Abstract

Even though lung and upper aero-digestive tract (UADT) cancers are predominantly caused by tobacco and alcohol, only a minority of heavy smokers and heavy drinkers will develop lung or UADT cancer. A possible explanation for this is that the metabolisation of carcinogenic products, the level of internal dose and subsequent DNA repair and cell cycle control mechanisms vary widely between individuals because of genetic factors. The broad long-term goal of this project will be to investigate in two separate studies the role of 45 genes which are potentially involved in the susceptibility of lung and UADT cancers. The first is a study of lung and UADT cancers in Central Europe, involving approximately 2300 lung cancer cases, 1200 UADT cancer cases and 2800 controls. The second is a separate study of UADT cancer in South America involving approximately 2100 cases and 1700 controls. Both studies are conducted to an identical protocol involving the collection of high quality detailed information on lifestyle and occupational history, as well as blood collection for DNA extraction. Genotyping of 108 SNPs for the 45 genes will be conducted using automated and pre-validated DNA microarrays. The genes comprise those involved in the metabolism of tobacco products, alcohol and other potential carcinogens (e.g. CYPs, GSTs, ADH2, ADH3, MPO), as well as genes involved in DNA repair (e.g. XRCC1, XRCC3, XPD, XPF), tumour suppression (p53, p16, CCND1 ) and nicotine addiction (dopamine D2 and D4 receptor genes). Using these large sample sizes, we will accurately measure the overall effect of each gene in lung and UADT cancer. Subsequently, the effect of combinations of genes will be measured (gene-gene interaction), as well as the effect of individual genes in specific subgroups identified by alcohol and tobacco consumption and occupational history (gene-environment interaction). Statistical techniques will include haplotype reconstruction, empirical Bayes and semi-Bayes analysis to control for false positive results, and modeling of complex pathways.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092039-02
Application #
6794946
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Arena, Jose Fernando
Project Start
2003-09-01
Project End
2006-08-31
Budget Start
2004-09-20
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$516,278
Indirect Cost

  Institution

Name
International Agency for Research on Cancer
Department
Type
DUNS #
279551881
City
Lyon
State
Country
France
Zip Code
69008

  Publications

Feng, Yun; Wang, Yanru; Liu, Hongliang et al. (2018) Novel genetic variants in the P38MAPK pathway gene ZAK and susceptibility to lung cancer. Mol Carcinog 57:216-224
Liu, Hongliang; Liu, Zhensheng; Wang, Yanru et al. (2017) Functional variants in DCAF4 associated with lung cancer risk in European populations. Carcinogenesis 38:541-551
Feng, Yun; Wang, Yanru; Liu, Hongliang et al. (2017) Genetic variants of PTPN2 are associated with lung cancer risk: a re-analysis of eight GWASs in the TRICL-ILCCO consortium. Sci Rep 7:825
Pan, Yongchu; Liu, Hongliang; Wang, Yanru et al. (2017) Associations between genetic variants in mRNA splicing-related genes and risk of lung cancer: a pathway-based analysis from published GWASs. Sci Rep 7:44634
Yin, Jieyun; Liu, Hongliang; Liu, Zhensheng et al. (2017) Pathway-analysis of published genome-wide association studies of lung cancer: A potential role for the CYP4F3 locus. Mol Carcinog 56:1663-1672
Zhou, Fei; Wang, Yanru; Liu, Hongliang et al. (2017) Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs. Mol Carcinog 56:1227-1238
Wang, Meilin; Liu, Hongliang; Liu, Zhensheng et al. (2016) Genetic variant in DNA repair gene GTF2H4 is associated with lung cancer risk: a large-scale analysis of six published GWAS datasets in the TRICL consortium. Carcinogenesis 37:888-896
Lesseur, Corina; Diergaarde, Brenda; Olshan, Andrew F et al. (2016) Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer. Nat Genet 48:1544-1550
Yuan, Hua; Liu, Hongliang; Liu, Zhensheng et al. (2016) A Novel Genetic Variant in Long Non-coding RNA Gene NEXN-AS1 is Associated with Risk of Lung Cancer. Sci Rep 6:34234
Patel, Yesha M; Park, Sunghim L; Han, Younghun et al. (2016) Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk. Cancer Res 76:5768-5776

Showing the most recent 10 out of 39 publications