Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer.
Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty-three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer [HetOR = 1.42 (1.15-1.74) and the HomOR = 1.63 (1.10-1.42), p-trend = 0.0002] and [HetOR = 0.97 (0.80-1.17), HomOR = 0.74 (0.58-0.93), p-trend = 0.009], respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele-specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele-specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer.
Notaridou
Maria
M
Gynaecological Oncology Unit, UCL EGA Institute for Women's Health, University College London, United Kingdom.
Quaye
Lydia
L
Dafou
Dimitra
D
Jones
Chris
C
Song
Honglin
H
Høgdall
Estrid
E
Kjaer
Susanne K
SK
Christensen
Lise
L
Høgdall
Claus
C
Blaakaer
Jan
J
McGuire
Valerie
V
Wu
Anna H
AH
Van Den Berg
David J
DJ
Pike
Malcolm C
MC
Gentry-Maharaj
Aleksandra
A
Wozniak
Eva
E
Sher
Tanya
T
Jacobs
Ian J
IJ
Tyrer
Jonathan
J
Schildkraut
Joellen M
JM
Moorman
Patricia G
PG
Iversen
Edwin S
ES
Jakubowska
Anna
A
Mędrek
Krzysztof
K
Lubiński
Jan
J
Ness
Roberta B
RB
Moysich
Kirsten B
KB
Lurie
Galina
G
Wilkens
Lynne R
LR
Carney
Michael E
ME
Wang-Gohrke
Shan
S
Doherty
Jennifer A
JA
Rossing
Mary Anne
MA
Beckmann
Matthias W
MW
Thiel
Falk C
FC
Ekici
Arif B
AB
Chen
Xiaoqing
X
Beesley
Jonathan
J
Gronwald
Jacek
J
Fasching
Peter A
PA
Chang-Claude
Jenny
J
Goodman
Marc T
MT
Chenevix-Trench
Georgia
G
Berchuck
Andrew
A
Pearce
C Leigh
CL
Whittemore
Alice S
AS
Menon
Usha
U
Pharoah
Paul D P
PD
Gayther
Simon A
SA
Ramus
Susan J
SJ
D000483:Alleles; D018797:Cell Cycle Proteins; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C406153:STAG3 protein, human