Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer.
Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) = 1.62, 95% CI = 1.38-1.89, P = 1.11 x 10(-9)). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r(2) = 0.995, D' = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR = 1.90, 95% CI = 1.56-2.33, P = 8.01 x 10(-11)). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.
Sakamoto
Hiromi
H
Yoshimura
Kimio
K
Saeki
Norihisa
N
Katai
Hitoshi
H
Shimoda
Tadakazu
T
Matsuno
Yoshihiro
Y
Saito
Daizo
D
Sugimura
Haruhiko
H
Tanioka
Fumihiko
F
Kato
Shunji
S
Matsukura
Norio
N
Matsuda
Noriko
N
Nakamura
Tsuneya
T
Hyodo
Ichinosuke
I
Nishina
Tomohiro
T
Yasui
Wataru
W
Hirose
Hiroshi
H
Hayashi
Matsuhiko
M
Toshiro
Emi
E
Ohnami
Sumiko
S
Sekine
Akihiro
A
Sato
Yasunori
Y
Totsuka
Hirohiko
H
Ando
Masataka
M
Takemura
Ryo
R
Takahashi
Yoriko
Y
Ohdaira
Minoru
M
Aoki
Kenichi
K
Honmyo
Izumi
I
Chiku
Suenori
S
Aoyagi
Kazuhiko
K
Sasaki
Hiroki
H
Ohnami
Shumpei
S
Yanagihara
Kazuyoshi
K
Yoon
Kyong-Ah
KA
Kook
Myeong-Cherl
MC
Lee
Yeon-Su
YS
Park
Sook Ryun
SR
Kim
Chan Gyoo
CG
Choi
Il Ju
IJ
Yoshida
Teruhiko
T
Nakamura
Yusuke
Y
Hirohashi
Setsuo
S
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000473:pathology; D000818:Animals; D000951:Antigens, Neoplasm; D016466:CHO Cells; D002291:Carcinoma, Papillary / Q000235:genetics / Q000473:pathology; D018279:Carcinoma, Signet Ring Cell / Q000235:genetics / Q000473:pathology; D016022:Case-Control Studies; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D004848:Epithelium; D005091:Exons / Q000235:genetics; D058851:GPI-Linked Proteins; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D007414:Intestinal Neoplasms; D007564:Japan; D007723:Korea; D015810:Linkage Disequilibrium; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D014158:Transcription, Genetic
D000951:Antigens, Neoplasm; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; D012333:RNA, Messenger