As a result of the already complete GWAS studies, outstanding loci for further functional characterization have already been identified. In particular, and as described in more detail below, the rs1696698 SNP in the nicotinic acetycholine receptor unit 5 (CHRNAS) influences risk for lung cancer and affects smoking behavior and has also been shown to affect the activity of the multimeric nicotinic receptor in vitro. While this variant has important effects on nicotine receptor activity, extensive studies in Caucasian and African-American populations show that it is not the only variant influencing lung cancer risk and smoking behavior in the region of chromosomes 15q24-25.1, and the effects of rsl 696698 remain poorly characterized. Therefore, we plan further studies to define effects of variations in this region on nicotinic receptor activity, expression of the genes in the region and on effects of variations on cellular phenotypes relating to cancer development and progression. In addition, GWAS studies have identified excellent candidates on chromosomes 5p and 6p that wanrant further detailed analyses.
For aim 1 of area 2 we propose to characterize methylation for the loci that have been identified. We also propose additional cellular phenotype based assays for loci that have been identified and the evaluation of phenotypes in existing animal models.
Aim 2 of area 2 will detemiine the effect of CHRNA3/CHRNA5 polymorphisms on the biophysical and pharmacological properties of neuronal nicotinic acetylcholine receptors (nAChRs). We also propose additional cellular phenotype based assays for loci that have been identified and the evaluation of phenotypes in existing and new animal models (Aims 3 &4 of area 2)..

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
7U19CA148127-03
Application #
8379648
Study Section
Special Emphasis Panel (ZCA1-SRLB-4)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$531,503
Indirect Cost
Name
Dartmouth College
Department
Type
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
David, Sean P; Wang, Ange; Kapphahn, Kristopher et al. (2016) Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans. EBioMedicine 4:153-61
Wang, Zhaoming; Seow, Wei Jie; Shiraishi, Kouya et al. (2016) Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women. Hum Mol Genet 25:620-9
Scarbrough, Peter M; Weber, Rachel Palmieri; Iversen, Edwin S et al. (2016) A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer. Cancer Epidemiol Biomarkers Prev 25:193-200
Lieberman, Rachel; Xiong, Donghai; James, Michael et al. (2016) Functional characterization of RAD52 as a lung cancer susceptibility gene in the 12p13.33 locus. Mol Carcinog 55:953-63
Puskás, László G; Mán, Imola; Szebeni, Gabor et al. (2016) Novel Anti-CRR9/CLPTM1L Antibodies with Antitumorigenic Activity Inhibit Cell Surface Accumulation, PI3K Interaction, and Survival Signaling. Mol Cancer Ther 15:985-97
Chen, Li-Shiun; Baker, Timothy; Hung, Rayjean J et al. (2016) Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis. EBioMedicine 11:219-226
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 37:280-9
Kachuri, Linda; Amos, Christopher I; McKay, James D et al. (2016) Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci. Carcinogenesis 37:96-105
Karami, Sara; Han, Younghun; Pande, Mala et al. (2016) Telomere structure and maintenance gene variants and risk of five cancer types. Int J Cancer 139:2655-2670
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

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