Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction.
The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.
Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. antonis@srl.cam.ac.uk
Antonis C
AC
Antoniou
Jonathan
J
Beesley
Lesley
L
McGuffog
Olga M
OM
Sinilnikova
Sue
S
Healey
Susan L
SL
Neuhausen
Yuan Chun
YC
Ding
Timothy R
TR
Rebbeck
Jeffrey N
JN
Weitzel
Henry T
HT
Lynch
Claudine
C
Isaacs
Patricia A
PA
Ganz
Gail
G
Tomlinson
Olufunmilayo I
OI
Olopade
Fergus J
FJ
Couch
Xianshu
X
Wang
Noralane M
NM
Lindor
Vernon S
VS
Pankratz
Paolo
P
Radice
Siranoush
S
Manoukian
Bernard
B
Peissel
Daniela
D
Zaffaroni
Monica
M
Barile
Alessandra
A
Viel
Anna
A
Allavena
Valentina
V
Dall'Olio
Paolo
P
Peterlongo
Csilla I
CI
Szabo
Michal
M
Zikan
Kathleen
K
Claes
Bruce
B
Poppe
Lenka
L
Foretova
Phuong L
PL
Mai
Mark H
MH
Greene
Gad
G
Rennert
Flavio
F
Lejbkowicz
Gord
G
Glendon
Hilmi
H
Ozcelik
Irene L
IL
Andrulis
Mads
M
Thomassen
Anne-Marie
AM
Gerdes
Lone
L
Sunde
Dorthe
D
Cruger
Uffe
U
Birk Jensen
Maria
M
Caligo
Eitan
E
Friedman
Bella
B
Kaufman
Yael
Y
Laitman
Roni
R
Milgrom
Maya
M
Dubrovsky
Shimrit
S
Cohen
Ake
A
Borg
Helena
H
Jernström
Annika
A
Lindblom
Johanna
J
Rantala
Marie
M
Stenmark-Askmalm
Beatrice
B
Melin
Kate
K
Nathanson
Susan
S
Domchek
Ania
A
Jakubowska
Jan
J
Lubinski
Tomasz
T
Huzarski
Ana
A
Osorio
Adriana
A
Lasa
Mercedes
M
Durán
Maria-Isabel
MI
Tejada
Javier
J
Godino
Javier
J
Benitez
Ute
U
Hamann
Mieke
M
Kriege
Nicoline
N
Hoogerbrugge
Rob B
RB
van der Luijt
Christi J
CJ
van Asperen
Peter
P
Devilee
E J
EJ
Meijers-Heijboer
Marinus J
MJ
Blok
Cora M
CM
Aalfs
Frans
F
Hogervorst
Matti
M
Rookus
Margaret
M
Cook
Clare
C
Oliver
Debra
D
Frost
Don
D
Conroy
D Gareth
DG
Evans
Fiona
F
Lalloo
Gabriella
G
Pichert
Rosemarie
R
Davidson
Trevor
T
Cole
Jackie
J
Cook
Joan
J
Paterson
Shirley
S
Hodgson
Patrick J
PJ
Morrison
Mary E
ME
Porteous
Lisa
L
Walker
M John
MJ
Kennedy
Huw
H
Dorkins
Susan
S
Peock
Andrew K
AK
Godwin
Dominique
D
Stoppa-Lyonnet
Antoine
A
de Pauw
Sylvie
S
Mazoyer
Valérie
V
Bonadona
Christine
C
Lasset
Hélène
H
Dreyfus
Dominique
D
Leroux
Agnès
A
Hardouin
Pascaline
P
Berthet
Laurence
L
Faivre
Catherine
C
Loustalot
Tetsuro
T
Noguchi
Hagay
H
Sobol
Etienne
E
Rouleau
Catherine
C
Nogues
Marc
M
Frénay
Laurence
L
Vénat-Bouvet
John L
JL
Hopper
Mary B
MB
Daly
Mary B
MB
Terry
Esther M
EM
John
Saundra S
SS
Buys
Yosuf
Y
Yassin
Alexander
A
Miron
David
D
Goldgar
Christian F
CF
Singer
Anne Catharina
AC
Dressler
Daphne
D
Gschwantler-Kaulich
Georg
G
Pfeiler
Thomas V O
TV
Hansen
Lars
L
Jønson
Bjarni A
BA
Agnarsson
Tomas
T
Kirchhoff
Kenneth
K
Offit
Vincent
V
Devlin
Ana
A
Dutra-Clarke
Marion
M
Piedmonte
Gustavo C
GC
Rodriguez
Katie
K
Wakeley
John F
JF
Boggess
Jack
J
Basil
Peter E
PE
Schwartz
Stephanie V
SV
Blank
Amanda Ewart
AE
Toland
Marco
M
Montagna
Cinzia
C
Casella
Evgeny
E
Imyanitov
Laima
L
Tihomirova
Ignacio
I
Blanco
Conxi
C
Lazaro
Susan J
SJ
Ramus
Lara
L
Sucheston
Beth Y
BY
Karlan
Jenny
J
Gross
Rita
R
Schmutzler
Barbara
B
Wappenschmidt
Christoph
C
Engel
Alfons
A
Meindl
Magdalena
M
Lochmann
Norbert
N
Arnold
Simone
S
Heidemann
Raymonda
R
Varon-Mateeva
Dieter
D
Niederacher
Christian
C
Sutter
Helmut
H
Deissler
Dorothea
D
Gadzicki
Sabine
S
Preisler-Adams
Karin
K
Kast
Ines
I
Schönbuchner
Trinidad
T
Caldes
Miguel
M
de la Hoya
Kristiina
K
Aittomäki
Heli
H
Nevanlinna
Jacques
J
Simard
Amanda B
AB
Spurdle
Helene
H
Holland
Xiaoqing
X
Chen
Radka
R
Platte
Georgia
G
Chenevix-Trench
Douglas F
DF
Easton
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006579:Heterozygote; D006609:High Mobility Group Proteins; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011980:Receptors, Progesterone / Q000235:genetics; D018570:Risk Assessment; D012307:Risk Factors; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics; D016019:Survival Analysis; D015534:Trans-Activators; D033921:Vesicular Transport Proteins / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D006609:High Mobility Group Proteins; D011980:Receptors, Progesterone; C422022:SLC4A7 protein, human; C498469:STXBP4 protein, human; D027982:Sodium-Bicarbonate Symporters; C521752:TOX3 protein, human; D015534:Trans-Activators; D033921:Vesicular Transport Proteins