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.
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
Christoph
C
Engel
Beatrix
B
Versmold
Barbara
B
Wappenschmidt
Jacques
J
Simard
Douglas F
DF
Easton
Susan
S
Peock
Margaret
M
Cook
Clare
C
Oliver
Debra
D
Frost
Rebecca
R
Mayes
D Gareth
DG
Evans
Rosalind
R
Eeles
Joan
J
Paterson
Carole
C
Brewer
Lesley
L
McGuffog
Antonis C
AC
Antoniou
Dominique
D
Stoppa-Lyonnet
Olga M
OM
Sinilnikova
Laure
L
Barjhoux
Marc
M
Frenay
Cécile
C
Michel
Dominique
D
Leroux
Helene
H
Dreyfus
Christine
C
Toulas
Laurence
L
Gladieff
Nancy
N
Uhrhammer
Yves-Jean
YJ
Bignon
Alfons
A
Meindl
Norbert
N
Arnold
Raymonda
R
Varon-Mateeva
Dieter
D
Niederacher
Sabine
S
Preisler-Adams
Karin
K
Kast
Helmut
H
Deissler
Christian
C
Sutter
Dorothea
D
Gadzicki
Georgia
G
Chenevix-Trench
Amanda B
AB
Spurdle
Xiaoqing
X
Chen
Jonathan
J
Beesley
Håkan
H
Olsson
Ulf
U
Kristoffersson
Hans
H
Ehrencrona
Annelie
A
Liljegren
Rob B
RB
van der Luijt
Theo A
TA
van Os
Flora E
FE
van Leeuwen
Susan M
SM
Domchek
Timothy R
TR
Rebbeck
Katherine L
KL
Nathanson
Ana
A
Osorio
Teresa
T
Ramón y Cajal
Irene
I
Konstantopoulou
Javier
J
Benítez
Eitan
E
Friedman
Bella
B
Kaufman
Yael
Y
Laitman
Phuong L
PL
Mai
Mark H
MH
Greene
Heli
H
Nevanlinna
Kristiina
K
Aittomäki
Csilla I
CI
Szabo
Trinidad
T
Caldes
Fergus J
FJ
Couch
Irene L
IL
Andrulis
Andrew K
AK
Godwin
Ute
U
Hamann
Rita K
RK
Schmutzler
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