Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot".
We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n=1,233 serous invasive cases; n=3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele>or=0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p=0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.
Johnatty
Sharon E
SE
Queensland Institute of Medical Research, Brisbane, Australia. sharonJo@qimr.edu.au
Beesley
Jonathan
J
Chen
Xiaoqing
X
Macgregor
Stuart
S
Duffy
David L
DL
Spurdle
Amanda B
AB
deFazio
Anna
A
Gava
Natalie
N
Webb
Penelope M
PM
Rossing
Mary Anne
MA
Doherty
Jennifer Anne
JA
Goodman
Marc T
MT
Lurie
Galina
G
Thompson
Pamela J
PJ
Wilkens
Lynne R
LR
Ness
Roberta B
RB
Moysich
Kirsten B
KB
Chang-Claude
Jenny
J
Wang-Gohrke
Shan
S
Cramer
Daniel W
DW
Terry
Kathryn L
KL
Hankinson
Susan E
SE
Tworoger
Shelley S
SS
Garcia-Closas
Montserrat
M
Yang
Hannah
H
Lissowska
Jolanta
J
Chanock
Stephen J
SJ
Pharoah
Paul D
PD
Song
Honglin
H
Whitemore
Alice S
AS
Pearce
Celeste L
CL
Stram
Daniel O
DO
Wu
Anna H
AH
Pike
Malcolm C
MC
Gayther
Simon A
SA
Ramus
Susan J
SJ
Menon
Usha
U
Gentry-Maharaj
Aleksandra
A
Anton-Culver
Hoda
H
Ziogas
Argyrios
A
Hogdall
Estrid
E
Kjaer
Susanne K
SK
Hogdall
Claus
C
Berchuck
Andrew
A
Schildkraut
Joellen M
JM
Iversen
Edwin S
ES
Moorman
Patricia G
PG
Phelan
Catherine M
CM
Sellers
Thomas A
TA
Cunningham
Julie M
JM
Vierkant
Robert A
RA
Rider
David N
DN
Goode
Ellen L
EL
Haviv
Izhak
I
Chenevix-Trench
Georgia
G
D016022:Case-Control Studies; D002895:Chromosomes, Human, Pair 5; D004847:Epithelial Cells / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017154:Stromal Cells / Q000473:pathology*; D019098:Telomerase / Q000235:genetics*; D044465:White People / Q000235:genetics
D019098:Telomerase