IJE Advance Access published online on September 23, 2009
International Journal of Epidemiology, doi:10.1093/ije/dyp288
Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17 000 individuals
1International Agency for Research on Cancer (IARC), Lyon, France.
2Samuel Lunenfeld Research Institute of the Mount Sinai Hospital, Toronto, Canada.
3Institute of Carcinogenesis, Cancer Research Centre, Moscow, Russia.
4Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland.
5Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland.
6Johan National Institute of Public Health, Budapest, Hungary.
7Regional Authority of Public Health in Banska Bystrica, Banska Bystrica, Slovakia.
8Institute of Public Health, Bucharest, Romania.
9Institute of Hygiene and Epidemiology, First Faculty of Medicine and General University Hospital, Charles University in Prague, Czech Republic.
10Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
11Palacky University, Olomouc, Czech Republic.
12Roy Castle Lung Cancer Research Programme, University of Liverpool Cancer Research Centre, Liverpool, UK.
13Cancer Care Ontario, Toronto, Canada.
14Princess Margaret Hospital, Ontario Cancer Institute, Toronto, Canada.
15Norwegian University of Science and Technology, Trondheim, Norway.
16A full list of authors appears in the Appendix list.
17INSERM U794, Paris, France.
18Institut Gustave Roussy, Villejuif, France.
19University of Athens School of Medicine, Athens, Greece.
20Cancer Epidemiology Unit and CeRMS, University of Turin, Turin, Italy.
21Cancer Registry of Norway, Oslo, Norway.
22Institut Català d'Oncologia (ICO)-IDIBELL, L'Hopitalet de Llobregat, Spain.
23CIBERESP, Barcelona, Spain.
24University of Aberdeen School of Medicine, Aberdeen, UK.
25General Hospital, Pordenone, Italy.
26Department of Environmental Medicine and Public Health, University of Padua, Padua, Italy.
27University of Newcastle Dental School, Newcastle, UK.
28University of Glasgow Medical Faculty Dental School, Glasgow, UK.
29Croatian National Cancer Registry, Croatian National Institute of Public Health, Zagreb, Croatia.
30Trinity College School of Dental Science, Dublin, Ireland.
31Hospital Araujo Jorge, Goiania, and Populational Cancer Register of Goiania, Goiania, Brazil.
32Escola Nacional de Saude Publica, Rio de Janeiro, Brazil.
33Universidade de Sao Paulo, Sao Paulo, Brazil.
34Institute of Oncology Angel H. Roffo, University of Buenos Aires, Buenos Aires, Argentina.
35Universidade Federal de Pelotas, Pelotas, Brazil.
36Institute of Oncology and Radiobiology, Havana, Cuba.
37Estonian Genome Project, Institute of Molecular and Cell Biology, University of Tartu/Estonian Biocentre, Tartu, Estonia.
38Centre National de Genotypage, Institut Genomique, Comissariat à l'énergie Atomique, Evry, France.
39Fondation Jean Dausset-CEPH, Paris, France.
* Corresponding author. International Agency for Research on Cancer, 150 cours Albert Thomas, 69008 Lyon, France. E-mail: brennan{at}iarc.fr
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Abstract |
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Background Genetic variants in 15q25 have been identified as potential risk markers for lung cancer (LC), but controversy exists as to whether this is a direct association, or whether the 15q variant is simply a proxy for increased exposure to tobacco carcinogens.
Methods We performed a detailed analysis of one 15q single nucleotide polymorphism (SNP) (rs16969968) with smoking behaviour and cancer risk in a total of 17 300 subjects from five LC studies and four upper aerodigestive tract (UADT) cancer studies.
Results Subjects with one minor allele smoked on average 0.3 cigarettes per day (CPD) more, whereas subjects with the homozygous minor AA genotype smoked on average 1.2 CPD more than subjects with a GG genotype (P < 0.001). The variant was associated with heavy smoking (>20 CPD) [odds ratio (OR) = 1.13, 95% confidence interval (CI) 0.96–1.34, P = 0.13 for heterozygotes and 1.81, 95% CI 1.39–2.35 for homozygotes, P < 0.0001]. The strong association between the variant and LC risk (OR = 1.30, 95% CI 1.23–1.38, P = 1 x 10–18), was virtually unchanged after adjusting for this smoking association (smoking adjusted OR = 1.27, 95% CI 1.19–1.35, P = 5 x 10–13). Furthermore, we found an association between the variant allele and an earlier age of LC onset (P = 0.02). The association was also noted in UADT cancers (OR = 1.08, 95% CI 1.01–1.15, P = 0.02). Genome wide association (GWA) analysis of over 300 000 SNPs on 11 219 subjects did not identify any additional variants related to smoking behaviour.
Conclusions This study confirms the strong association between 15q gene variants and LC and shows an independent association with smoking quantity, as well as an association with UADT cancers.
Keywords Lung cancer, nicotine dependence, smoking quantity, UADT cancer
Accepted 29 July 2009