A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers.
BACKGROUND
We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.


METHODS
IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.


RESULTS
Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03).


CONCLUSIONS
The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers.


CONCLUSIONS
These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Yuan C
YC
Ding
Lesley
L
McGuffog
Sue
S
Healey
Eitan
E
Friedman
Yael
Y
Laitman
Shani-
S
Paluch-Shimon
Bella
B
Kaufman
Annelie
A
Liljegren
Annika
A
Lindblom
Håkan
H
Olsson
Ulf
U
Kristoffersson
Marie
M
Stenmark-Askmalm
Beatrice
B
Melin
Susan M
SM
Domchek
Katherine L
KL
Nathanson
Timothy R
TR
Rebbeck
Anna
A
Jakubowska
Jan
J
Lubinski
Katarzyna
K
Jaworska
Katarzyna
K
Durda
Jacek
J
Gronwald
Tomasz
T
Huzarski
Cezary
C
Cybulski
Tomasz
T
Byrski
Ana
A
Osorio
Teresa Ramóny
TR
Cajal
Alexandra V
AV
Stavropoulou
Javier
J
Benítez
Ute
U
Hamann
Matti
M
Rookus
Cora M
CM
Aalfs
Judith L
JL
de Lange
Hanne E J
HE
Meijers-Heijboer
Jan C
JC
Oosterwijk
Christi J
CJ
van Asperen
Encarna B
EB
Gómez García
Nicoline
N
Hoogerbrugge
Agnes
A
Jager
Rob B
RB
van der Luijt
Douglas F
DF
Easton
Susan
S
Peock
Debra
D
Frost
Steve D
SD
Ellis
Radka
R
Platte
Elena
E
Fineberg
D Gareth
DG
Evans
Fiona
F
Lalloo
Louise
L
Izatt
Ros
R
Eeles
Julian
J
Adlard
Rosemarie
R
Davidson
Diana
D
Eccles
Trevor
T
Cole
Jackie
J
Cook
Carole
C
Brewer
Marc
M
Tischkowitz
Andrew K
AK
Godwin
Harsh
H
Pathak
Dominique
D
Stoppa-Lyonnet
Olga M
OM
Sinilnikova
Sylvie
S
Mazoyer
Laure
L
Barjhoux
Mélanie
M
Léoné
Marion
M
Gauthier-Villars
Virginie
V
Caux-Moncoutier
Antoine
A
de Pauw
Agnès
A
Hardouin
Pascaline
P
Berthet
Hélène
H
Dreyfus
Sandra Fert
SF
Ferrer
Marie-Agnès
MA
Collonge-Rame
Johanna
J
Sokolowska
Saundra
S
Buys
Mary
M
Daly
Alex
A
Miron
Mary Beth
MB
Terry
Wendy
W
Chung
Esther M
EM
John
Melissa
M
Southey
David
D
Goldgar
Christian F
CF
Singer
Muy-Kheng Maria
MK
Tea
Daphne
D
Gschwantler-Kaulich
Anneliese
A
Fink-Retter
Thomas V O
TV
Hansen
Bent
B
Ejlertsen
Oskar T
OT
Johannsson
Kenneth
K
Offit
Kara
K
Sarrel
Mia M
MM
Gaudet
Joseph
J
Vijai
Mark
M
Robson
Marion R
MR
Piedmonte
Lesley
L
Andrews
David
D
Cohn
Leslie R
LR
DeMars
Paul
P
DiSilvestro
Gustavo
G
Rodriguez
Amanda Ewart
AE
Toland
Marco
M
Montagna
Simona
S
Agata
Evgeny
E
Imyanitov
Claudine
C
Isaacs
Ramunas
R
Janavicius
Conxi
C
Lazaro
Ignacio
I
Blanco
Susan J
SJ
Ramus
Lara
L
Sucheston
Beth Y
BY
Karlan
Jenny
J
Gross
Patricia A
PA
Ganz
Mary S
MS
Beattie
Rita K
RK
Schmutzler
Barbara
B
Wappenschmidt
Alfons
A
Meindl
Norbert
N
Arnold
Dieter
D
Niederacher
Sabine
S
Preisler-Adams
Dorotehea
D
Gadzicki
Raymonda
R
Varon-Mateeva
Helmut
H
Deissler
Andrea
A
Gehrig
Christian
C
Sutter
Karin
K
Kast
Heli
H
Nevanlinna
Kristiina
K
Aittomäki
Jacques
J
Simard
Amanda B
AB
Spurdle
Jonathan
J
Beesley
Xiaoqing
X
Chen
Gail E
GE
Tomlinson
Jeffrey
J
Weitzel
Judy E
JE
Garber
Olufunmilayo I
OI
Olopade
Wendy S
WS
Rubinstein
Nadine
N
Tung
Joanne L
JL
Blum
Steven A
SA
Narod
Sean
S
Brummel
Daniel L
DL
Gillen
Noralane
N
Lindor
Zachary
Z
Fredericksen
Vernon S
VS
Pankratz
Fergus J
FJ
Couch
Paolo
P
Radice
Paolo
P
Peterlongo
Mark H
MH
Greene
Jennifer T
JT
Loud
Phuong L
PL
Mai
Irene L
IL
Andrulis
Gord
G
Glendon
Hilmi
H
Ozcelik
Anne-Marie
AM
Gerdes
Mads
M
Thomassen
Uffe Birk
UB
Jensen
Anne-Bine
AB
Skytte
Maria A
MA
Caligo
Andrew
A
Lee
Georgia
G
Chenevix-Trench
Antonis C
AC
Antoniou
Susan L
SL
Neuhausen
D001943:Breast Neoplasms / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D055504:Insulin Receptor Substrate Proteins