Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer.
We conducted a genome-wide association study on 969 bladder cancer cases and 957 controls from Texas. For fast-track validation, we evaluated 60 SNPs in three additional US populations and validated the top SNP in nine European populations. A missense variant (rs2294008) in the PSCA gene showed consistent association with bladder cancer in US and European populations. Combining all subjects (6,667 cases, 39,590 controls), the overall P-value was 2.14 x 10(-10) and the allelic odds ratio was 1.15 (95% confidence interval 1.10-1.20). rs2294008 alters the start codon and is predicted to cause truncation of nine amino acids from the N-terminal signal sequence of the primary PSCA translation product. In vitro reporter gene assay showed that the variant allele significantly reduced promoter activity. Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense SNP in PSCA. Our data identify rs2294008 as a new bladder cancer susceptibility locus.
Wu
Xifeng
X
Ye
Yuanqing
Y
Kiemeney
Lambertus A
LA
Sulem
Patrick
P
Rafnar
Thorunn
T
Matullo
Giuseppe
G
Seminara
Daniela
D
Yoshida
Teruhiko
T
Saeki
Norihisa
N
Andrew
Angeline S
AS
Dinney
Colin P
CP
Czerniak
Bogdan
B
Zhang
Zuo-feng
ZF
Kiltie
Anne E
AE
Bishop
D Timothy
DT
Vineis
Paolo
P
Porru
Stefano
S
Buntinx
Frank
F
Kellen
Eliane
E
Zeegers
Maurice P
MP
Kumar
Rajiv
R
Rudnai
Peter
P
Gurzau
Eugene
E
Koppova
Kvetoslava
K
Mayordomo
Jose Ignacio
JI
Sanchez
Manuel
M
Saez
Berta
B
Lindblom
Annika
A
de Verdier
Petra
P
Steineck
Gunnar
G
Mills
Gordon B
GB
Schned
Alan
A
Guarrera
Simonetta
S
Polidoro
Silvia
S
Chang
Shen-Chih
SC
Lin
Jie
J
Chang
David W
DW
Hale
Katherine S
KS
Majewski
Tadeusz
T
Grossman
H Barton
HB
Thorlacius
Steinunn
S
Thorsteinsdottir
Unnur
U
Aben
Katja K H
KK
Witjes
J Alfred
JA
Stefansson
Kari
K
Amos
Christopher I
CI
Karagas
Margaret R
MR
Gu
Jian
J
D000483:Alleles; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8; D058851:GPI-Linked Proteins; D005787:Gene Frequency; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D015999:Multivariate Analysis; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D015203:Reproducibility of Results; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000276:immunology
D000951:Antigens, Neoplasm; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human