International Lung Cancer Consortium: coordinated association study of 10 potential lung cancer susceptibility variants.
ABSTRACT Analysis of candidate genes in individual studies has had only limited success in identifying particular gene variants that are conclusively associated with lung cancer risk. In the International Lung Cancer Consortium (ILCCO), we conducted a coordinated genotyping study of 10 common variants selected because of their prior evidence of an association with lung cancer. These variants belonged to candidate genes from different cancer-related pathways including inflammation (IL1B), folate metabolism (MTHFR), regulatory function (AKAP9 and CAMKK1), cell adhesion (SEZL6) and apoptosis (FAS, FASL, TP53, TP53BP1 and BAT3).
Genotype data from 15 ILCCO case-control studies were available for a total of 8431 lung cancer cases and 11 072 controls of European descent and Asian ethnic groups. Unconditional logistic regression was used to model the association between each variant and lung cancer risk.
Only the association between a non-synonymous variant of TP53BP1 (rs560191) and lung cancer risk was significant (OR = 0.91, P = 0.002). This association was more striking for squamous cell carcinoma (OR = 0.86, P = 6 x 10(-4)). No heterogeneity by center, ethnicity, smoking status, age group or sex was observed. In order to confirm this association, we included results for this variant from a set of independent studies (9966 cases/11,722 controls) and we reported similar results. When combining all these studies together, we reported an overall OR = 0.93 (0.89-0.97) (P = 0.001). This association was significant only for squamous cell carcinoma [OR = 0.89 (0.85-0.95), P = 1 x 10(-4)].
This study suggests that rs560191 is associated to lung cancer risk and further highlights the value of consortia in replicating or refuting published genetic associations.
- SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: The TP53BP1 gene may be involved in the development of cancer through disrupting DNA repair. However, studies investigating the relationship between TP53BP1 Glu353Asp (rs560191) polymorphism and cancer yielded contradictory and inconclusive outcomes. In order to realize these ambiguous findings, a meta-analysis was performed to assess the association between the TP53BP1 Glu353Asp (rs560191) polymorphism and susceptibility to cancer. We conducted a search of all English reports on studies for the association between the TP53BP1 Asp353Glu (rs560191) polymorphism and susceptibility to cancer using Medline, the Cochrane Library, EMbase, Web of Science, Google (scholar), and all Chinese reports were identified manually and on-line using CBMDisc, Chongqing VIP database, and CNKI database. The strict selection criteria and exclusion criteria were determined, and odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. The fixed or random effect model was selected based on the heterogeneity test among studies. Publication bias was estimated using funnel plots and Egger's regression test. A total of seven studies were included in the meta-analysis including 3,213 cases and 3,849 controls. The results indicated that the Glu353Asp (rs560191) polymorphism in TP53BP1 gene had no association with cancer risk for all genetic models. In the subgroup analysis, the results suggested that Glu353Asp polymorphism was not associated with the risk of cancer according to ethnicity, cancer type, genotyping method, adjusted with control or not, HWE and quality score. This meta-analysis suggested that the Glu353Asp (rs560191) polymorphism in TP53BP1 gene was not associated with risk of cancer.PLoS ONE 01/2014; 9(3):e90931. · 3.73 Impact Factor
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ABSTRACT: Interleukin 1, beta (IL1B) plays a key role in mediating acute and chronic inflammation, which is further correlated with lung carcinogenesis. Several polymorphisms on IL1B gene have been identified, and a series of epidemiological studies have examined the association between IL1B polymorphisms and lung cancer risk. However, these findings are inconclusive. To derive a precise estimation of the relationship, a meta-analysis was performed. We summarized 12 eligible publications on three commonly studied IL1B polymorphisms (i.e., -31 T/C, -511 T/C, and +3954 C/T) by searching electronic databases. Combined odds ratio (OR) with 95 % confidence interval (CI) was calculated to assess the strength of association between them. Heterogeneity and publication bias were also assessed. We observed a significant association between IL1B polymorphisms and lung cancer. For -31T/C, the overall OR (95 % CI) of TT/TC versus CC was 1.23 (1.06-1.43). For +3954 C/T, the overall OR (95 % CI) of CC versus TT and CC versus CT/TT were 0.92 (0.86-0.99) and 0.92 (0.86-0.99), respectively. In conclusion, this meta-analysis suggests that the IL1B -31 T/C and +3954 C/T polymorphisms are associated with lung cancer risk. However, larger number of samples and studies with homogeneous lung cancer patients are needed to confirm these findings.Tumor Biology 06/2013; · 2.52 Impact Factor
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ABSTRACT: The study investigated several common SNPs in the tumor protein p53 binding protein 1 gene and tumor protein p53 gene in 640 lung cancer cases and 685 controls in Han Chinese to determine if these single nucleotide polymorphisms (SNPs) were associated with lung cancer risk. Several studies indicated that SNPs in the 53BP1 and TP53 gene are associated with cancer risk. We investigated the association between common SNP variants in the 53BP1, TP53 gene and lung cancer risk. We used real-time PCR method to investigate the genotypic frequencies of rs2602141, rs560191 and rs689647 in 53BP1 and rs1042522 in TP53 in 640 cases of lung cancer and 685 controls. SNPs rs2602141, rs560191 and rs689647 in 53BP1 were in complete linkage disequilibrium in Han Chinese. The frequencies of the G/G, G/T and T/T genotypes of rs2602141 were 17.5, 50.3 and 32.2% in cases and 21.0, 49.3 and 29.6% in controls, respectively and distributions were not significantly different (p = 0.236). The rs2602141 T/T genotype increased NSCLC risk (OR = 1.56, 95% CI = 1.10-2.21). The genotype distribution frequency of rs1042522 does not demonstrate significant differences between cases and control group. 53BP1 and TP53 gene interactions were not associated with lung cancer risk.Archives of medical research 12/2013; · 1.88 Impact Factor
Carcinogenesis vol.31 no.4 pp.625–633, 2010
Advance Access publication January 27, 2010
International Lung Cancer Consortium: Coordinated association study of 10 potential
lung cancer susceptibility variants
Therese Truong1,2, Wiebke Sauter3,4, James D.McKay1,
H.Dean Hosgood III5, Carla Gallagher6, Christopher
I.Amos7, Margaret Spitz7, Joshua Muscat6, Philip
Lazarus6, Thomas Illig3, H.Erich Wichmann3,4,8, Heike
Bickebo ¨ller9, Angela Risch10, Hendrik Dienemann11,
Zuo-Feng Zhang12, Behnaz Pezeshki Naeim12, Ping Yang13,
Shanbeh Zienolddiny14, Aage Haugen14, Loı ¨c Le
Marchand15, Yun-Chul Hong16,17, Jin Hee Kim16,17, Eric
J.Duell1,18,19, Angeline S.Andrew18, Chikako Kiyohara20,
Hongbing Shen21, Keitaro Matsuo22, Takeshi Suzuki22,
Adeline Seow23, Daniel P.K.Ng23, Qing Lan5, David
Zaridze24, Neonilia Szeszenia-Dabrowska25, Jolanta
Lissowska26, Peter Rudnai27, Eleonora Fabianova28,29, Vali
Constantinescu30, Vladimir Bencko31, Lenka Foretova32,
Vladimir Janout33, Neil E.Caporaso34, Demetrius
Albanes34, Michael Thun35, Maria Teresa Landi34, Joanna
Trubicka36, Marcin Lener36, Jan Lubin ´ski36, EPIC-lungy,
Ying Wang37, Ame ´lie Chabrier1, Paolo Boffetta1, Paul
Brennan1,?and Rayjean J.Hung1,37
1International Agency for Research on Cancer, Lyon 69008, France,
2Environmental epidemiology of cancer, CESP Centre for research in
Epidemiology and Population Health, U1018, Inserm, F-94807, Villejuif,
France,3Institute of Epidemiology, Helmholtz Zentrum Mu ¨nchen, German
Research Center for Environmental Health, 85764 Neuherberg, Germany,
4Institute of Medical Informatics, Biometry and Epidemiology, Chair of
Epidemiology, Ludwig-Maximilians-Universita ¨t, 81377 Munich, Germany,
5Division of Cancer Epidemiology and Genetics, National Cancer Institute,
Bethesda, MD 20852, USA,6Penn State College of Medicine, Hershey, PA
17033, USA,7University of Texas M. D. Anderson Cancer Center, Houston,
TX 77030, USA,8Klinikum Grosshadern, 81377 Munich, Germany,
9University of Goettingen, Medical School, 37073 Goettingen, Germany,
10DKFZ German Cancer Research Center, 69120 Heidelberg, Germany, ,
11Thoraxklinik Heidelberg, University of Heidelberg, 69126 Heidelberg,
Germany,12University of California at Los Angeles, Los Angeles, CA 90095-
1772, USA,13Mayo Clinic Cancer Center, Rochester, MN 55905, USA,
14National Institute of Occupational Health, 0167 Oslo, Norway,15University
of Hawaii, Honolulu, HI 9681, USA,16Department of Preventive Medicine,
Seoul National University College of Medicine, Seoul 110-799, Republic of
Korea,17Institute of Environmental Medicine, Seoul National University
Medical Research Center, Seoul 110-799, Republic of Korea,18Norris Cotton
Cancer Center and Department of Community and Family Medicine,
Dartmouth Medical School, Lebanon, NH 03756, USA,19Unit of Nutrition,
Environment and Cancer, Cancer Epidemiology Research Programme,
Catalan Institute of Oncology. L’Hospitalet de Llobregat, 08907 Barcelona,
Spain,20Kyushu University, Fukuoka 812-8582, Japan,21Nanjing Medical
University School of Public Health, Nanjing 210029, China,22Aichi Cancer
Center Research Institute, Nagoya Aichi 464-8681, Japan,23Department of
Community, Occupational and Family Medicine. National University of
Singapore, Singapore 117597, Singapore,24Institute of carcinogenesis, cancer
research center, Moscow 115478, Russia,25Department of Epidemiology,
Institute of occupational medecine, Lodz 90950, Poland,26The M.
Sklodowska-Curie memorial cancer center and institute of oncology, Warsaw
02781, Poland,27National institute of environmental health, Budapest 1097,
Hungary,28Specialized Institute of Hygiene and Epidemiology, 97556 Banska ´
Bystrica, Slovakia,29Regional Authority of Public Health, 97556 Banska ´
Bystrica, Slovakia,30Institute of Public Health, Bucharest 050463, Romania,
31Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles
University in Prague, CZ 12800, Czech Republic,32Department of cancer
epidemiology and genetics, Masaryk Memorial cancer institute, Brno 65653,
Czech Republic,33Palacky University, Olomouc 77515, Czech Republic,
34Division of Cancer Epidemiology and Genetics, National Cancer Institute,
National Institutes of Health, Department of Health and Human Services,
Bethesda, MD 20892, USA,35American Cancer Society, Epidemiology and
Surveillance Research, Atlanta, GA 30301, USA,36Department of Genetics
and Pathomorphology, Pomeranian Medical University, International
Hereditary Cancer Center, 70-204 Szczecin, Poland and37Samuel Lununfeld
Research Institute, Toronto M5T 3L9, Canada
?To whom correspondence should be addressed. International Agency for
Research on Cancer, Genetic Epidemiology Group, 150 Cours Albert Thomas,
69372 Lyon Cedex 08, France. Tel: þ33 4 72 73 83 91;
Fax: þ33 4 72 73 83 42;
Background. Analysis of candidate genes in individual studies has
had only limited success in identifying particular gene variants
that are conclusively associated with lung cancer risk. In the In-
ternational Lung Cancer Consortium (ILCCO), we conducted
a coordinated genotyping study of 10 common variants selected
because of their prior evidence of an association with lung cancer.
These variants belonged to candidate genes from different cancer-
related pathways including inflammation (IL1B), folate metabo-
lism (MTHFR), regulatory function (AKAP9 and CAMKK1), cell
adhesion (SEZL6) and apoptosis (FAS, FASL, TP53, TP53BP1 and
BAT3). Methods. Genotype data from 15 ILCCO case–control
studies were available for a total of 8431 lung cancer cases and
11 072 controls of European descent and Asian ethnic groups.
Unconditional logistic regression was used to model the associa-
tion between each variant and lung cancer risk. Results. Only the
association between a non-synonymous variant of TP53BP1
(rs560191) and lung cancer risk was significant (OR 5 0.91,
P 5 0.002). This association was more striking for squamous cell
carcinoma (OR 5 0.86, P 5 6 3 1024). No heterogeneity by cen-
ter, ethnicity, smoking status, age group or sex was observed. In
order to confirm this association, we included results for this
variant from a set of independent studies (9966 cases/11 722 con-
trols) and we reported similar results. When combining all these
studies together, we reported an overall OR 5 0.93 (0.89–0.97)
(P 5 0.001). This association was significant only for squamous
cell carcinoma [OR 5 0.89 (0.85–0.95), P 5 1 3 1024]. Conclu-
sion. This study suggests that rs560191 is associated to lung cancer
risk and further highlights the value of consortia in replicating or
refuting published genetic associations.
It has been long recognized that there is a genetic component for lung
cancer based on familial studies and analysis of family cancer history
in case–control studies (1–5). However, progress in identifying spe-
cific susceptibility loci and genes has been slow, mainly due to in-
adequate study designs, underpowered sample sizes and preferential
reporting of false-positive findings. Recently, several genome-wide
association studies (GWAS) reported lung cancer susceptibility loci
at 15q25, 6p21 and 5p15.33, providing additional evidence of
a genetic contribution to lung cancer (6–10).
Although replication of findings is fundamental to the GWAS ap-
proach, the replication of significant variants in studies based on the
more traditional candidate gene approach may also be an important
procedure. To confirm the role of candidate genetic variants that were
found to be associated with lung cancer risk, we established a fast-
track replication mechanism for testing genetic variants within the
framework of the International Lung Cancer Consortium (ILCCO).
Abbreviations: GWAS, genome-wide association studies; ILCCO, Interna-
tional Lung Cancer Consortium; SNPs, single nucleotide polymorphisms.
ySee Appendix for the complete list of co-authors of EPIC-lung and their
? The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com
ILCCO was established in 2004 with the aim of sharing comparable
data from ongoing lung cancer case–control and cohort studies. The
overall objectives are to increase statistical power, especially for
subgroup analyses, reduce duplication of research efforts, replicate
novel findings and afford substantial cost savings through large col-
laborative efforts. Details on the organization of the consortium have
been published previously (11).
In order to prioritize genetic variants for this rapid replication
within the consortium, a procedure was established to replicate ge-
netic variants newly associated with risk in previous lung cancer
studies. Two criteria were used to prioritize the genetic variants: (i)
a similar significant main effect (P , 0.05) in at least two studies,
both of which had sample sizes of at least 500 case–control pairs or
(ii) a strongly significant main effect (P , 0.001) from a single study.
Ten potential lung cancer susceptibility variants meeting the criteria
were proposed by the consortium members for replication (Table I).
These variants belonged to genes from various cancer-related path-
ways including inflammation (IL1B), folate metabolism (MTHFR),
regulatory function (AKAP9 and CAMKK1), cell adhesion (SEZL6)
and apoptosis (FAS, FASL, TP53, TP53BP1 and BAT3). The descrip-
tion of the selected variants is detailed in supplementary Table I
(available at Carcinogenesis Online).
Materials and methods
In the current study, we conducted a coordinated genotyping of 10 potential
lung cancer susceptibility variants in 15 studies. From these studies, six were
conducted in the USA, six in Asia and three in Europe. Study designs are
briefly outlined in Table II, and more detailed information for some of these
studies has been published previously (6,20–31). Studies are referred to by
study location or coordinating institute.
Eligibility criteria based on age were applied in two studies: ?50 years for the
German study and ,65 years for the University of California, Los Angeles study.
Eligibility criteria based on smoking status were applied in three studies: the
Singapore study was restricted to never-smoking women, whereas the MD
Anderson and Norway studies included only ever smokers. In all studies, cases
were histologically or cytologically confirmed, except in the NCI-China study
where the inclusion criteria comprise a positive histology or cytology, or clinically
diagnosed cases that died within a 1 year period. Therefore, the NCI-China study
did not have information on histology for all cases. The Norway study was re-
ethnicity, residence area or smoking status, and two studies did not apply any
matching factors (Kyushu University and Mayo clinic studies).
Written informed consent was obtained from all study subjects, and approval
from the relevant ethicsboardwasobtained at each studycenter. Genotype data
whom68%where Europeandescent,28%were Asianand4% wereofdifferent
ethnic groups (African-American, Hispanic, Native Hawaiian and American
Indian). Only European descent (5876 cases and 7874 controls) and Asian
The remaining ethnic groups were excluded due to small sample size.
Genotyping and quality control
Genomic DNA was extracted from blood samples in all centers, except in the
Penn State College of Medicine and the NCI-China studies for which DNAwas
extracted from oral buccal mucosa cells. Several studies had independently gen-
otyped some of the selected variants prior to this initiative using their own
protocol and did not genotype additional variant (German, MD Anderson,
NCI-China, Aichi and Nanjing-China studies). The genotyping procedures of
these studies are described elsewhere (6,23,24,28,31). For all other centers, the
genotyping was done locally using Taqman (Applied Biosystems, Forster City,
CA). Three studies (Kyushu, Seoul and Singapore studies) genotyped a subset of
the selected single nucleotide polymorphisms (SNPs) due to DNA availability.
Proceduresfor inter-laboratoryquality control were appliedfor the Germanstudy
and all centers that used Taqman probes: each genotyped a generic series of
common DNAs (either SNP500, HapMap CEU trios or International Agency
for Research on Cancer generic series) using their local genotyping facility.
The genotype concordance across studies was subsequently computed for each
genotyping assay. Discrepancies rates for all assays were ,5%. Studies with
a call rate of ,90% for a variant were excluded from analysis for that variant.
Table III shows the number of cases and controls included in analysis and minor
allele frequency among controls for each variant and each study by ethnic group.
It should be noted that in this replication study, centers that have generated the
hypothesis on a variant were excluded from analysis for the corresponding var-
iant. As the number of participating studies differed for each variant, subjects
included in analysis varied greatly from a variant to another especially in Asians.
We used a Chi-squared test with one degree of freedom to verify that allele
distributions for each of the 10 SNPs were in Hardy–Weinberg equilibrium
within each study and among European descent controls and Asian controls
separately. A Bonferroni correction for multiple tests was applied for the
Hardy–Weinberg equilibrium test giving an indicative P-value of 5 ? 10?4
(based on ?100 tests carried out). All genotype distributions respected Hardy–
Smoking status was categorized into three categories as never, former and cur-
rent smokers. Former smokers were defined as smokers who stopped smoking
for at least 2 yearsprior tothe diagnosis (forcases)orinterview (forcontrols).In
the Norway and NCI-China studies, it was not possible to distinguish former
from current smokers and ever smokers were considered as current smokers.
We used unconditional logistic regression to estimate odds ratios (ORs) and
95% confidence intervals. Pooled ORs were calculated using individual-level
data from ILCCO studies. The heterozygous and homozygous carriers of the
minor allele were each compared with the homozygous carriers of the major
allele. OR per allele or P-values for trend were calculated assuming a log-
additive genetic model with one degree of freedom. European descent and
Asian subjects were analyzed as separate groups as well as together. Models
were adjusted for study-matching variables and potential confounders
Table I. Evidence from genetic studies: summary of results that generated hypothesis on the 10 selected variants
Studies providing initial resultsStudy setting Cases/controls VariantLevel of evidence
Rudd et al. (12)UK1529/2707 BAT3 S625P (rs1052486)
CAMKK1 E375G (rs7214723)
TP53BP1 D353E (rs560191)
AKAP9 M463I (rs6964587)
IL1B 3954C.T (rs1143634)
OR 5 0.84 (0.77–0.92), P 5 0.0002
OR 5 1.18 (1.08–1.29), P 5 0.0003
OR 5 0.85 (0.77–0.92), P 5 0.0009
OR 5 1.32 (1.15–1.52), P 5 0.0001a
OR 5 1.27 (1.10–1.47), P 5 0.001a
Engels et al., (13)
(MD Anderson study)
Gorlov et al., (14)
SEZ6L M430I (rs663048)Combined OR: wTT versus GG:
3.32 (1.81–7.21), P 5 0.0006
OR 5 1.79 (1.26–2.52), P 5 0.001b
OR 5 1.59 (1.21–2.10), P 5 0.001b
OR 5 2.49 (1.41–4.42), P 5 0.002a
TT versus CC: OR 5 2.40 (1.61–3.59)
OR 5 1.37 (1.10–1.71), P 5 0.005b
P , 0.001
OR 5 1.99 (1.27–3.13), P 5 0.003b
Zhang et al., (15) FASL 844T.C (rs763110)
FAS 1377G.A (rs2234767)
MTHFR 677C.T (rs1801133)Shen et al., (16) (China study)
Zhang et al., (17)
Hung et al., (18) (IARC study)
Wu et al., (19) (MD Anderson study)
Hung et al., (20) (IARC study)
TP53 intron3 16 bp duplication
IARC, International Agency for Research on Cancer.
bRecessive model, otherwise log-additive model.
T.Truong et al.
including age, sex, smoking status and center when appropriate. We conducted
stratified analysis by smoking status and age of diagnosis to evaluate effect
modification. We also analyzed the association of genetic variants and lung
cancer risk by major histological subtypes (squamous cell carcinoma, adeno-
carcinoma and small cell carcinoma). Heterogeneity of ORs across the studies
and across the stratification groups (age, sex and ethnicity) was assessed using
the Cochran’s Q-test. All analysis was conducted with SAS 9.1.
Additional replication analysis
In orderto confirm the associationwe foundbetween rs560191(TP53BP1) and
lung cancer risk in the ILCCO sample, we have genotyped additionally 1996
cases and 3487 controls from two further case–control studies (Poland and
EPIC-lung) using Taqman. We have also incorporated results from several
GWAS on lung cancer (National Cancer Institute, Texas, Canada, Tromso,
CARET) including a total of 7970 cases and 8235 controls, as this variant is
tagged on the Illumina panel by the proxy rs2602141 (R25 1.00, D#51.00).
The Polish study is a hospital-based case–control study conducted in Szcze-
cin between 2004 and 2007 (32). No data on smoking status were available for
this study. EPIC-lung study is a case–control study nested in the EPIC cohort
(European Prospective Investigation into Cancer and Nutrition) that was con-
ducted in 10 European countries (Sweden, Denmark, The Netherlands, UK,
France, Germany, Spain, Italy, Greece and Norway). This study was described
in detail previously (7,33).
The NCI, Texas, Canada, HUNT2/Tromso and CARET GWAS studies
were part of a meta-analysis that was conducted previously (34). Briefly,
the NCI GWAS (National Cancer Institute) was drawn from four different
studies: the Environment and Genetics in Lung Cancer Etiology, a popula-
tion-based case–control study conducted in Italy in 2002–2005 (35); the
Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (36), a cohort
study including male smokers enrolled in Finland in 1985–1993; the Prostate,
Lung, Colon, Ovary Screening Trial, a randomized trial conducted in 10 US
centers between 1992 and 2001 (37) and the Cancer Prevention Study II
Nutrition Cohort, a cohort study conducted across all US in 1992–
2001(38). The Texas study is a hospital-based case–control study including
only smokers; cases with non-small cell lung cancer were diagnosed at the
University of Texas MD Anderson Cancer Center since 1991 (6). The
CARET cohort study (Carotene and Retinol Efficacy Trial) was conducted
in six US centers between 1983 and 1994 and included only smokers with
a smoking history of at least 20 pack-years (39). The HUNT2/Tromso study
included cases and controls from two large population-based studies: the
North Trondelag Health Study (HUNT2) conducted in 1995–1997 and the
Tromso IV study conducted in 1994–1995. The Canada study is a hospital-
based case–control study conducted at the University of Toronto and the
Samuel Lunenfeld Research Institute in 1997–2002 (7).
All these cases and controls were of European descents. As no heterogeneity
wasdetectedacrossstudies, we useda fixed-effects modelto calculateORs and
95% confidence intervals for all studies combined.
Table IV shows the ORs of lung cancer for the 10 selected variants, for
all subjects and stratified by ethnicity. No significant heterogeneity
across ethnic groups was reported. We did not observe an association
between any of the variants and risk of lung cancer, except rs560191
(TP53BP1), which was significantly associated with lung cancer risk in
European descents and Asians [overall OR per rare allele 5 0.91
(0.86–0.97), P-value 5 0.002]. When considering both ethnic groups,
no significant heterogeneity by study, histology, smoking status, age
group or sex was observed (supplementary Figure 1 is available at
Carcinogenesis Online). However, even if the heterogeneity by histol-
ogy was non-significant (P 5 0.15), the association was more striking
forsquamouscellcarcinoma[OR 5 0.86(0.79–0.94),P 5 6 ? 10?4]
than for adenocarcinoma [OR 5 0.97 (0.89–1.04), P 5 0.39] or small
cell carcinoma [OR 5 0.91 (0.80–1.03), P 5 0.14].
In order to confirm the findings on rs560191, we have genotyped
this variant in two additional studies (EPIC-Lung and Poland) and we
have also incorporated results from several GWAS studies on
rs2602141 (a proxy of rs560191). The results of this meta-analysis
are reported in Table V. The associations found are similar to those of
the ILCCO study. Overall, we reported an OR of 0.95 (0.91–0.99)
(P 5 0.02). The association was significant for squamous cell carci-
noma [OR 5 0.92 (0.86–0.99), P 5 0.03] but not for adenocarci-
noma [OR 5 0.95(0.89–1.02)]
[OR 5 0.98 (0.88–1.09)] (P-heterogeneity by histology 5 0.60).
Table II. Description of the participating studies
Period of case
Number of casesa
National Institute of Occupational Health, Oslo
From the Oslo health screening 2000–2001, current
smokers or quit smoking ,5 years
Employees from Fukuoka prefectural government
University of California, Los Angeles
18- to 65-year-old, Los Angeles resident at time of re-
Helmholtz Centers Heidelberg and Munich
From KORA study: ,50 years old
MD Anderson Cancer Center
Cancer-free patients, ever smokers
Patients with non-tobacco related disease
National Cancer Institute
Residence in Xuan Wei county
Seoul National University
National University of Singapore
Never smokers; no diagnosis or suspicion of malignancy
or chronic respiratory disease
University of Hawaii
26- to 79-year-old, Hawaii residents, with no history of
Aichi Cancer Center
Norris Cotton Cancer Center, Dartmouth Medical
Random sample from commercial database
Penn State College of Medicine
Subjects from screening clinics with no history of can-
Nanjing Medical University School of Public Health
Community residents with no history of cancer
IARC, International Agency for Research on Cancer.
aMaximum number of cases and controls of all ethnic groups with DNA.
International Lung Cancer Consortium
Table III. Number of cases and controls included in analysis and minor allele frequency among controls
Ca/CoMAFCa/Co MAFCa/CoMAFCa/Co MAFCa/Co MAFCa/Co MAF Ca/CoMAF Ca/CoMAFCa/CoMAFCa/CoMAF
0.300.29 0.250.440.010.19 0.270.720.08
0.28 0.12 0.240.030.630.67 0.37 0.00080.84
—, Not genotyped; Ca, number of cases; Co, number of controls; IARC, International Agency for Research on Cancer; MAF, minor allele frequency; P-heterogeneity, heterogeneity test across MAF; O, study that
generated the hypothesis; UCLA, University of California, Los Angeles; x, excluded because of QC failure.
T.Truong et al.
The result of the combined analysis of the ILCCO study and the
additional studies is shown in Figure 1. We reported an overall OR of
0.93 (0.89–0.97) (P 5 0.001), and we found that this association con-
cerned mostly squamous cell carcinoma [OR 5 0.89 (0.85–0.95), P 5 1
? 10?4]. When combined with the initial association that generated the
hypothesis reported by Rudd et al. [OR 5 0.85 (0.77–0.92)], P 5 9
? 10?4, Table II), the allelic OR was 0.91 (0.88–0.95), P 5 6 ? 10?6.
Stratified analyses were also performed for the other variants consid-
ered, and the results showed no consistent patterns (results not shown).
This replication study was based on common variants that were pre-
viously found associated with lung cancer risk in a candidate gene
approach. We evaluated the effect of 10 variants proposed by the
ILCCO members on lung cancer risk in a pooled analysis of 15
studies. The large sample size collected in European descent and
Asian groups permitted us to analyze potential effect modification
in subgroups of interest (by smoking status, age of onset and histo-
logical subtypes). We found that rs560191 (TP53BP1) was associated
with a decreased risk of lung cancer. This association was more strik-
ing for squamous cell carcinoma. This result was replicated in a meta-
analysis of eight independent studies based on an additional 9966
cases and 11 722 controls.
We did not find an association between lung cancer risk and any of
the other variants. With the exception of MTHFR C677T, none of
these variants had been previously analyzed in the context of a pooled
or a meta-analysis of lung cancer studies (40,41).
Table IV. Association between the 10 selected variants and lung cancer risk in European descent and Asian
CaCo OR95% CI Ca CoOR95% CI CaCoOR95% CI
BAT3 (rs1052486) AA
P-trend 5 0.86
P-trend 5 0.97
P-trend 5 0.74
P 5 0.28
Number of studies
P-trend 5 0.98
P-trend 5 0.89
P-trend 5 0.80
P 5 0.69
Number of studies
P-trend 5 0.002
P-trend 5 0.02
P-trend 5 0.05P 5 0.54
Number of studies
P-trend 5 0.11
P-trend 5 0.33
P-trend 5 0.10
P 5 0.17
Number of studies
P-trend 5 0.99
P-trend 5 0.80
P-trend 5 0.11
P 5 0.12
Number of studies
P-trend 5 0.45
P-trend 5 0.35
P-trend 5 0.41
P 5 0.62
Number of studies
P-trend 5 0.23
P-trend 5 0.34
P-trend 5 0.42
P 5 0.84
Number of studies
P-trend 5 0.16
P-trend 5 0.52
P-trend 5 0.10P 5 0.29
Number of studies
P-trend 5 0.63
P-trend 5 0.66
P-trend 5 0.82
P 5 0.89
Number of studies
TP53 intron 3
P-trend 5 0.33
P-trend 5 0.56
P 5 0.42
Number of studies211
OR adjusted for sex, age, center and smoking status. Ca, number of cases; Co, number of control.
International Lung Cancer Consortium
To our knowledge, only one study has investigated the role of
TP53BP1 variants in lung cancer susceptibility (12). This study ana-
lyzed the association between lung cancer and 1476 non-synonymous
variants from871 candidate cancergenesina large case–controlstudy
conducted in UK (1529 cases and 2797 controls) and reported a de-
creased risk of lung cancer among rare allele carriers of rs560191 [OR
per allele 5 0.85 (0.77–0.93)]. This result was replicated in the pres-
ent study [OR 5 0.93 (0.89–0.97), P 5 0.001]. This association re-
mains significant after a Bonferroni correction for multiple tests based
on 10 independent tests carried out (corresponding to the number of
variants analyzed) and then considering a threshold P-value of 0.005.
No heterogeneity across studies and ethnic groups was observedin the
overall analysis. However, even if the test for heterogeneity was non-
significant across histology groups (P 5 0.23), we reported a stronger
Table V. Meta-analysis of the association between rs560191/rs2602141and lung cancer risks in additional studies independent from ILCCO
All histology AdenocarcinomasSquamous cell carcinomasSmall cell carcinomas
Ca/CoOR (95% CI)pCa/CoOR (95% CI)PCa/Co OR (95% CI)PCa/Co OR (95% CI)P
0.50 1315/5848 0.95
Texas1154/1137 0.05628/11370.18309/1137 0.02—
Canada 291/4750.4490/475 0.58 50/475 0.9722/475 0.85
Poland855/10210.02 180/10210.10318/1021 0.0291/10210.98
Overall 9966/11 722 0.95
P-heterogeneity 5 0.20
0.02 2974/11 722 0.95
P-heterogeneity 5 0.52
0.13 2398/11 722 0.92
P-heterogeneity 5 0.13
0.03 987/10 377 0.98
P-heterogeneity 5 0.23
All OR are adjusted for age, sex and smoking status, except for Poland study for which smoking status was not available. Ca, number of cases; CARET, Carotene
and Retinol Efficacy Trial; Co, number of controls; GWAS, genome-wide association studies; NCI, National Cancer Institute.
Fig. 1. Forest plot representing association between rs560191/rs2602141 (TP53BP1) and lung cancer risk by study and by histology. Ca, number of cases;
Co, number of controls; Overall OR and ORs by histology are derived from a fixed effect model OR by study are adjusted for age, sex and smoking status, except
the Polish study that was adjusted for age and sex only (as smoking status was not available).
T.Truong et al.
association between squamous cell carcinoma and rs560191
[OR 5 0.89 (0.85–0.95), P 5 1 ? 10?4].
rs560191 is a non-synonymous variant of TP53BP1, although no
report on any functional relevance of this variant was published so
far. TP53BP1 is one of the TP53-regulated genes and it is known to
be involved in DNA damage–signaling pathways, in checkpoint signal-
tional activation (44). One study suggested that TP53BP1 may have
protective effects on squamous cell carcinoma of the head and neck risk
but such effects were confined to TP53 variant allele/haplotype carriers
(45). In the present pooled analysis, only one study had data for both
TP53BP1 and TP53 intron 3, and we did not observe any interaction
between these two variants in lung cancer risk (data not shown).
Several case–control studies have reported previously on the asso-
ciation between the MTHFR C677T variant and lung cancer risk,
including predominantly European (18,46–48) and Asian studies
(16,17,49,50). Some of these studies (16,18,28,46) also analyzed pos-
sible effect modification by folate intake, as the MTHFR enzyme is
involved in folate metabolism. A recent meta-analysis of these studies
(41) suggested no evidence for a major role of the MTHFR C677T
polymorphisms in carcinogenesis of lung cancer. Another recent
meta-analysis (40), including stratified analysis by folate intake lev-
els, observed a non-significant increased risk of lung cancer among
MTHFR 677 TT individuals with low folate intake. In the present
study, no association between MTHFR C677T and lung cancer risk
was observed; however, information on folate intake was not available.
Few studies have investigated the association between the other
variants considered and lung cancer risk. AKAP9 M463I, CAMKK1
E375G and BAT3 S625P were detected as candidate variants in the
same study mentioned above that highlighted TP53BP1 D353E (12).
Interestingly, a variant in BAT3 was recently found strongly associated
with lung cancer risk (10), although D# 5 1.0 and r2, 0.08 with
BAT3 S625P. Association between IL1B C3954Tand lung cancer risk
wasreportedina studyfromUSthatevaluated apanelof59variantsin
37 inflammation-related genes (13). Another study also found such an
association with this variant, but only among former smokers and men
(51). Conversely, a study conducted in Norway found no association
between IL1B C3954T and lung cancer risk but reported significant
detected as a candidate variant affecting lung cancer risk in a pilot
study testing 83 715 SNPs and this association was confirmed in two
replication studies (14). FAS G1377A and FASL C844T were investi-
gated in a case–control study conducted in China (15). This study
reported an increase risk of lung cancer among wild allele carriers
for both SNPs and a multiplicative gene–gene interaction. These re-
sults were not replicated in two other independent studies, one con-
ducted in Korea (54) and the other conducted in US (51). Association
between the TP53 intron 3 polymorphism and lung cancer risk was
examined by three studies. Two studies conducted, respectively, in US
TP53 intron 3 increased the risk of lung cancer, whereas another study
conducted in Sweden (55) did not detect any association.
The present study shows the importance of consortia in replicating
potential significant results from candidate gene studies. Only for 1 of
10 variants was the association replicated, suggesting that initial pos-
itive results for the other SNPs may be false.
In conclusion, among the 10 variants selected for replication based
on prior evidence of a potential association with lung cancer risk, we
reported significant results only for rs560191 (TP53BP1). Rare allele
carriers of this variant were found to have a modest decreased risk of
lung cancer. This association concerned mainly squamous cell carci-
nomas. Subsequent studies from ILCCO will focus on replication of
lung cancer susceptibility variants identified by GWAs.
Supplementary Table 1 and Figure 1 can be found at http://carcin
US National Institutes of Health, National Cancer Institute (R03
CA133939-01); Central Europe study—World Cancer Research
Fund and European Commission’s INCO-COPERNICUS Program
(IC15-CT98-0332); Norvegian study—The Norwegian Research
Council; Norwegian Cancer Society; Aichi Cancer Center study—-
Grants-in-Aid for Scientific Research, Ministry of Education, Sci-
ence, Sports, Culture and Technology of Japan; MD Anderson
study—National Institutes of Health (CA127219, CA55769,
CA121197); Penn State study—Public Health Service grants (K99
CA131477), National Institutes of Health (P01 CA68384, K07
CA104231); NCI-China study—Intramural National Cancer Insti-
National Medical Research Council; Seoul study—Eco-technopia
21 project, Ministry of Environment, Republic of Korea; ‘‘Deutsche
Krebshilfe’’ (70-2387, 70-2919); Mayo Clinic study—National In-
stitutes of Health (CA77118, CA80127, CA84354); Norris Cotton
Cancer Center study—National Center for Research Resources,
National Institutes of Health (P20RR018787). Environment and
Genetics in Lung Cancer Etiology, Prostate, Lung, Colon, Ovary
Screening Trial, Alpha-Tocopherol, Beta-Carotene Cancer Preven-
tion studies, genotyping of Alpha-Tocopherol, Beta-Carotene Can-
cer Prevention study, Cancer Prevention Study II Nutrition Cohort
and part of Prostate, Lung, Colon, Ovary Screening Trial—Intramural
Research Program, National Institutes of Health, National Cancer
Institute, Division of Cancer Epidemiology and Genetics; Alpha-
Tocopherol, Beta-Carotene Cancer Prevention study—US Public
Health Service contracts, National Cancer Institute (N01-CN-45165,
N01-RC-45035, N01-RC-37004); PLCO study was also supported by
individual contracts from the National Cancer Institute to the Univer-
sity of Colorado Denver (NO1-CN-25514); Georgetown University
(NO1-CN-25522); Pacific Health Research Institute (NO1-CN-
25515); Henry Ford Health System (NO1-CN-25512); University of
Minnesota (NO1-CN-25513); Washington University (NO1-CN-
25516); University of Pittsburgh (NO1-CN-25511); University of
Utah (NO1-CN-25524); Marshfield Clinic Research Foundation
(NO1-CN-25518); University of Alabama at Birmingham (NO1-
CN-75022); Westat (NO1-CN-25476); University of California, Los
Angeles (NO1-CN-25404); The Cancer Prevention Study II Nutrition
Cohort was supported by the American Cancer Society; The NIH
Genes, Environment and Health Initiative partly funded DNA extrac-
tion and statistical analyses (HG-06-033-NCI-01, RO1HL091172-
01); genotyping at the Johns Hopkins University Center for Inherited
Disease Research (U01HG004438, NIH HHSN268200782096C);
study coordination at the GENEVA Coordination Center (U01
HG004446) for Environment and Genetics in Lung Cancer Etiology
and part of PLCO studies. German study—BMBF, Germany (Compe-
tence Network Radiation Research, project: individual susceptibility
and genomic instability); KORA research platform—the Helmholtz
Center Munich, German Research Center for Environmental Health.
Conflict of Interest Statement: None declared.
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Received July 22, 2009; revised December 11, 2009;
accepted December 20, 2009
EPIC-Lung co-authors list
Paolo Vineis (Servizio di Epidemiologia dei Tumori, Universita ` di
Torino and CPO-Piemonte, Turin, Italy; Department of Epidemiology
and Public Health, Imperial College, London, UK), Francoise Clavel-
Chapelon [INSERM (Institut National de la Sante ´ et de la Recherche
Me ´dicale), ERI 20, EA 4045, and Institut Gustave Roussy, Villejuif,
F-94805 France], Domenico Palli [Molecular and Nutrional Epide-
miology Unit, Cancer Research and Prevention Institute (ISPO),
Florence, Italy], Rosario Tumino (Cancer Registry and Histopathol-
ogy Unit, Department of Oncology, ‘‘Civile M.P.Arezzo’’ Hospital,
ASP 7, Italy), Vittorio Krogh (Nutritional Epidemiology Unit,
T.Truong et al.
Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy),
Salvatore Panico (Dipartimento di Medicina Clinica e Sperimentale,
Universita di Napoli, Federico II, Naples, Italy), Carlos A. Gonza ´lez
(Unit of Nutrition, Environment and Cancer, Cancer Epidemiology
Research Programme, Catalan Institute of Oncology. L’Hospitalet de
Llobregat, Barcelona, Spain), Jose ´ Ramo ´n Quiro ´s (Jefe Seccio ´n
Informacio ´n Sanitaria, Consejerı ´a de Servicios Sociales, Principado
de Asturias, Oviedo, Spain), Carmen Martı ´nez (Escuela Andaluza de
Salud Pu ´blica, Granada, Spain), Carmen Navarro (Epidemiology De-
partment, Murcia Health Council, Murcia, Spain; CIBER Epidemio-
logia y Salud Publica (CIBERESP), Spain), Eva Ardanaz (Registro de
Ca ´ncer de Navarra, Instituto de Salud Pu ´blica, Gobierno de Navarra,
Spain), Nerea Larran ˜aga (Subdireccio ´n de Salud Pu ´blica de Gipuzkoa,
Gobierno Vasco, San Sebastian, Spain), Kay Tee Khaw (University of
Cambridge, UK), Timothy Key (Cancer Research UK, University of
Oxford, Oxford, UK), H.Bas Bueno-de-Mesquita [Centre for Food
and Health, National Institute for Public Health and the Environment
(RIVM), Bilthoven, The Netherlands], Petra.HM Peeters (Julius Center
for Health Sciences and Primary Care, Department of Epidemiology,
(WHO Collaborating Center, Department of Hygiene, Epidemiology
dation, Athens, Greece), Rudolf Kaaks (Division of Clinical Epi-
demiology, German Cancer Research Centre, Heidelberg, Germany),
Heiner Boeing (Department of Epidemiology, Deutsches Institut fu ¨r
Erna ¨hrungsforschung,Potsdam-Rehbru ¨cke,Germany),Go ¨ranHallmans
(Department of Public Health and Clinical Medicine, University of
Umea ˚, Umea ˚, Sweden), Kim Overvad (School of Public Health, Aarhus
University, 8000 Aarhus C, Denmark), Anne Tjønneland (The Danish
Cancer Society, Institute of Cancer Epidemiology, Copenhagen,
Denmark), Merethe Kumle (Institute of Community Medicine, Univer-
sity of Tromsø, Tromsø, Norway), Elio Riboli (Department of
Epidemiology and Public Health, Imperial College, London, UK).
International Lung Cancer Consortium