A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24.
Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2). Here, we report on nine additional candidate loci (defined as having P ≤ 10⁻⁴) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P ≤ 5 × 10⁻⁸ (8q24, P = 8.0 × 10⁻¹⁵ and 2q31, P = 3.8 × 10⁻¹⁴) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10⁻⁸ and 17q21, P = 1.4 × 10⁻⁷). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development.
Goode
Ellen L
EL
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Chenevix-Trench
Georgia
G
Song
Honglin
H
Ramus
Susan J
SJ
Notaridou
Maria
M
Lawrenson
Kate
K
Widschwendter
Martin
M
Vierkant
Robert A
RA
Larson
Melissa C
MC
Kjaer
Susanne K
SK
Birrer
Michael J
MJ
Berchuck
Andrew
A
Schildkraut
Joellen
J
Tomlinson
Ian
I
Kiemeney
Lambertus A
LA
Cook
Linda S
LS
Gronwald
Jacek
J
Garcia-Closas
Montserrat
M
Gore
Martin E
ME
Campbell
Ian
I
Whittemore
Alice S
AS
Sutphen
Rebecca
R
Phelan
Catherine
C
Anton-Culver
Hoda
H
Pearce
Celeste Leigh
CL
Lambrechts
Diether
D
Rossing
Mary Anne
MA
Chang-Claude
Jenny
J
Moysich
Kirsten B
KB
Goodman
Marc T
MT
Dörk
Thilo
T
Nevanlinna
Heli
H
Ness
Roberta B
RB
Rafnar
Thorunn
T
Hogdall
Claus
C
Hogdall
Estrid
E
Fridley
Brooke L
BL
Cunningham
Julie M
JM
Sieh
Weiva
W
McGuire
Valerie
V
Godwin
Andrew K
AK
Cramer
Daniel W
DW
Hernandez
Dena
D
Levine
Douglas
D
Lu
Karen
K
Iversen
Edwin S
ES
Palmieri
Rachel T
RT
Houlston
Richard
R
van Altena
Anne M
AM
Aben
Katja K H
KK
Massuger
Leon F A G
LF
Brooks-Wilson
Angela
A
Kelemen
Linda E
LE
Le
Nhu D
ND
Jakubowska
Anna
A
Lubinski
Jan
J
Medrek
Krzysztof
K
Stafford
Anne
A
Easton
Douglas F
DF
Tyrer
Jonathan
J
Bolton
Kelly L
KL
Harrington
Patricia
P
Eccles
Diana
D
Chen
Ann
A
Molina
Ashley N
AN
Davila
Barbara N
BN
Arango
Hector
H
Tsai
Ya-Yu
YY
Chen
Zhihua
Z
Risch
Harvey A
HA
McLaughlin
John
J
Narod
Steven A
SA
Ziogas
Argyrios
A
Brewster
Wendy
W
Gentry-Maharaj
Aleksandra
A
Menon
Usha
U
Wu
Anna H
AH
Stram
Daniel O
DO
Pike
Malcolm C
MC
Beesley
Jonathan
J
Webb
Penelope M
PM
Chen
Xiaoqing
X
Ekici
Arif B
AB
Thiel
Falk C
FC
Beckmann
Matthias W
MW
Yang
Hannah
H
Wentzensen
Nicolas
N
Lissowska
Jolanta
J
Fasching
Peter A
PA
Despierre
Evelyn
E
Amant
Frederic
F
Vergote
Ignace
I
Doherty
Jennifer
J
Hein
Rebecca
R
Wang-Gohrke
Shan
S
Lurie
Galina
G
Carney
Michael E
ME
Thompson
Pamela J
PJ
Runnebaum
Ingo
I
Hillemanns
Peter
P
Dürst
Matthias
M
Antonenkova
Natalia
N
Bogdanova
Natalia
N
Leminen
Arto
A
Butzow
Ralf
R
Heikkinen
Tuomas
T
Stefansson
Kari
K
Sulem
Patrick
P
Besenbacher
Sören
S
Sellers
Thomas A
TA
Gayther
Simon A
SA
Pharoah
Paul D P
PD
D014408:Biomarkers, Tumor / Q000235:genetics; D016022:Case-Control Studies; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics*; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics
C484527:BNC2 protein, human; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C442019:HOXD1 protein, human; D018398:Homeodomain Proteins; D010750:Phosphoproteins; D020598:Proto-Oncogene Proteins c-myb; C108336:SKAP1 protein, human