Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
BACKGROUND
The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population.


METHODS
To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).


RESULTS
The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76-0.97; P(trend) = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53-0.89; P(trend) = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers.


CONCLUSIONS
CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers.


CONCLUSIONS
The combined application of these and other recently identified genetic risk modifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers.
Engel
Christoph
C
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
Versmold
Beatrix
B
Wappenschmidt
Barbara
B
Simard
Jacques
J
Easton
Douglas F
DF
Peock
Susan
S
Cook
Margaret
M
Oliver
Clare
C
Frost
Debra
D
Mayes
Rebecca
R
Evans
D Gareth
DG
Eeles
Rosalind
R
Paterson
Joan
J
Brewer
Carole
C
McGuffog
Lesley
L
Antoniou
Antonis C
AC
Stoppa-Lyonnet
Dominique
D
Sinilnikova
Olga M
OM
Barjhoux
Laure
L
Frenay
Marc
M
Michel
Cécile
C
Leroux
Dominique
D
Dreyfus
Helene
H
Toulas
Christine
C
Gladieff
Laurence
L
Uhrhammer
Nancy
N
Bignon
Yves-Jean
YJ
Meindl
Alfons
A
Arnold
Norbert
N
Varon-Mateeva
Raymonda
R
Niederacher
Dieter
D
Preisler-Adams
Sabine
S
Kast
Karin
K
Deissler
Helmut
H
Sutter
Christian
C
Gadzicki
Dorothea
D
Chenevix-Trench
Georgia
G
Spurdle
Amanda B
AB
Chen
Xiaoqing
X
Beesley
Jonathan
J
Olsson
Håkan
H
Kristoffersson
Ulf
U
Ehrencrona
Hans
H
Liljegren
Annelie
A
van der Luijt
Rob B
RB
van Os
Theo A
TA
van Leeuwen
Flora E
FE
Domchek
Susan M
SM
Rebbeck
Timothy R
TR
Nathanson
Katherine L
KL
Osorio
Ana
A
Ramón y Cajal
Teresa
T
Konstantopoulou
Irene
I
Benítez
Javier
J
Friedman
Eitan
E
Kaufman
Bella
B
Laitman
Yael
Y
Mai
Phuong L
PL
Greene
Mark H
MH
Nevanlinna
Heli
H
Aittomäki
Kristiina
K
Szabo
Csilla I
CI
Caldes
Trinidad
T
Couch
Fergus J
FJ
Andrulis
Irene L
IL
Godwin
Andrew K
AK
Hamann
Ute
U
Schmutzler
Rita K
RK
D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics*; D053455:Caspase 10 / Q000235:genetics*; D053181:Caspase 8 / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
C505530:CASP8 protein, human; D053455:Caspase 10; D053181:Caspase 8; C506438:CASP10 protein, human