Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers.
BACKGROUND
More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers.


METHODS
We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement.


RESULTS
The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement.


CONCLUSIONS
Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.
Karoline B
KB
Kuchenbaecker
Susan L
SL
Neuhausen
Mark
M
Robson
Daniel
D
Barrowdale
Lesley
L
McGuffog
Anna Marie
AM
Mulligan
Irene L
IL
Andrulis
Amanda B
AB
Spurdle
Marjanka K
MK
Schmidt
Rita K
RK
Schmutzler
Christoph
C
Engel
Barbara
B
Wappenschmidt
Heli
H
Nevanlinna
Mads
M
Thomassen
Melissa
M
Southey
Paolo
P
Radice
Susan J
SJ
Ramus
Susan M
SM
Domchek
Katherine L
KL
Nathanson
Andrew
A
Lee
Sue
S
Healey
Robert L
RL
Nussbaum
Timothy R
TR
Rebbeck
Banu K
BK
Arun
Paul
P
James
Beth Y
BY
Karlan
Jenny
J
Lester
Ilana
I
Cass
Mary Beth
MB
Terry
Mary B
MB
Daly
David E
DE
Goldgar
Saundra S
SS
Buys
Ramunas
R
Janavicius
Laima
L
Tihomirova
Nadine
N
Tung
Cecilia M
CM
Dorfling
Elizabeth J
EJ
van Rensburg
Linda
L
Steele
Thomas
T
v O Hansen
Bent
B
Ejlertsen
Anne-Marie
AM
Gerdes
Finn C
FC
Nielsen
Joe
J
Dennis
Julie
J
Cunningham
Steven
S
Hart
Susan
S
Slager
Ana
A
Osorio
Javier
J
Benitez
Mercedes
M
Duran
Jeffrey N
JN
Weitzel
Isaac
I
Tafur
Mary
M
Hander
Paolo
P
Peterlongo
Siranoush
S
Manoukian
Bernard
B
Peissel
Gaia
G
Roversi
Giulietta
G
Scuvera
Bernardo
B
Bonanni
Paolo
P
Mariani
Sara
S
Volorio
Riccardo
R
Dolcetti
Liliana
L
Varesco
Laura
L
Papi
Maria Grazia
MG
Tibiletti
Giuseppe
G
Giannini
Florentia
F
Fostira
Irene
I
Konstantopoulou
Judy
J
Garber
Ute
U
Hamann
Alan
A
Donaldson
Carole
C
Brewer
Claire
C
Foo
D Gareth
DG
Evans
Debra
D
Frost
Diana
D
Eccles
Fiona
F
Douglas
Angela
A
Brady
Jackie
J
Cook
Marc
M
Tischkowitz
Julian
J
Adlard
Julian
J
Barwell
Kai-ren
KR
Ong
Lisa
L
Walker
Louise
L
Izatt
Lucy E
LE
Side
M John
MJ
Kennedy
Mark T
MT
Rogers
Mary E
ME
Porteous
Patrick J
PJ
Morrison
Radka
R
Platte
Ros
R
Eeles
Rosemarie
R
Davidson
Shirley
S
Hodgson
Steve
S
Ellis
Andrew K
AK
Godwin
Kerstin
K
Rhiem
Alfons
A
Meindl
Nina
N
Ditsch
Norbert
N
Arnold
Hansjoerg
H
Plendl
Dieter
D
Niederacher
Christian
C
Sutter
Doris
D
Steinemann
Nadja
N
Bogdanova-Markov
Karin
K
Kast
Raymonda
R
Varon-Mateeva
Shan
S
Wang-Gohrke
Andrea
A
Gehrig
Birgid
B
Markiefka
Bruno
B
Buecher
Cédrick
C
Lefol
Dominique
D
Stoppa-Lyonnet
Etienne
E
Rouleau
Fabienne
F
Prieur
Francesca
F
Damiola
Laure
L
Barjhoux
Laurence
L
Faivre
Michel
M
Longy
Nicolas
N
Sevenet
Olga M
OM
Sinilnikova
Sylvie
S
Mazoyer
Valérie
V
Bonadona
Virginie
V
Caux-Moncoutier
Claudine
C
Isaacs
Tom
T
Van Maerken
Kathleen
K
Claes
Marion
M
Piedmonte
Lesley
L
Andrews
John
J
Hays
Gustavo C
GC
Rodriguez
Trinidad
T
Caldes
Miguel
M
de la Hoya
Sofia
S
Khan
Frans B L
FB
Hogervorst
Cora M
CM
Aalfs
J L
JL
de Lange
Hanne E J
HE
Meijers-Heijboer
Annemarie H
AH
van der Hout
Juul T
JT
Wijnen
K E P
KE
van Roozendaal
Arjen R
AR
Mensenkamp
Ans M W
AM
van den Ouweland
Carolien H M
CH
van Deurzen
Rob B
RB
van der Luijt
Edith
E
Olah
Orland
O
Diez
Conxi
C
Lazaro
Ignacio
I
Blanco
Alex
A
Teulé
Mireia
M
Menendez
Anna
A
Jakubowska
Jan
J
Lubinski
Cezary
C
Cybulski
Jacek
J
Gronwald
Katarzyna
K
Jaworska-Bieniek
Katarzyna
K
Durda
Adalgeir
A
Arason
Christine
C
Maugard
Penny
P
Soucy
Marco
M
Montagna
Simona
S
Agata
Manuel R
MR
Teixeira
Curtis
C
Olswold
Noralane
N
Lindor
Vernon S
VS
Pankratz
Emily
E
Hallberg
Xianshu
X
Wang
Csilla I
CI
Szabo
Joseph
J
Vijai
Lauren
L
Jacobs
Marina
M
Corines
Anne
A
Lincoln
Andreas
A
Berger
Anneliese
A
Fink-Retter
Christian F
CF
Singer
Christine
C
Rappaport
Daphne Gschwantler
DG
Kaulich
Georg
G
Pfeiler
Muy-Kheng
MK
Tea
Catherine M
CM
Phelan
Phuong L
PL
Mai
Mark H
MH
Greene
Gad
G
Rennert
Evgeny N
EN
Imyanitov
Gord
G
Glendon
Amanda Ewart
AE
Toland
Anders
A
Bojesen
Inge Sokilde
IS
Pedersen
Uffe Birk
UB
Jensen
Maria A
MA
Caligo
Eitan
E
Friedman
Raanan
R
Berger
Yael
Y
Laitman
Johanna
J
Rantala
Brita
B
Arver
Niklas
N
Loman
Ake
A
Borg
Hans
H
Ehrencrona
Olufunmilayo I
OI
Olopade
Jacques
J
Simard
Douglas F
DF
Easton
Georgia
G
Chenevix-Trench
Kenneth
K
Offit
Fergus J
FJ
Couch
Antonis C
AC
Antoniou
D000328:Adult; D000368:Aged; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human