu
X
Fredericksen
Zachary S
ZS
McGuffog
Lesley
L
Tarrell
Robert
R
Sinilnikova
Olga M
OM
Healey
Sue
S
Morrison
Jonathan
J
Kartsonaki
Christiana
C
Lesnick
Timothy
T
Ghoussaini
Maya
M
Barrowdale
Daniel
D
Peock
Susan
S
Cook
Margaret
M
Oliver
Clare
C
Frost
Debra
D
Eccles
Diana
D
Evans
D Gareth
DG
Eeles
Ros
R
Izatt
Louise
L
Chu
Carol
C
Douglas
Fiona
F
Paterson
Joan
J
Stoppa-Lyonnet
Dominique
D
Houdayer
Claude
C
Mazoyer
Sylvie
S
Giraud
Sophie
S
Lasset
Christine
C
Remenieras
Audrey
A
Caron
Olivier
O
Hardouin
Agnès
A
Berthet
Pascaline
P
Hogervorst
Frans B L
FB
Rookus
Matti A
MA
Jager
Agnes
A
van den Ouweland
Ans
A
Hoogerbrugge
Nicoline
N
van der Luijt
Rob B
RB
Meijers-Heijboer
Hanne
H
Gómez García
Encarna B
EB
Devilee
Peter
P
Vreeswijk
Maaike P G
MP
Lubinski
Jan
J
Jakubowska
Anna
A
Gronwald
Jacek
J
Huzarski
Tomasz
T
Byrski
Tomasz
T
Górski
Bohdan
B
Cybulski
Cezary
C
Spurdle
Amanda B
AB
Holland
Helene
H
Goldgar
David E
DE
John
Esther M
EM
Hopper
John L
JL
Southey
Melissa
M
Buys
Saundra S
SS
Daly
Mary B
MB
Terry
Mary-Beth
MB
Schmutzler
Rita K
RK
Wappenschmidt
Barbara
B
Engel
Christoph
C
Meindl
Alfons
A
Preisler-Adams
Sabine
S
Arnold
Norbert
N
Niederacher
Dieter
D
Sutter
Christian
C
Domchek
Susan M
SM
Nathanson
Katherine L
KL
Rebbeck
Timothy
T
Blum
Joanne L
JL
Piedmonte
Marion
M
Rodriguez
Gustavo C
GC
Wakeley
Katie
K
Boggess
John F
JF
Basil
Jack
J
Blank
Stephanie V
SV
Friedman
Eitan
E
Kaufman
Bella
B
Laitman
Yael
Y
Milgrom
Roni
R
Andrulis
Irene L
IL
Glendon
Gord
G
Ozcelik
Hilmi
H
Kirchhoff
Tomas
T
Vijai
Joseph
J
Gaudet
Mia M
MM
Altshuler
David
D
Guiducci
Candace
C
Loman
Niklas
N
Harbst
Katja
K
Rantala
Johanna
J
Ehrencrona
Hans
H
Gerdes
Anne-Marie
AM
Thomassen
Mads
M
Sunde
Lone
L
Peterlongo
Paolo
P
Manoukian
Siranoush
S
Bonanni
Bernardo
B
Viel
Alessandra
A
Radice
Paolo
P
Caldes
Trinidad
T
de la Hoya
Miguel
M
Singer
Christian F
CF
Fink-Retter
Anneliese
A
Greene
Mark H
MH
Mai
Phuong L
PL
Loud
Jennifer T
JT
Guidugli
Lucia
L
Lindor
Noralane M
NM
Hansen
Thomas V O
TV
Nielsen
Finn C
FC
Blanco
Ignacio
I
Lazaro
Conxi
C
Garber
Judy
J
Ramus
Susan J
SJ
Gayther
Simon A
SA
Phelan
Catherine
C
Narod
Stephen
S
Szabo
Csilla I
CI
Benitez
Javier
J
Osorio
Ana
A
Nevanlinna
Heli
H
Heikkinen
Tuomas
T
Caligo
Maria A
MA
Beattie
Mary S
MS
Hamann
Ute
U
Godwin
Andrew K
AK
Montagna
Marco
M
Casella
Cinzia
C
Neuhausen
Susan L
SL
Karlan
Beth Y
BY
Tung
Nadine
N
Toland
Amanda E
AE
Weitzel
Jeffrey
J
Olopade
Olofunmilayo
O
Simard
Jacques
J
Soucy
Penny
P
Rubinstein
Wendy S
WS
Arason
Adalgeir
A
Rennert
Gad
G
Martin
Nicholas G
NG
Montgomery
Grant W
GW
Chang-Claude
Jenny
J
Flesch-Janys
Dieter
D
Brauch
Hiltrud
H
Severi
Gianluca
G
Baglietto
Laura
L
Cox
Angela
A
Cross
Simon S
SS
Miron
Penelope
P
Gerty
Sue M
SM
Tapper
William
W
Yannoukakos
Drakoulis
D
Fountzilas
George
G
Fasching
Peter A
PA
Beckmann
Matthias W
MW
Dos Santos Silva
Isabel
I
Peto
Julian
J
Lambrechts
Diether
D
Paridaens
Robert
R
Rüdiger
Thomas
T
Försti
Asta
A
Winqvist
Robert
R
Pylkäs
Katri
K
Diasio
Robert B
RB
Lee
Adam M
AM
Eckel-Passow
Jeanette
J
Vachon
Celine
C
Blows
Fiona
F
Driver
Kristy
K
Dunning
Alison
A
Pharoah
Paul P D
PP
Offit
Kenneth
K
Pankratz
V Shane
VS
Hakonarson
Hakon
H
Chenevix-Trench
Georgia
G
Easton
Douglas F
DF
Couch
Fergus J
FJ
D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics*
D019313:BRCA1 Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human