Lung cancer is the leading cause of cancer-related mortality in the U.S. and the world. The genetic factors that commonly influence lung cancer susceptibility have not yet been investigated thoroughly, but eight genome-viride association studies have been performed. In area 1 of our response, we propose to integrate data from these eight studies that comprise over 13,000 lung cancer cases and 25,000 controls to increase power to detect genetic factors influencing all types of lung cancer and to allow us to analyze specific subsets, such as cases with early onset, specific histological sets, gender-defined groups and never smokers and the extended sample size will allow us to study gene-environment interactions. Existing genome-wide association studies have not analyzed data from nonCaucasian ethnic backgrounds and we therefore propose characterizing and fine mapping genetic factoid In 1500 African-American and 1500 Asian case-control pairs along with an additional 3000 Caucasian case-control pairs. We will then replicate our findings in a broader collection of an additional 12,000 case-control pairs. In area 2, we will evaluate genes in specific loci including nicotinic acetycholine receptor subunits CHRNA5 and CHRNA3 for the effiects that identified SNPs from area 1 have upon these genes functions. We will also study several other loci that have been identified through existing GWAS as strongly associated with lung cancer risk, including PSMA4, hTERT, CLPT1 ML, BAT3, and hMSHS. For each of these genes, we will study modulation of these genes using cellular models relevant to their known functions. In area 3, we propose epidemiological characterization of genetic and environmental risk factors for lung cancer. We will characterize mechanisms by which variation in the loci identified in area 1 influence risk, in conjunction with smoking and other exposures. We will also evaluate the calibration of existing risk prediction models for lung cancer and then develop new models based upon genetic and environmental data from this initiative. The overarching goal of our proposal is the identification of individuals at high risk for lung cancer development for whom screening and eariy detection would be most beneficial in reducing the burden of lung cancer.

Public Health Relevance

Our proposal will combine existing genome-wide association data from over 13,000 lung cancer cases and 25,000 controls. We will analyze these data jointly to identify novel genetic factors and gene-environment interactions that influence risk for lung cancer and evaluate biological mechanisms by which they cause lung cancer We will evaluate joint effects of smoking and genetic factors in diverse populations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19CA148127-04
Application #
8550777
Study Section
Special Emphasis Panel (ZCA1-SRLB-4)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$240,036
Indirect Cost
$49,611
Name
Dartmouth College
Department
Type
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Liu, Changlu; Ma, Jianzhong; Amos, Christopher I (2015) Bayesian variable selection for hierarchical gene-environment and gene-gene interactions. Hum Genet 134:23-36
Zhang, Ruyang; Chu, Minjie; Zhao, Yang et al. (2014) A genome-wide gene-environment interaction analysis for tobacco smoke and lung cancer susceptibility. Carcinogenesis 35:1528-35
Xiao, Feifei; Ma, Jianzhong; Cai, Guoshuai et al. (2014) Natural and orthogonal model for estimating gene-gene interactions applied to cutaneous melanoma. Hum Genet 133:559-74
Muldoon, P P; Jackson, K J; Perez, E et al. (2014) The ?3?4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies. Br J Pharmacol 171:3845-57
Kim, Claire H; Lee, Yuan-Chin Amy; Hung, Rayjean J et al. (2014) Exposure to secondhand tobacco smoke and lung cancer by histological type: a pooled analysis of the International Lung Cancer Consortium (ILCCO). Int J Cancer 135:1918-30
Chu, Minjie; Zhang, Ruyang; Zhao, Yang et al. (2014) A genome-wide gene-gene interaction analysis identifies an epistatic gene pair for lung cancer susceptibility in Han Chinese. Carcinogenesis 35:572-7
Dao, Dang Q; Perez, Erika E; Teng, Yanfen et al. (2014) Nicotine enhances excitability of medial habenular neurons via facilitation of neurokinin signaling. J Neurosci 34:4273-84
Morel, C; Fattore, L; Pons, S et al. (2014) Nicotine consumption is regulated by a human polymorphism in dopamine neurons. Mol Psychiatry 19:930-6
Tang, Hongwei; Wei, Peng; Duell, Eric J et al. (2014) Axonal guidance signaling pathway interacting with smoking in modifying the risk of pancreatic cancer: a gene- and pathway-based interaction analysis of GWAS data. Carcinogenesis 35:1039-45
Gorlov, Ivan P; Yang, Ji-Yeon; Byun, Jinyoung et al. (2014) How to get the most from microarray data: advice from reverse genomics. BMC Genomics 15:223

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