Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer.
High-risk susceptibility genes explain <40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)-tagging approach to evaluate common variants in 13 genes involved in cell cycle control-CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D-and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark ( approximately 1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States ( approximately 2,000 cases and approximately 3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85-0.98) for rs3731257; and OR, 0.93 (0.87-0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies.
Gayther
Simon A
SA
Translational Research Laboratories, University College London, London, United Kingdom. s.gayther@ucl.ac.uk
Song
Honglin
H
Ramus
Susan J
SJ
Kjaer
Susan Krüger
SK
Whittemore
Alice S
AS
Quaye
Lydia
L
Tyrer
Jonathan
J
Shadforth
Danielle
D
Hogdall
Estrid
E
Hogdall
Claus
C
Blaeker
Jan
J
DiCioccio
Richard
R
McGuire
Valerie
V
Webb
Penelope M
PM
Beesley
Jonathan
J
Green
Adele C
AC
Whiteman
David C
DC
Goodman
Marc T
MT
Lurie
Galina
G
Carney
Michael E
ME
Modugno
Francesmary
F
Ness
Roberta B
RB
Edwards
Robert P
RP
Moysich
Kirsten B
KB
Goode
Ellen L
EL
Couch
Fergus J
FJ
Cunningham
Julie M
JM
Sellers
Thomas A
TA
Wu
Anna H
AH
Pike
Malcolm C
MC
Iversen
Edwin S
ES
Marks
Jeffrey R
JR
Garcia-Closas
Montserrat
M
Brinton
Louise
L
Lissowska
Jolanta
J
Peplonska
Beata
B
Easton
Douglas F
DF
Jacobs
Ian
I
Ponder
Bruce A J
BA
Schildkraut
Joellen
J
Pearce
C Leigh
CL
Chenevix-Trench
Georgia
G
Berchuck
Andrew
A
Pharoah
Paul D P
PD
D016022:Case-Control Studies; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D016213:Cyclins / Q000235:genetics; D005260:Female; D018816:Genes, cdc; D020022:Genetic Predisposition to Disease; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide
D018797:Cell Cycle Proteins; D016213:Cyclins; D018844:Cyclin-Dependent Kinases