Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.
The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.
Pearce
C L
CL
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. cpearce@usc.edu
Near
A M
AM
Van Den Berg
D J
DJ
Ramus
S J
SJ
Gentry-Maharaj
A
A
Menon
U
U
Gayther
S A
SA
Anderson
A R
AR
Edlund
C K
CK
Wu
A H
AH
Chen
X
X
Beesley
J
J
Webb
P M
PM
Holt
S K
SK
Chen
C
C
Doherty
J A
JA
Rossing
M A
MA
Whittemore
A S
AS
McGuire
V
V
DiCioccio
R A
RA
Goodman
M T
MT
Lurie
G
G
Carney
M E
ME
Wilkens
L R
LR
Ness
R B
RB
Moysich
K B
KB
Edwards
R
R
Jennison
E
E
Kjaer
S K
SK
Hogdall
E
E
Hogdall
C K
CK
Goode
E L
EL
Sellers
T A
TA
Vierkant
R A
RA
Cunningham
J M
JM
Cunningham
J C
JC
Schildkraut
J M
JM
Berchuck
A
A
Moorman
P G
PG
Iversen
E S
ES
Cramer
D W
DW
Terry
K L
KL
Vitonis
A F
AF
Titus-Ernstoff
L
L
Song
H
H
Pharoah
P D P
PD
Spurdle
A B
AB
Anton-Culver
H
H
Ziogas
A
A
Brewster
W
W
Galitovskiy
V
V
Chenevix-Trench
G
G
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors
D004268:DNA-Binding Proteins; C000607893:LIG4 protein, human; C113187:XRCC2 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011088:DNA Ligases; D000072481:DNA Ligase ATP