Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies.
Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10(-8), and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19-1.40) and P= 7.63 × 10(-10). An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-7236, USA. abnetc@mail.nih.gov
Christian C
CC
Abnet
Zhaoming
Z
Wang
Xin
X
Song
Nan
N
Hu
Fu-You
FY
Zhou
Neal D
ND
Freedman
Xue-Min
XM
Li
Kai
K
Yu
Xiao-Ou
XO
Shu
Jian-Min
JM
Yuan
Wei
W
Zheng
Sanford M
SM
Dawsey
Linda M
LM
Liao
Maxwell P
MP
Lee
Ti
T
Ding
You-Lin
YL
Qiao
Yu-Tang
YT
Gao
Woon-Puay
WP
Koh
Yong-Bing
YB
Xiang
Ze-Zhong
ZZ
Tang
Jin-Hu
JH
Fan
Charles C
CC
Chung
Chaoyu
C
Wang
William
W
Wheeler
Meredith
M
Yeager
Jeff
J
Yuenger
Amy
A
Hutchinson
Kevin B
KB
Jacobs
Carol A
CA
Giffen
Laurie
L
Burdett
Joseph F
JF
Fraumeni
Margaret A
MA
Tucker
Wong-Ho
WH
Chow
Xue-Ke
XK
Zhao
Jiang-Man
JM
Li
Ai-Li
AL
Li
Liang-Dan
LD
Sun
Wu
W
Wei
Ji-Lin
JL
Li
Peng
P
Zhang
Hong-Lei
HL
Li
Wen-Yan
WY
Cui
Wei-Peng
WP
Wang
Zhi-Cai
ZC
Liu
Xia
X
Yang
Wen-Jing
WJ
Fu
Ji-Li
JL
Cui
Hong-Li
HL
Lin
Wen-Liang
WL
Zhu
Min
M
Liu
Xi
X
Chen
Jie
J
Chen
Li
L
Guo
Jing-Jing
JJ
Han
Sheng-Li
SL
Zhou
Jia
J
Huang
Yue
Y
Wu
Chao
C
Yuan
Jing
J
Huang
Ai-Fang
AF
Ji
Jian-Wei
JW
Kul
Zhong-Min
ZM
Fan
Jian-Po
JP
Wang
Dong-Yun
DY
Zhang
Lian-Qun
LQ
Zhang
Wei
W
Zhang
Yuan-Fang
YF
Chen
Jing-Li
JL
Ren
Xiu-Min
XM
Li
Jin-Cheng
JC
Dong
Guo-Lan
GL
Xing
Zhi-Gang
ZG
Guo
Jian-Xue
JX
Yang
Yi-Ming
YM
Mao
Yuan
Y
Yuan
Er-Tao
ET
Guo
Wei
W
Zhang
Zhi-Chao
ZC
Hou
Jing
J
Liu
Yan
Y
Li
Sa
S
Tang
Jia
J
Chang
Xiu-Qin
XQ
Peng
Min
M
Han
Wan-Li
WL
Yin
Ya-Li
YL
Liu
Yan-Long
YL
Hu
Yu
Y
Liu
Liu-Qin
LQ
Yang
Fu-Guo
FG
Zhu
Xiu-Feng
XF
Yang
Xiao-Shan
XS
Feng
Zhou
Z
Wang
Yin
Y
Li
She-Gan
SG
Gao
Hai-Lin
HL
Liu
Ling
L
Yuan
Yan
Y
Jin
Yan-Rui
YR
Zhang
Ilyar
I
Sheyhidin
Feng
F
Li
Bao-Ping
BP
Chen
Shu-Wei
SW
Ren
Bin
B
Liu
Dan
D
Li
Gao-Fu
GF
Zhang
Wen-Bin
WB
Yue
Chang-Wei
CW
Feng
Qirenwang
Q
Qige
Jian-Ting
JT
Zhao
Wen-Jun
WJ
Yang
Guang-Yan
GY
Lei
Long-Qi
LQ
Chen
En-Min
EM
Li
Li-Yan
LY
Xu
Zhi-Yong
ZY
Wu
Zhi-Qin
ZQ
Bao
Ji-Li
JL
Chen
Xian-Chang
XC
Li
Xiang
X
Zhuang
Ying-Fa
YF
Zhou
Xian-Bo
XB
Zuo
Zi-Ming
ZM
Dong
Lu-Wen
LW
Wang
Xue-Pin
XP
Fan
Jin
J
Wang
Qi
Q
Zhou
Guo-Shun
GS
Ma
Qin-Xian
QX
Zhang
Hai
H
Liu
Xin-Ying
XY
Jian
Sin-Yong
SY
Lian
Jin-Sheng
JS
Wang
Fu-Bao
FB
Chang
Chang-Dong
CD
Lu
Jian-Jun
JJ
Miao
Zhi-Guo
ZG
Chen
Ran
R
Wang
Ming
M
Guo
Zeng-Lin
ZL
Fan
Ping
P
Tao
Tai-Jing
TJ
Liu
Jin-Chang
JC
Wei
Qing-Peng
QP
Kong
Lei
L
Fan
Xian-Zeng
XZ
Wang
Fu-Sheng
FS
Gao
Tian-Yun
TY
Wang
Dong
D
Xie
Li
L
Wang
Shu-Qing
SQ
Chen
Wan-Cai
WC
Yang
Jun-Yan
JY
Hong
Liang
L
Wang
Song-Liang
SL
Qiu
Alisa M
AM
Goldstein
Zhi-Qing
ZQ
Yuan
Stephen J
SJ
Chanock
Xue-Jun
XJ
Zhang
Philip R
PR
Taylor
Li-Dong
LD
Wang
D044466:Asian People / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002681:China; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic