During the first 30 months of the original grant (R01 CA 092039-01A2), we have successfully contributed to our understanding of the genetic epidemiology of lung cancer and upper aerodigestive tract (UADT) cancer by identification of several genes that are very strongly associated with them, including CHEK2 and ADH1B. We have also demonstrated how genetic variants interact strongly with dietary and environmental exposures for these cancers. Given the enormous increase in genetic information over the last 3 years we plan to build on our initial results and comprehensively evaluate the role of genes in 5 specific pathways for these cancers. To test the robustness of the positive associations observed, we will conduct independent replication of findings in other large studies. We therefore propose a multistage study with the following specific aims: Stage 1 will involve a comprehensive evaluation of 5 candidate gene pathways among 2200 European case-control pairs of lung cancer and 1000 case-control pairs of UADT cancer, involving over 1500 informative variants as well as inclusion of biologically relevant variants. Stage 2 will involve rapid replication of important positive results in other large independent European studies including (i) EPIC lung cancer based on 1200 lung cancer cases and 2400 controls, and (ii) the 'ARCAGE' Western European study of 2000 case-control pairs of UADT cancer. The choice of variants passing from Stage 1 to Stage 2 will be based on hierarchical bayes approach incorporating genomic information such as sequence conservation. Important confirmed genes will be resequenced and further replicated in a third IARC study of UADT cancer from Latin American study comprising 2000 case-control pairs of head and neck cancer. As an important component of this proposal, we will conduct functional studies of the genes that are replicated including differential mRNA expression. All results will be made available to the research community of tobacco and alcohol related cancers via collaboration within 2 international consortia of lung cancer and head and neck cancers. Relevance of research to public health: Large genetic epidemiology studies have the potential to identify individuals at particularly high risk of developing cancer, as well as helping identify why these cancers develop. By incorporating multiple large studies of cancers related to tobacco and alcohol (specifically lung, and UADT cancer) we aim to provide knowledge that will inform future prevention efforts.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA092039-05S1
Application #
7693189
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Gillanders, Elizabeth
Project Start
2001-10-01
Project End
2011-04-30
Budget Start
2008-06-11
Budget End
2009-04-30
Support Year
5
Fiscal Year
2008
Total Cost
$400,000
Indirect Cost
Name
International Agency for Research on Cancer
Department
Type
DUNS #
279551881
City
Lyon
State
Country
France
Zip Code
69008
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
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
Kang, Xiaozheng; Liu, Hongliang; Onaitis, Mark W et al. (2016) Polymorphisms of the centrosomal gene (FGFR1OP) and lung cancer risk: a meta-analysis of 14,463 cases and 44,188 controls. Carcinogenesis 37:280-289
Dunkhase, Eva; Ludwig, Kerstin U; Knapp, Michael et al. (2016) Nonsyndromic cleft lip with or without cleft palate and cancer: Evaluation of a possible common genetic background through the analysis of GWAS data. Genom Data 10:22-9
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

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