Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium.
BACKGROUND
Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies.


METHODS
Genotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided.


RESULTS
Associations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, P(trend) = 2 x 10(-26)), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, P(trend) = 1 x 10(-10)) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, P(trend) = 5 x 10(-8)) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, P(trend) = 2 x 10(-5); rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, P(trend) = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer.


CONCLUSIONS
In this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histology.
Truong
Therese
T
Genetic Epidemiology Group, International Agency for Research on Cancer, 150 Cours Albert Thomas, Lyon Cedex 08, France. Brennan@iarc.fr
Hung
Rayjean J
RJ
Amos
Christopher I
CI
Wu
Xifeng
X
Bickeböller
Heike
H
Rosenberger
Albert
A
Sauter
Wiebke
W
Illig
Thomas
T
Wichmann
H-Erich
HE
Risch
Angela
A
Dienemann
Hendrik
H
Kaaks
Rudolph
R
Yang
Ping
P
Jiang
Ruoxiang
R
Wiencke
John K
JK
Wrensch
Margaret
M
Hansen
Helen
H
Kelsey
Karl T
KT
Matsuo
Keitaro
K
Tajima
Kazuo
K
Schwartz
Ann G
AG
Wenzlaff
Angie
A
Seow
Adeline
A
Ying
Chen
C
Staratschek-Jox
Andrea
A
Nürnberg
Peter
P
Stoelben
Erich
E
Wolf
Jürgen
J
Lazarus
Philip
P
Muscat
Joshua E
JE
Gallagher
Carla J
CJ
Zienolddiny
Shanbeh
S
Haugen
Aage
A
van der Heijden
Henricus F M
HF
Kiemeney
Lambertus A
LA
Isla
Dolores
D
Mayordomo
Jose Ignacio
JI
Rafnar
Thorunn
T
Stefansson
Kari
K
Zhang
Zuo-Feng
ZF
Chang
Shen-Chih
SC
Kim
Jin Hee
JH
Hong
Yun-Chul
YC
Duell
Eric J
EJ
Andrew
Angeline S
AS
Lejbkowicz
Flavio
F
Rennert
Gad
G
Müller
Heiko
H
Brenner
Hermann
H
Le Marchand
Loïc
L
Benhamou
Simone
S
Bouchardy
Christine
C
Teare
M Dawn
MD
Xue
Xiaoyan
X
McLaughlin
John
J
Liu
Geoffrey
G
McKay
James D
JD
Brennan
Paul
P
Spitz
Margaret R
MR
D000230:Adenocarcinoma / Q000208:ethnology / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics*; D002170:Canada / Q000453:epidemiology; D018287:Carcinoma, Large Cell / Q000208:ethnology / Q000235:genetics; D018288:Carcinoma, Small Cell / Q000208:ethnology / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000208:ethnology / Q000235:genetics; D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15; D002895:Chromosomes, Human, Pair 5; D002896:Chromosomes, Human, Pair 6; D005060:Europe; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007391:International Cooperation; D007564:Japan / Q000453:epidemiology; D007723:Korea / Q000453:epidemiology; D015810:Linkage Disequilibrium / Q000235:genetics; D008175:Lung Neoplasms / Q000208:ethnology* / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011786:Quality Control; D018570:Risk Assessment; D012307:Risk Factors; D012846:Singapore / Q000453:epidemiology; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics; D014029:Tobacco Use Disorder / Q000208:ethnology* / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics*